Infectious Diseases

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Chapter 18 Infectious Diseases

Introduction to Antibiotics

Antibiotics is the term used to describe drugs that kill or inhibit the growth of bacteria. The more general term antiinfective describes drugs that do the same to any type of organism that could infect humans, including viruses, parasites, and bacteria.

Important Considerations

Learning about antibiotics can be overwhelming for the following reasons:

image There are many antibiotics.
image There are many, many infectious organisms.
image Every year, drug resistance patterns change.
image Geographically, drug resistance patterns are different.
image Multiple drugs are used to treat multiple different bacteria.

Therefore it might be helpful to organize your approach to learning the antibiotics. This introduction will offer some suggestions to assist you.

Suggestions

image Know which category the individual drugs belong to, and learn the category as a whole. For example, ceftriaxone is a third-generation cephalosporin. Therefore learn about cephalosporins in general, and then know the general differences among first-, second-, third-, and fourth-generation cephalosporins. In some circumstances there might be one or two extra important bits of information pertaining to individual drugs that are important to learn.
image Learn the unique common side effects of the drug.

image For example, many drugs cause nausea, rash, diarrhea, and gastrointestinal (GI) upset. It is good to know these side effects, but these are common, and if a patient is experiencing these signs and symptoms, a drug should always be considered as a potential cause.

image Learn the dangerous (and usually rare) side effects of the drug.

image If a side effect were dangerous and common, the drug would not be used. Therefore the really dangerous side effects are usually rare and therefore easily forgotten about. Do not forget about them.

image Antibiotics can usually be classified in terms of the categories of bacteria they kill. These categories include the following:

image Gram-positive organisms (which are usually cocci but sometimes rods)
image Gram-negative organisms (which are usually rods but sometimes cocci)
image Anaerobes
image Atypical organisms (e.g., Chlamydia, Rickettsia)
image Mycobacterial organisms (tuberculosis [TB])

image For each drug, make a small table to summarize what categories of bacteria it usually kills.
image You will have to learn “bugs” (not covered in this text) and drugs in at least three different frameworks:

image Drugs: Which bugs do they kill?

• List the bugs that are sensitive to penicillin.

image Bugs: Which drugs kill them?

• Methicillin-resistant Staphylococcus aureus (MRSA) is usually sensitive to (killed by) which drugs?

image Clinical infections: Which bugs usually cause them, and by extension, which drugs should be used to treat them?

• Dental abscesses are most commonly caused by…and treated with….

image To adequately study infectious disease, you will need to establish a mental framework that organizes your knowledge in the methods just described.

Important Considerations

image It is required that you learn the mechanism of action (MOA) of a drug and also the mechanism of resistance, which enables an organism to live in the presence of the drug. This is important because when you are selecting an antibiotic, if your first choice does not work, you will have a better understanding of why it did not work and will be better educated to select a different antibiotic that will have a greater probability of killing the organism. For example, if a penicillin (a β-lactam) was given and the bug is known to produce β-lactamase, a third-generation cephalosporin (another β-lactam) might be a poor next choice.
image Make sure that the drug you select can get to the tissue in which the infection is located. Special examples include the following:

image Gut (intraintestinal, not intraperitoneal) infections are often best treated with oral medications that cannot be absorbed into the body (because they remain in the gut, which is where the infection is)—for example, oral vancomycin for C. difficile colitis.
image Central nervous system (CNS) infections: Some drugs do not penetrate the blood-brain barrier. These would be poor choices for treatment of bacterial meningitis.
image Abscesses: There is no blood flow to an abscess. Therefore how can antibiotics get to the site of infection? They cannot. Abscesses have to be physically drained.

image The choice of antibiotic (oral versus intravenous, broad-spectrum versus narrow-spectrum agents) is usually determined by how sick the patient is and how certain you are about which bacterium is causing the infection. If you are uncertain, choose a broad-spectrum drug.
image If you can do cultures, try to do them before the patient starts taking antibiotics, because after you administer antibiotics the drug will be in the patient’s system and will inhibit growth of specimens collected from the patient after that point in time.
image If you have positive cultures, then adjust your antibiotics to ensure proper coverage.
image Broad-spectrum drugs tend to be more expensive and more “powerful” and should be reserved for situations in which narrow-spectrum agents are not indicated. Development of resistance is a very real risk every time an antibiotic is used. Always using the powerful drugs will result in bacterial resistance to them. Then what will you use?

It is important to understand the MOA of a given antimicrobial because two drugs of a different class will have a higher probability of being synergistic and making the kill compared with two drugs that act on the same part of the bug. This does not mean that antibiotics should always be doubled up, but when they do need to be, MOA is an important consideration.

Note that antimicrobial means any drug that kills any living organism. Therefore antimicrobials include the following:

image Antibiotics (kill bacteria)
image Antifungals (kill fungi)
image Antiparasitics (kill parasites)

Viruses are technically not alive, so antivirals are usually not referred to as antimicrobials.

Advanced Killing Techniques

Knowledge of pharmacokinetics is required to enable a clinician to be really good at knowing how to kill off an infection. Understanding some very important fundamental concepts are required (Figure 18-1).

image Minimum inhibitory concentration (MIC): The MIC of an antimicrobial is the minimum concentration that will inhibit growth of a pathogen. Obviously, it is desirable to have the concentration in the patient’s infected tissues to be greater than the MIC. If drug A has a lower MIC than drug B, then drug A kills the pathogen at a lower concentration of drug and would therefore be better at killing that particular pathogen, assuming all other factors are identical. When the MIC level of a drug for a given pathogen is low, the pathogen is considered sensitive to the drug (i.e., the drug will kill it). When the MIC is a moderate value, the pathogen’s sensitivity to the drug will be intermediate, and when the MIC is high, the pathogen will be resistant to that drug. Laboratory values often report sensitivities as S, I, or R to report sensitive, intermediate, and resistant, respectively.
image

Figure 18-1

Now, exactly how the concentration of the antimicrobial stays above the MIC in the body is very important and is different for different drugs. The most important concepts are illustrated in Figure 18-1 and include:

image Time dependence is the total length of time that a drug level stays above the MIC. What matters is the total duration that the concentration is above the MIC. These drugs are called time-dependent antimicrobials. β-Lactams (penicillins, cephalosporins, and carbapenems) all fall into this category. Note that it does not matter if the drug level is just barely above the MIC or is 10 times the MIC.
image CMAX/MIC is the maximum concentration of the drug compared with the MIC. In other words, some drugs kill better when the maximum concentration of the drug is very high. These drugs are called concentration-dependent antimicrobials. As a general rule, it is important to measure drug concentrations of these drugs. Vancomycin and aminoglycosides fall into this category and it is common to measure levels of both of them. Note that it does not matter how long the concentration stays above the MIC for these drugs, which is in complete contrast to the time-dependent drugs.
image AUC > MIC: This is the area under the curve (AUC), above the MIC. For these drugs, both time and concentration are important components (and when multiplied result in the area under the curve). Both the higher the concentration and the longer the concentration remains above MIC are important.

Antibiotic Spectra Explanation

For each class of antibiotic, an abbreviated description of which bacteria are susceptible is included. The terms very good, good, poor, and resistant are used to describe the extent to which a given organism is susceptible to the antibiotic. Very good refers to very low rates of resistance, and resistant refers to very high rates, with good and poor being in between.

In addition to the categories of gram-positive, gram-negative, anaerobic, and commonly resistant organisms, additional special organisms that are susceptible to the antibiotic are also listed.

Penicillins

Description

Penicillins belong to a class of antibiotics known as β-lactams.

Prototypes and common drugs

image Prototypes: Penicillin G, Penicillin V

Others

image Narrow-spectrum penicillins:

image Cloxacillin, oxacillin, nafcillin

image Aminopenicillins:

image Ampicillin, amoxicillin

image Broad-spectrum penicillins:

image Piperacillin, ticarcillin

Moa (Mechanism of Action)

image Two major components are required for β-lactam activity:

1 The first is the binding to penicillin-binding proteins.
2 The second is the destruction of the bacterial cell wall.

image All β-lactams (penicillins, carbapenems, and cephalosporins) act through this common sequence of events.

Binding

image Virtually all bacteria contain penicillin-binding proteins.
image Different bacteria have different amounts and different types of penicillin-binding proteins. For example, Escherichia coli has seven types, and Staph. aureus has four.
image Different penicillin-binding proteins have different affinities for β-lactams, and therefore different bacteria will demonstrate different sensitivities to β-lactams.

Cell Wall Destruction

image Transpeptidases are enzymes that cross-link peptidoglycan molecules in bacterial cell walls. Cross-linking these molecules gives strength to the cell wall.
image β-Lactams work by inhibiting transpeptidase, preventing it from forming cross-links. This results in a bacterium with a structurally deficient cell wall, typically leading to bacterial lysis (Figure 18-2).
image Gram-positive bacteria have a thick peptidoglycan layer. They are therefore sensitive to β-lactams.
image Gram-negative bacteria have a thinner peptidoglycan layer, but external to this layer is a lipopolysaccharide layer. This lipopolysaccharide layer protects the peptidoglycan layer from β-lactam activity, and therefore gram-negative bacteria are significantly more resistant to β-lactams.
image β-Lactamase inhibitors are added to some β-lactam antibiotics to overcome resistance caused by β-lactamase. Although β-lactamase inhibitors do contain a β-lactam, they are not toxic to the bacteria; they merely bind to β-lactamase. Examples of β-lactamase inhibitors include the following:

image Clavulanic acid (added to amoxicillin)
image Tazobactam (added to piperacillin)

image Narrow-spectrum penicillins contain a larger molecule on the penicillin molecule side chain that confers steric hindrance: the inability to twist the molecule into other stereoisomers. This results in these penicillins being resistant to β-lactamase but at the same time restricts their spectrum of activity (thus they are said to be narrow-spectrum agents).
image Aminopenicillins have an added amino group (NH2) that makes the molecule more hydrophilic and thus able to cross the lipopolysaccharide layer more easily. Therefore aminopenicillins have greater activity against gram-negative bacteria.
image Broad-spectrum penicillins are modifications of aminopenicillins: nitrogen and carbon atoms are added to the molecule. This increases the range of bacteria that are sensitive to the antibiotic. These penicillins are usually coadministered with a β-lactamase inhibitor because they are β-lactamase sensitive (a common example is “Pip/Tazo,” which is piperacillin and tazobactam).
image

Figure 18-2

Mechanisms of Resistance

image Gram-negative bacteria, as described previously, inherently have an outer protective lipopolysaccharide layer that guards the peptidoglycan layer from attack by some β-lactams.
image The main mechanisms of resistance to β-lactams include the following:

image Variation of the penicillin-binding protein leading to decreased binding of the β-lactam
image Production of β-lactamase, which enzymatically destroys the four-carbon β-lactam ring

• Genes for β-lactamase may exist on plasmids or on bacterial chromosomes and may be produced constitutively (all the time) or can be induced.
• Genes that are on plasmids can readily be passed from one bacterium to another; thus resistance can be transmitted to different species.
• There are a few different classification schemes for β-lactamases, and there are many different individual β-lactamase enzymes. Some other names of β-lactams include penicillinase and carbapenemase.

image Changes in membrane channels called porins that are important in allowing influx of the antibiotic
image Efflux pump mechanisms, which pump the drug out of the bacteria

Pharmacokinetics

image Eighty percent of penicillin is cleared by the kidneys within 4 hours. Therefore it is very quickly eliminated from the body, which is an undesirable characteristic if the goal is to expose the bacterial infection to prolonged concentrations of the drug.
image Probenecid, a uricosuric, competes with penicillin in the organic acid transporter in the kidney and therefore decreases renal clearance of penicillin, thereby prolonging high tissue concentrations and a longer half life. It is coadministered with penicillin.
image Most penicillins are renally cleared, and the dose must be adjusted in patients with renal dysfunction. However, cloxacillin is hepatically cleared and does not require dose adjustment in patients with renal dysfunction.

Spectra at a Glance

image Gram-positive: very good, especially for the narrow-spectrum penicillins
image Gram-negative: good for aminopenicillins and broad-spectrum penicillins
image Anaerobes: very good but only with broad-spectrum penicillins
image Resistant organisms:

image Methicillin-resistant Staph aureus (MRSA): resistant
image Vancomycin-resistant Enterococcus (VRE): resistant
image Pseudomonas: good, but only with broad-spectrum penicillins

image Special sensitivities:

image Neisseria meningitidis (a gram-negative coccus) is an important cause of life-threatening (and reportable) meningitis and is susceptible to intravenous penicillin G.

Contraindications

image Hypersensitivity (allergy)

image Incidence is as high as 10%.
image Signs and symptoms are as follows:

• Maculopapular rash (mostly flat and confluent, not itchy)
• Urticarial rash (hives)
• Anaphylaxis

image Cross-reactivity between penicillin allergy and other β-lactam antibiotics (cephalosporins and carbapenems) is around 1% to 10%.

Side Effects

image Hypersensitivity: most commonly only a rash, but can include anaphylaxis
image Nausea and vomiting if given orally
image Diarrhea
image Stinging in the vein if given intravenously (IV)

Important Notes

image Methicillin is no longer used clinically, because of toxicity. It is, however, used to determine whether a staphylococcal infection is sensitive to the penicillins in its class. The term methicillin-resistant Staph. aureus (MRSA) is now commonly used to describe these organisms.
image MRSA is a huge problem. The problem of resistance will continue to get worse as continued exposure to antibiotics creates an environment for bacteria that promotes the survival of resistant strains.

FYI

image A lactam is a chemical ring. A β-lactam is a four-molecule ring (three carbons and one nitrogen) and is the nucleus of the penicillin molecule. The penicillin nucleus is shown in Figure 18-3. Modifications to the five-membered ring are the basis on which cephalosporins and carbapenems (two other β-lactam antibiotics) were derived.
image Penicillin was originally isolated from the mold Penicillium.
image Peptidoglycans are polymers of sugars and amino acids. Cross-linking of these polymers results in a rigid crystal structure.
image The clinically significant difference between amoxicillin and ampicillin is that amoxicillin is generally administered orally whereas ampicillin is generally administered IV.
image Pip/Tazo is a commonly used abbreviation for piperacillin plus tazobactam.
image A common dose for Pip/Tazo is 3.375 g, which means 3 g of piperacillin and 375 mg of tazobactam.
image Penicillin G, benzylpenicillin, is only given intravenously.
image Penicillin V, phenoxymethylpenicillin, is only given orally.
image It would be nice for memorization if penicillin G were given in the gut and penicillin V were given IV; unfortunately, it is the other way around.
image Uricosurics are drugs that promote the excretion of uric acid and are used in patients who have gout (high uric acid levels leading to uric acid crystal formation in joints).
image

Figure 18-3

Cephalosporins

Description

Cephalosporins are antibiotics that belong to the class of β-lactams.

Prototypes and common drugs

image First-generation agent: cephalexin

image Others: cefazolin, cefadroxil, cephalothin, cephapirin, cephradine

image Second-generation agents: cefaclor and cefuroxime

image Others: cefoxitin, cefamandole, cefmetazole, cefonicid, cefotetan, cefoxitin, cefprozil, loracarbef

image Third-generation agent: ceftazidime

image Others: ceftriaxone, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftibuten, ceftizoxime

image Fourth-generation agent: cefepime

Moa (Mechanism of Action)

image Two major components are required for β-lactam activity:

1 The first is the binding to penicillin-binding proteins.
2 The second is the destruction of the bacterial cell wall.

image All β-lactams (penicillins, carbapenems, and cephalosporins) act through this common sequence of events.

Binding

image Virtually all bacteria contain penicillin-binding proteins.
image Different bacteria have different amounts and different types of penicillin-binding proteins. For example, E. coli has seven types and S. aureus has four.
image Different penicillin-binding proteins have different affinities for β-lactams, and therefore different bacteria will demonstrate different sensitivities to β-lactams.

Cell Wall Destruction

image Transpeptidases are enzymes that cross-link peptidoglycan molecules in bacterial cell walls. Cross-linking these molecules gives strength to the cell wall (see Figure 18-2).
image β-lactams work by inhibiting transpeptidase, preventing it from forming cross-links. This results in a bacterium with a structurally deficient cell wall, typically leading to bacterial lysis.
image Gram-positive bacteria have a thick peptidoglycan layer. They are therefore sensitive to β-lactams.
image Gram-negative bacteria have a thinner peptidoglycan layer, but external to this layer is a lipopolysaccharide layer. This lipopolysaccharide layer protects the peptidoglycan layer from β-lactam activity, and therefore gram-negative bacteria are significantly more resistant to β-lactams.

Mechanisms of Resistance

image The main mechanisms of resistance to β-lactams include the following:

image Variation of the penicillin-binding protein, leading to decreased binding of the β-lactam
image Production of β-lactamase, which enzymatically destroys the four-carbon β-lactam ring

• Genes for β-lactamase may exist on plasmids or on bacterial chromosomes and may be produced constitutively (all the time) or can be induced.
• Genes that are on plasmids can readily be passed from one bacterium to another; thus resistance can be transmitted to different species.
• There are a few different classification schemes for β-lactamases, and there are many different individual β-lactamase enzymes. Some other names of β-lactams include penicillinase and carbapenemase.

image Changes in membrane channels called porins that are important in allowing influx of the antibiotic
image Efflux pump mechanisms

Pharmacokinetics

image Cephalosporins are mainly renally excreted, except ceftriaxone, excretion of which is 50% hepatic.
image Penetration to the brain through the blood-brain barrier is a very important factor for antibiotics because it will determine whether or not an antibiotic will be effective against bacterial meningitis. Third-generation cephalosporins have good CNS penetration.

Spectra at a Glance

image Gram-positive: very good, especially the first-generation agents
image Gram-negative: third-generation agents very good, second-generation agents good
image Anaerobes: resistant against first-generation agents, good with second- and third-generation agents
image Resistant organisms:

image MRSA: resistant
image VRE: resistant
image Pseudomonas: very good with ceftazidime (third-generation agent) and fourth-generation agents only

image Special sensitivities:

image N. meningitidis (a gram-negative coccus) is an important cause of life-threatening (and reportable) meningitis and is susceptible to intravenous third-generation agents.

Contraindications

image Anaphylaxis to penicillins is an absolute contraindication.
image Nonanaphylactic allergy to penicillins is a relative contraindication; however, the cross-reactivity is reported to be 2% to 10%, and cephalosporins have been used frequently in patients with a penicillin allergy.
image Maculopapular rash (flat confluent red rash)
image Urticaria (itchy hives)
image Eosinophilia (which is common to allergic reactions)

image Side effects (GI upset, nausea) are sometimes called allergies by patients when in fact they are not allergies. Always ask what reaction the patient experienced. Side effects are not a contraindication.

Side Effects

image Hematologic: rare cases of bone marrow suppression resulting in a low white blood cell (WBC) count (aka neutropenia or granulocytopenia)
image Nephrotoxicity: occasional interstitial nephritis and tubular necrosis
image Pseudomembranous colitis: many antibiotics, including cephalosporins, can wipe out gut flora and permit the bacterium C. difficile to colonize, which causes this condition. This is more common in the broad-spectrum (higher-generation) agents.

Important Notes

image First-generation cephalosporins are:

image Good for skin infections (which are commonly Streptococcus or Staphylococcus)
image Commonly used as prophylactic antibiotics (preventative) given before surgery to prevent wound infections

image Second-generation cephalosporins are:

image Good for Bacteroides infection (anaerobic), which can occur with intraabdominal infections
image Used less commonly for severe infections because third-generation cephalosporins are more efficacious. Second-generation cephalosporins can be used for mild infections in which gram-negative organisms are predicted or known

image Third-generation cephalosporins are:

image Commonly used for severe infections in combination with another drug of a different class (different MOA)

image Fourth-generation cephalosporins are:

image Reserved for severe nosocomial (hospital-acquired) infections, which have a tendency to be:

• Resistant to multiple other antibiotics
• More severe infections
• Commonly caused by gram-negative organisms

FYI

image Note how the four-membered ring (the β-lactam) is the same as in penicillins; however, the other ring is six-membered, whereas in penicillins it is five-membered. The diagram shows the core nucleus of cephalosporins. There are currently four generations of cephalosporins (Figure 18-4).
image Cephalosporins were first isolated from Cephalosporium acremonium from the sea near a sewer outlet in 1948. They were initially found to cure Staph. aureus infection and typhoid.
image The suffix -penia means low cell counts. WBCs are granulocytes. The most abundant type of WBC is the neutrophil. Thus a low WBC count can be referred to as granulocytopenia or neutropenia.
image Eosinophilia occurs in drug hypersensitivity reactions and also in other conditions. The mnemonic CHINA can help you remember the common causes of eosinophilia:

image Connective tissue diseases, such as Churg-Strauss syndrome
image Helminthic (worm) parasitic infections
image Idiopathic eosinophilia
image Neoplastic (cancer) conditions, such as certain leukemias and lymphomas
image Allergic reactions, including interstitial nephritis

image Pseudomembranous colitis is treated with antibiotics that kill C. difficile: metronidazole or vancomycin. Because the infection is in the gut, oral administration of these antibiotics delivers high concentrations of drug to the site of infection.
image

Figure 18-4

Carbapenems

Description

Carbapenems are antibiotics that belong to the class called β-lactams.

Prototype and common drugs

image Prototype: imipenem
image Others: meropenem, ertapenem, doripenem

Moa (Mechanism of Action)

image Two major components are required for β-lactam activity:

1 The first is the binding to penicillin-binding proteins.
2 The second is the destruction of the bacterial cell wall.

image All β-lactams (penicillins, carbapenems, and cephalosporins) act through this common sequence of events.

Binding

image Virtually all bacteria contain penicillin-binding proteins.
image Different bacteria have different amounts and different types of penicillin-binding proteins. For example, E. coli has seven types and S. aureus has four.
image Different penicillin-binding proteins have different affinities for β-lactams, and therefore different bacteria will demonstrate different sensitivities to β-lactams.

Cell Wall Destruction

image Transpeptidases are enzymes that cross-link peptidoglycan molecules in bacterial cell walls. Cross-linking these molecules gives strength to the cell wall (Figure 18-5).
image β-Lactams work by inhibiting transpeptidase, preventing it from forming cross-links. This results in a bacterium with a structurally deficient cell wall, typically leading to bacterial lysis.
image

Figure 18-5

Mechanisms of Resistance

image The main mechanisms of resistance to β-lactams include the following:

image Variation of the penicillin-binding protein, leading to decreased binding of the β-lactam
image Production of β-lactamase, which enzymatically destroys the four-carbon β-lactam ring

• Genes for β-lactamase may exist on plasmids or on bacterial chromosomes and may be produced constitutively (all the time) or can be induced.
• Genes that are on plasmids can readily be passed from one bacterium to another; thus resistance can be transmitted to different species.
• There are a few different classification schemes for β–lactamases, and there are many different individual β-lactamase enzymes. Some other names of β–lactams include penicillinase and carbapenemase.
• Carbapenems are resistant to most β-lactamases but are generally not resistant to metallo-β-lactamases.

image Changes in membrane channels called porins that are important in allowing influx of the antibiotic
image Efflux pump mechanisms

Pharmacokinetics

image Carbapenems are administered via IV.
image Carbapenems are eliminated by the kidneys.
image Imipenem is hydrolyzed by renal tubular dipeptidase. Imipenem is therefore always combined with cilastatin, which inhibits this breakdown. Other carbapenems do not require coadministration with cilastatin because they are not metabolized by dipeptidase.
image Doses must be reduced in patients with renal dysfunction. With imipenem, there is increased risk for seizures in patients with renal dysfunction.
image Ertapenem has a longer half-life and can be administered once a day.

Spectra at a Glance

image Gram-positive: very good
image Gram-negative: very good
image Anaerobes: very good
image Resistant organisms:

image MRSA: resistant
image VRE: good to poor
image Pseudomonas: very good

image Special sensitivities:

image SPACEs:

• Refers to five genera of gram-negative rods (Enterobacteriaceae) that are commonly resistant to β-lactams: Serratia, Pseudomonas, Acinetobacter, Citrobacter, and Enterobacter

image ESBL:

• Refers to extended-spectrum β–lactamase, which is able to deactivate third-generation cephalosporins and also confer resistance to non–β-lactam antibiotics, including aminoglycosides and fluoroquinolones

Indications

image Carbapenems are generally reserved for very severe infections.

Contraindication

image Seizure history: Imipenem causes seizures in approximately 1.5% of patients. Patients with a seizure history should not receive imipenem. Other carbapenems do not share this neurotoxicity and therefore have largely replaced imipenem.

Side Effects

image Nausea and vomiting
image Neurotoxicity: Imipenem can cause seizures. Meropenem and ertapenem do not.
image Fever: This can cause diagnostic dilemmas because carbapenems are administered to patients with suspected infections, who usually already have a fever. If the drug starts to create a fever, then it can be very difficult to know when the infection is gone (which is usually accompanied by a normalization of the patient’s temperature).

Important Notes

image MRSA is an important resistant strain of S. aureus. It is not sensitive to carbapenems. It is treated with vancomycin.
image VRE is another important resistant strain. About 50% of VRE infections are sensitive to carbapenems.
image Carbapenems are very broad-spectrum agents. They are considered “big guns” and are used only in patients who are very sick or suspected of having resistant organisms. They are generally not used as first-line treatment.

Advanced

image Meropenem and ertapenem are not broken down by a renal dehydropeptidase and therefore are not coadministered with cilastatin.
image Ertapenem is not active against Pseudomonas or Enterococcus.
image Meropenem is more active against Pseudomonas and less active against S. aureus and Enterococcus than imipenem is.

FYI

image Carbapenems differ structurally from penicillins in that the five-membered ring that is attached to the β-lactam ring contains a carbon atom instead of a sulfur atom. The name carbapenem comes from carbon and penicillin. Figure 18-6 shows the core structure of a carbapenem but does not show the side chains.
image The entero- in Enterobacteriaceae refers to enteral, or within the GI tract, which is where Enterobacteriaceae (and Enterococcus) colonize.

image Enteral feeding is feeding into the GI tract (either orally or by feeding tube). Parenteral feeding is via the intravenous route (i.e., around or not directly into the GI tract); it has nothing to do with a parent feeding a child.

image

Figure 18-6

Glycopeptides

Description

Glycopeptides are antibiotics that are cell wall synthesis inhibitors.

Prototype and common drugs

image Prototype: Vancomycin
image Others: Teicoplanin, telavancin

Moa (Mechanism of Action)

image Glycopeptides inhibit cell wall synthesis by attaching to the end of the peptidoglycan precursor units (a short four– or five–amino acid sequence called the d-alanyl-d-alanine [D-ALA-D-ALA] terminus) that are required to be laid down into the matrix. This step is catalyzed by transglycosylase. Because the glycopeptide binds to the end of the precursor, the precursor is not released from the carrier and thus peptidoglycan synthesis stops (Figure 18-7).
image Glycopeptides are bactericidal in organisms that are dividing, because a dividing bacterium requires new cell wall synthesis, and the absence of the new cell wall results in death of the organism.
image As a result of targeting the peptidoglycan layer, glycopeptides are effective only against gram-positive organisms. This is because gram-negative bacteria possess a thick outer layer of lipopolysaccharide that covers the peptidoglycan layer.
image

Figure 18-7

Mechanisms of Resistance

image A change to the end of the amino acid precursor (which has a d-alanyl-d-alanine terminus) can result in the drug not binding to the precursor. This is the most common method by which Enterococcus becomes resistant (and is then called VRE, vancomycin-resistant Enterococcus).
image Excess cell wall production by the bacteria.
image Biofilm production: Staphylococcus epidermidis can produce a film that can block penetration of the antibiotic. This is a slimy way to become resistant.
image The mechanisms by which S. aureus develops resistance to vancomycin are still being investigated.

Pharmacokinetics

image The half-life of vancomycin is 6 hours, whereas the half-life of teicoplanin is much longer, as high as 100 hours (assuming normal kidney function).
image Glycopeptides are very poorly absorbed from the GI tract. If the infection that is being treated is inside the GI tract (for example, C. difficile colitis, also called “C diff colitis,” or pseudomembranous colitis), then administering the drug orally provides the highest exposure of antibiotic to the infection.
image If the infection is anywhere other than inside the GI tract (e.g., blood, soft tissues, brain, heart), then the drug must be administered via the intravenous route—or, for teicoplanin, also intramuscularly.
image They are renally cleared, and in patients who have renal dysfunction or renal failure, the frequency of administration must be dramatically reduced (sometimes as infrequently as one dose every 2 to 3 days) and should be guided by drug levels in the blood. Because teicoplanin has a longer half-life, it can actually be administered once a week in patients without any renal function.
image Glycopeptides are cleared by dialysis. This is important because patients on dialysis usually get dialyzed three times a week. The best time to administer vancomycin would be just after dialysis, which would result in the drug remaining at high levels in the blood and tissues for the full 2 to 3 days until next dialysis. It would not be logical to give the drug right before dialysis.

Spectra at a Glance

image Gram-positive: very good
image Gram-negative: resistant
image Anaerobes: resistant
image Resistant organisms:

image MRSA: very good
image VRE: resistant
image Pseudomonas: resistant

image Special:

image C. difficile
image Enterococcus (excluding VRE)

Contraindications

image None

Side Effects

image Flushing: When vancomycin is administered quickly, the blood pressure can fall because of histamine release. Therefore vancomycin must be administered slowly (usually over 1 hour). The flushing caused by histamine release has been called red man syndrome and is not an allergy but a predictable response to rapidly administered vancomycin.
image Ototoxicity is very rare, unless vancomycin is administered with another ototoxic agent such as aminoglycosides.
image Nephrotoxicity is rare (6% to 7%), unless administered with another nephrotoxic agent such as aminoglycosides. The role of vancomycin as a nephrotoxic agent is probably overestimated, and it should probably be considered to be only very weakly nephrotoxic.
image Neutropenia (a low neutrophil [WBC] count): Vancomycin is administered in the setting of infection, and if it simultaneously weakens the immune system by lowering the WBC count, this will potentially be a very serious problem.

Important Notes

image Although vancomycin can kill S. aureus organisms that are resistant to cloxacillin (or methicillin [i.e., MRSA]), cloxacillin has a lower MIC than vancomycin for strains that are β-lactam susceptible. Therefore cloxacillin is a better killer of S. aureus when there is no resistance. Vancomycin is not a stronger antibiotic. It is simply a different but paradoxically slightly weaker one that avoids β-lactam resistance.
image An important resistant strain of bacteria is VRE.

FYI

image Common levels that are reported for serum vancomycin levels are peak (right after a dose) and trough (right before a dose). The trough should range from 15 to 25.
image VRE is currently treated with linezolid.
image MRSA is treated with vancomycin; the first MRSA strain that was resistant to vancomycin was reported in Japan in 1997.
image Teicoplanin is approved in Europe but not in North America.

Fluoroquinolones

Description

Fluoroquinolones are antibiotics.

Prototype and common drugs

image Prototype: ciprofloxacin
image Others: levofloxacin, moxifloxacin, norfloxacin

MOA (Mechanism of Action)

image DNA is normally supercoiled. Supercoiled DNA is under too much tension to be separated, so an extra step is required before replication and transcription can occur. DNA gyrase relaxes supercoiled DNA by cutting it, allowing rotation to occur, and then reattaching it.
image Fluoroquinolones bind to and inhibit DNA gyrase (also called topoisomerase II) and topoisomerase IV. Fluoroquinolones inhibit DNA gyrase in gram-negative organisms and topoisomerase IV in gram-positive organisms (Figure 18-8).
image The fluoroquinolones inhibit DNA gyrase after the cutting step, preventing reattachment from occurring. At high doses this leads to the release of these broken segments of DNA. It is thought that the accumulation of these DNA fragments leads to cell death, accounting for the bactericidal action of fluoroquinolones.
image Inhibiting topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division. Thus cell division is halted.
image Eukaryotes (humans) possess different forms of topoisomerase II and topoisomerase IV.
image

Figure 18-8

Mechanisms of Resistance

image Mutations in the genes that encode type II topoisomerase result in the enzyme not being inhibited by the fluoroquinolone.
image Alterations in membrane porins or efflux pumps that actively pump the drug out of the bacterial cell result in lower drug levels inside the bacteria.

Pharmacokinetics

image Fluoroquinolones can enter human cells easily and therefore are often used to treat intracellular pathogens.
image Fluoroquinolones are absorbed very well from the gut. Therefore if a person can tolerate oral medication, he or she can usually be switched from an intravenous form to an oral form.
image Most fluoroquinolones are cleared renally, and dose adjustment may be required in patients with renal impairment.

image An exception is moxifloxacin, which is cleared by the liver and therefore contraindicated in patients with hepatic failure.

Spectra at a Glance

image Gram-positive: good
image Gram-negative: very good
image Anaerobes: good with levofloxacin and moxifloxacin
image Resistant organisms:

image MRSA: resistant
image VRE: resistant
image Pseudomonas: poor to good

image Special sensitivities:

image Intracellular organisms:

• Chlamydia
• Mycobacterium avium

Contraindications

image Pregnancy
image Children: Joint pain (arthralgia) and swelling has occurred, and therefore administration to children is not common.

Side Effects

image Generally well tolerated
image Nausea, vomiting, diarrhea
image Tendon ruptures (Achilles, shoulder); occur rarely. The mechanism of this complication is not well understood.

Important Notes

image Originally, quinolones were mainly effective against gram-negative bacteria, but newer agents are useful against gram-positive cocci as well.
image Drugs from a different but similarly named class called quinolines do not have antibacterial properties but rather are antimalarials.

Advanced

Drug Interactions

image With NSAIDS, fluoroquinolones may potentiate CNS toxicity and cause seizures.
image With theophylline, they will increase theophylline levels and increase risk of theophylline toxicity.

FYI

image As the name suggests, fluoroquinolones possess a fluorine ion. They all contain two six-membered rings. Ciprofloxacin is shown in the diagram (Figure 18-9). Earlier generations of fluoroquinolones were not fluorinated and were simply called quinolones. They are infrequently used now.
image An isomerase converts a molecule from one isomer to another isomer. Topo- refers to topographic, or surface shape. Therefore topoisomerase enzymes convert DNA molecules from one shape to another shape.
image More than 30 different fluoroquinolones exist. Some are used for veterinary purposes only.
image Many fluoroquinolones have been withdrawn from the market because of side effects:

image Gatifloxacin: hyperglycemia
image Trovafloxacin: acute liver failure and death
image Temafloxacin: hemolytic anemia
image Grepafloxacin: long qt syndrome and sudden death
image Fleroxacin: phototoxicity

image

Figure 18-9

Aminoglycosides

Description

Aminoglycosides are a form of antibiotics that are derived from bacteria.

Prototype and common drugs

image Prototype: gentamicin
image Others: tobramycin, amikacin, neomycin, streptomycin, kanamycin, paromomycin

MOA (Mechanism of Action)

image The production of proteins from mRNA is called translation; this step requires ribosomes, transfer RNA (tRNA), and messenger RNA (mRNA) (Figure 18-10).
image mRNA contains the sequencing code based on DNA; tRNA contains single amino acids and binds to a three-base sequence of mRNA; ribosomes are like assembly line processing machinery, bringing the mRNA and tRNA together to assemble sequences of amino acids.
image The ribosomes are different sizes:

image Prokaryotes (bacteria) have 70S ribosomes made of a small (30S) and a large (50S) subunit.

• The 50S subunit is composed of a 5S and a 23S subunit plus 34 other proteins.

image Eukaryotes (humans) have 80S ribosomes, composed of a small (40S) and a large (60S) subunit.

image Ribosomes have different binding sites, named:

image Aminoacyl (A): Incoming tRNA binds to this site.
image Peptidyl (P): This is where the existing amino acid chain (connected to tRNA) is elongated when the incoming amino acid is transferred to it through the action of peptidyl transferase.
image Exit or egress (E): After the tRNA gives up the amino acid chain, it must leave so that new tRNA can take its place.

image There are two theories about how aminoglycosides work:

1 Aminoglycosides are protein synthesis inhibitors. They irreversibly bind the 30S ribosomal subunit (RSU). At low concentrations they cause misreading of the mRNA by ribosomes, leading to synthesis of proteins with incorrect amino acid sequences. At higher concentrations they halt protein synthesis, trapping the ribosomes at the AUG start codon. Accumulation of these abnormal initiation complexes halts translation.
2 Recent experimental studies show that the initial site of action is the outer bacterial membrane. The cationic antibiotic molecules create fissures and pores in the outer cell membrane, resulting in leakage of intracellular contents and enhanced antibiotic uptake.

• This rapid action at the outer membrane probably accounts for most of the bactericidal activity.
• Energy is needed for aminoglycoside uptake into the bacterial cell. Anaerobes have less energy available for this uptake; therefore aminoglycosides are less active against anaerobes.

image Aminoglycosides are particularly effective against gram-negative bacteria.
image Many other protein synthesis inhibitors are bacteriostatic (only inhibit replication of bacteria versus killing bacteria). The action of aminoglycosides on the outer bacterial membrane, in addition to its protein synthesis inhibition, is thought to be the reason that aminoglycosides are bactericidal.
image

Figure 18-10

Mechanisms of Resistance

image Three mechanisms of resistance have been recognized:

image Ribosome alteration
image Decreased permeability
image Inactivation by aminoglycoside modifying enzymes

image The third mechanism is of most clinical importance, because the genes encoding aminoglycoside-modifying enzymes can be disseminated by plasmids, which are segments of DNA that are outside of the chromosome.

Pharmacokinetics

image Penetration of biologic membranes is poor because of the drug’s polar structure. Therefore all aminoglycosides are poorly absorbed in the GI tract and are not administered orally, and intracellular concentrations are usually low.

image The exception to this rule is the proximal tubule in the kidney. Aminoglycosides accumulate inside these kidney cells, and this is the basis for nephrotoxicity of this drug.

image The most common route of administration is the intravenous route, but tobramycin can be inhaled (for treatment of severe pneumonia), and some aminoglycosides are available as topical drops for the ears or eyes.
image Aminoglycosides are rapidly excreted by glomerular filtration in the kidney, resulting in a plasma half-life of 2 hours in a patient with normal renal function, but up to 30 to 60 hours in patients who have nonfunctioning kidneys. Therefore repeat doses in patients with renal dysfunction will lead to very high levels in the body and will cause toxicity.

image Kidney function in all patients receiving aminoglycosides must be measured before administration and monitored throughout treatment.

image Aminoglycosides have a narrow therapeutic index. Toxicity occurs at a serum concentration just slightly higher than the therapeutic concentration.
image Paromomycin is effective against GI parasites and is poorly absorbed in the GI tract. Administering this aminoglycoside results in high levels of drug inside the GI tract (where the parasite exists) with negligible systemic absorption.

Spectra at a Glance

image Gram-positive: poor, unless in combination with other antibiotic active against gram-positive organisms
image Gram-negative: very good
image Anaerobes: resistant
image Resistant organisms:

image MRSA: resistant
image VRE: resistant
image Pseudomonas: good

image Special sensitivities:

image Multidrug-resistant organisms: amikacin
image Intestinal parasites (Entamoeba, Cryptosporidium): paromomycin
image TB: streptomycin

Contraindication

image Renal dysfunction: Patients starting with poor functioning kidneys can experience a further decline in kidney function if exposed to aminoglycosides.

Side Effects

image Ototoxicity (damage to the inner ear)

image Occurs in about 10% of patients
image Is caused by inhibition of human mitochondrial ribosomes, damaging the hair cells of the inner ear
image Symptoms can include the following:

• Decreased hearing
• Tinnitus (ringing in the ear)
• Vertigo (a spinning type of dizziness)

image Nephrotoxicity

image Occurs in up to 10% of patients and in up to 25% of patients who are critically ill
image Drug accumulates in proximal tubule cells, leading to mitochondrial poisoning and cell membrane disruptions. If the serum creatinine starts to rise during administration, then there must be a very high suspicion that kidney damage secondary to the aminoglycoside is occurring. The aminoglycoside should be immediately stopped.
image Nephrotoxicity is usually mild and reversible if the drug is stopped.
image Elevated “trough” levels (the lowest serum concentrations, just before a dose) are correlated with toxicity. Peak levels (the highest serum concentrations, just after a dose) are not correlated to toxicity.
image Risk factors for nephrotoxicity include the following:

• Low perfusion states (heart failure or septic shock)
• Advanced age
• Preexisting renal disease
• Failure to monitor creatinine and drug trough levels

Important Notes

image Serum levels of aminoglycosides must be monitored. Peak and trough levels help determine required doses.
image Doses must be adjusted according to the patient’s renal function (creatinine clearance).
image Amikacin is particularly effective when used against bacteria that are resistant to other aminoglycosides, because its chemical structure makes it less susceptible to inactivating enzymes.

Advanced

image Neuromuscular blockade occurs because of a reduction in acetylcholine release. These drugs do not paralyze patients, but under anesthesia in patients who are already receiving a neuromuscular blocking drug (such as rocuronium or vecuronium), the duration of blockade can be longer than normal. Other conditions in which neuromuscular blockade could become problematic are:

image Myasthenia gravis (weakness caused by antibodies to the ACh receptors in the neuromuscular junction)
image Hypocalcemia (causes weakness)

image In patients on dialysis, about 65% to 75% of a given dose will be removed by a single treatment of dialysis. The objective with antibiotics is to maintain a concentration in the blood that will kill bacteria (and not be toxic to the patient); if the drug is immediately removed after it is administered, this objective will not be met. Common sense dictates, therefore, that the drug should be given after a dialysis run and not before.

FYI

image Nomenclature:

image The suffix –mycin is for drugs that are derived from Streptomyces, a genus of bacteria commonly found in soil. Streptomycin is named after Streptomyces, but it is no longer commonly used.
image The suffix –micin is for drugs that are derived from Micromonospora, also a genus of bacteria found in soil.
image The suffix –mycin is a common antibiotic suffix. Be aware of confusion with names:

• Vancomycin is not an aminoglycoside. It is a glycopeptide.
• Erythromycin, clarithromycin, and azithromycin are not aminoglycosides. They are macrolides.

image Amikacin is an aminoglycoside, even though its name does not exactly follow the pattern of other aminoglycosides.

image The S in 50S and 23S refers to Svedberg units. A Svedberg unit is a measurement of time and equals 10-13 seconds. It is used to describe speed of sedimentation during centrifuging. Combining two molecules (30S + 50S) and predicting the combined Svedberg units is not simply an additive process because the surface area changes. Thus in the bacterial ribosome, 30S + 50S = 70S (and not 80).
image Glycosides are molecules produced in nature that contain sugar molecules. Therefore aminoglycosides contain amino groups connected to sugar molecules. Gentamicin, with three sugar molecules and five amino groups, is shown in Figure 18-11.
image The first aminoglycoside was streptomycin and was discovered in 1943.
image Gentamicin, the most commonly used aminoglycoside, was discovered in 1963.
image Neomycin is used only in creams or drops (for the ear). It is not administered systemically.
image Tobramycin is available in an inhaled form and is used for patients with cystic fibrosis who develop chronic gram-negative infections (particularly Pseudomonas). Inhaled administration increases the dose of drug delivered to the site of infection.
image Digoxin, is also a glycoside, but it is not an antibiotic. It is used for cardiac purposes and is derived from a purple flowered plant called foxglove.
image

Figure 18-11

Lincosamides

Description

Lincosamides are antibiotics that inhibit the 23S bacterial ribosome.

Prototype and common drugs

image Prototype: clindamycin
image Others: lincomycin

MOA (Mechanism of Action)

image The production of proteins from mRNA is called translation; this step requires ribosomes, tRNA, and mRNA.
image mRNA contains the sequencing code based on DNA; tRNA contains single amino acids and binds to a three-base sequence of mRNA. Ribosomes are like “assembly line” processing machinery, bringing the mRNA and tRNA together to assemble sequences of amino acids (Figure 18-12).
image The ribosomes are different sizes:

image Prokaryotes (bacteria) have 70S ribosomes made of a small (30S) and a large (50S) subunit.

• The 50S subunit is composed of a 5S and a 23S subunit plus 34 other proteins.

image Eukaryotes (humans) have 80S ribosomes, composed of a small (40S) and a large (60S) subunit.

image Ribosomes have different binding sites, named:

image Aminoacyl (A): Incoming tRNA binds to this site.
image Peptidyl (P): This is where the existing amino acid chain (connected to tRNA) is elongated when the incoming amino acid is transferred to it through the action of peptidyl transferase.
image Exit or egress (E): After the tRNA gives up the amino acid chain, it must leave so that new tRNA can take its place.

image Lincosamides bind the 23S rRNA molecule of the 50S RSU and inhibit peptidyl transferase, blocking the transfer of the new amino acid onto the growing chain.
image Inhibition of protein synthesis does not typically kill bacteria cells, so these agents are generally bacteriostatic but in high concentrations can be bactericidal.
image Clindamycin, because of its action on protein synthesis, has been postulated to be beneficial in toxin-producing infections; most bacterially produced toxins are proteins, so an added benefit of a protein synthesis inhibitor is reduced toxin production, in addition to slowed bacterial growth.
image

Figure 18-12

Mechanisms of Resistance

image Mutation of the ribosomal receptor site or modification of the receptor by a methylase enzyme results in decreased binding to the 50S subunit.
image Enzymatic inactivation of clindamycin occurs.
image Some bacteria possess an efflux-based pump mechanism (which lowers bacterial intracellular drug levels and confers resistance) to other ribosomal inhibitors, such as macrolides. However, bacteria that are resistant to macrolides because of the presence of these efflux pumps are not resistant to clindamycin. Even though these drugs act very similarly, they are chemically different, and clindamycin is unaffected by the pump.

image However, resistance to clindamycin usually implies cross-resistance also to macrolides.

Pharmacokinetics

image Clindamycin is well absorbed orally and is metabolized by the liver. Dose adjustments are not required in patients with renal dysfunction but are required in those with severe hepatic dysfunction.
image Clindamycin penetrates bone well and is therefore effective for dental infections that might have bony involvement.
image Clindamycin does not penetrate into the brain very well; therefore, it should not be used for CNS infections.
image Coadministration of two different antibiotic classes that both bind the 50S subunit (e.g., lincosamides, oxazolidinones, macrolides) is not recommended because although the drugs bind different sites on the subunit, they can displace each other and result in being less effective than if administered alone.

Spectra at a Glance

image Gram-positive: good
image Gram-negative: resistant
image Anaerobes: very good, especially for oral anaerobes
image Resistant organisms:

image MRSA: poor to good
image VRE: resistant
image Pseudomonas: resistant

image Special sensitivities:

image In combination with other bactericidal drugs for severe gram-positive infections

Contraindications

image None

Side Effects

image Pseudomembranous colitis (aka C. difficile colitis or “C diff” colitis) may occur. Bacterial flora of the colon changes with antibiotic administration. Some antibiotics (clindamycin is the worst offender) wipe out the normal flora and enable pathologic flora to grow, resulting in inflammation of the colon and diarrhea. This is a major problem and requires a second antibiotic (usually metronidazole or vancomycin) to be used to treat the diarrhea, which can be moderate to severe in intensity. C. difficile infections can sometimes be very difficult to eradicate.

Important Notes

image Although a very effective antibiotic for gram-positive infections, the extremely high incidence of C. difficile colitis severely limits the use of clindamycin when other, alternative antibiotics can be used effectively.
image Clindamycin is commonly used in infections in and around the oral cavity because of the high preponderance of anaerobic bacteria causing these infections.
image Lincomycin has been essentially replaced by clindamycin.
image Toxic shock syndrome is an inflammatory response resulting from a Staphylococcus or Streptococcus infection by a strain of bacteria that produces proteins that function as superantigens and trigger a full-blown inflammatory response. Clindamycin is thought to be helpful with these infections because it inhibits the production of the superantigen protein.
image Necrotizing fasciitis is also called flesh-eating disease and is caused by group A streptococci (GAS). GAS is also a toxin-producing strain and produces a superantigen that can cause a dramatic, amplified, and virtually unregulated inflammatory cascade resulting in life-threatening illness. In addition, the infection causes severe necrosis of soft tissues and spreads faster than antibiotics can treat (because blood vessels are destroyed in the area of the infection and intravenous antibiotics cannot actually be delivered to the site of the infection). Management requires surgical removal of the infected tissue (sometimes limb amputation) and high-dose antibiotics.

FYI

image The S in 50S and 23S refers to Svedberg units. A Svedberg unit is a measurement of time and equals 10-13 seconds. It is used to describe speed of sedimentation during centrifuging. Combining two molecules (30S + 50S) and predicting the combined Svedberg units are not simply an additive process because the surface area changes. Thus in the bacterial ribosome, 30S + 50S = 70S (and not 80).

Tetracyclines

Description

Tetracyclines are antibiotics, chemically composed of four rings.

Prototype and common drugs

image Prototype: tetracycline
image Others: doxycycline, minocycline, demeclocycline, tigecycline

MOA (Mechanism of Action)

image The production of proteins from mRNA is called translation; this step requires ribosomes, transfer RNA (tRNA), and messenger RNA (mRNA) (Figure 18-13).
image mRNA contains the sequencing code based on DNA; tRNA contains single amino acids and binds to a three-base sequence of mRNA; ribosomes are like “assembly line” processing machinery, bringing the mRNA and tRNA together to assemble sequences of amino acids.
image The ribosomes are different sizes:

image Prokaryotes (bacteria) have 70S ribosomes made of a small (30S) and a large (50S) subunit.

• The 50S subunit is composed of a 5S and a 23S subunit plus 34 other proteins.

image Eukaryotes (humans) have 80S ribosomes, composed of a small (40S) and a large (60S) subunit.

image Ribosomes have different binding sites, named:

image Aminoacyl (A): Incoming tRNA binds to this site.
image Peptidyl (P): This is where the existing amino acid chain (connected to tRNA) is elongated when the incoming amino acid is transferred to it through the action of peptidyl transferase.
image Exit or egress (E): After the tRNA gives up the amino acid chain, it must leave so that new tRNA can take its place.

image Tetracyclines must first enter the microorganism before they can exert their antimicrobial effects. Microbes that actively take in tetracycline develop increased susceptibility to the drug because intracellular levels of the drug are high.
image Tetracyclines bind reversibly to the 16S subunit of the 30S RSU and inhibit translation (protein synthesis). Binding of tetracycline to the ribosome weakens the ribosome-tRNA interaction; this prevents addition of amino acids to the growing peptide. This is in contrast to antibiotics that bind the 23S subunit and inhibit the initiation of translation.
image Because tetracyclines stop protein synthesis, they are bacteriostatic. When drug levels fall, the protein synthesis can continue.
image Mammalian cells lack the active transport system that bacteria use to take up tetracycline; this provides part of the basis of selectivity of tetracyclines on microbes and not the host. Different ribosome shapes and sizes also confer selectivity of bacterial versus human ribosome binding.
image Demeclocycline has a further action, which is to inhibit the binding of antidiuretic hormone (ADH) to its receptor. This is clinically important and is the basis for using this drug for treatment of a condition in which ADH levels are too high.
image

Figure 18-13

Mechanisms of Resistance

image There are three commonly recognized mechanisms by which tetracycline resistance is conferred to organisms:

1 Efflux by tetracycline-specific pumps: The drug is actively pumped out of the bacterial cell (the drug is unchanged). The newer drug tigecycline is not a substrate for these pumps, and therefore microbes that are resistant to other tetracyclines by this method are still sensitive to tigecycline.
2 Ribosomal protection: Despite high levels of drug inside the bacterial cell, the ribosome is still able to function because of complex interactions with other proteins that are produced by the bacteria. These other proteins interfere with the binding of tetracycline to the ribosome and impart some degree of protection against it.
3 Enzymatic inactivation: The drug is broken down inside the cell. This is a less common mechanism of resistance.

Pharmacokinetics

image Tetracyclines are bound and inactivated by divalent cations such as calcium and magnesium, and co-ingestion of these agents (e.g., in the form of calcium supplements or antacids) interferes with the effectiveness of tetracyclines. Therefore, tetracyclines should be taken on an empty stomach.
image Tigecycline is not well absorbed and therefore is administered only via the intravenous route.
image All tetracyclines are excreted in urine and bile; doses should be reduced in patients with advanced renal dysfunction. Doxycycline is less dependent on renal excretion, because a lower fraction is excreted renally.

Spectra at a Glance

image Gram-positive: good
image Gram-negative: good
image Anaerobes: poor to good
image Resistant organisms:

image MRSA: resistant
image VRE: resistant
image Pseudomonas: resistant

image Special sensitivities:

image Intracellular organisms: Chlamydia, Mycoplasma, and Rickettsia
image Spirochetes (syphilis and borreliosis)
image Malaria
image Stenotrophomonas (minocycline only)

Contraindications

image Pregnancy and lactation
image Children under 8 years old, because of tooth discoloration (see Side Effects)

Side Effects

image GI: Significant nausea, vomiting, and diarrhea are caused by direct irritation to the GI tract. This is more of a problem with tetracycline than the other tetracyclines.
image Mottling of teeth: Because of binding with calcium, this is a particular problem in newborns; therefore it is contraindicated in pregnancy and lactation. Furthermore, it can permanently stain teeth in children whose adult teeth are still being formed and is therefore contraindicated in children under the age of 8.
image Photosensitivity: This results in skin damage caused by sunlight (ultraviolet-A in particular). It resembles an exaggerated sunburn and can involve blistering. The exact mechanism is not fully elucidated. Absorbed photons are converted into chemical energy, such as oxygen free radicals. These species then result in chemical damage to nearby tissues. Of particular interest is the fact that tetracycline is used for malaria prophylaxis, and many regions in which malaria is endemic are very sunny.
image Superinfection: Superinfection is a rare but serious side effect. Because of the wide spectrum of activity, tetracyclines can wipe out normal flora, which provides an opportunistic environment in which pathogens can grow. This complication is more common in patients who are also immunocompromised.
image Diabetes insipidus: Demeclocycline blocks ADH and therefore can cause diabetes insipidus (water wasting in the urine because of impaired water reabsorption in the collecting duct) if it is used in patients who do not have syndrome of inappropriate ADH secretion (SIADH).
image Liver damage: Liver enzymes can be elevated from tetracyclines. Significant hepatic dysfunction and damage are very rare.
image Kidney damage: Acute tubular necrosis is a rare complication.

Important Notes

image Important clinical uses for tetracyclines include the following:

image Treatment of acne (for role of eradication of bacteria)
image Malaria prophylaxis
image Treatment of intracellular or atypical infections

image Although demeclocycline is classified as an antibiotic, its clinical use is pretty much limited to treating patients diagnosed with SIADH. Remember that a diuretic produces increased urine volume, so ADH works to decrease urine volume (via reabsorption of water).
image Tigecycline is a new tetracycline and is classified as a glycylcycline; antibiotics of this class are derivatives of tetracyclines and were designed to overcome the two primary methods of resistance—namely, efflux pumps and ribosomal protection.
image Tetracycline spontaneously degrades over time (before it is ingested). Ingesting outdated tetracycline is dangerous because the degradation products are nephrotoxic and can cause a condition called Fanconi’s syndrome, which is characterized by damage to the proximal tubules, resulting in impaired reabsorption of glucose, amino acids, and other compounds from the ultrafiltrate within the tubule.

Advanced

image Porphyria cutanea tarda is a form of porphyria that affects the skin. Porphyria is a group of diseases caused by enzyme deficiencies resulting in accumulation of porphyrins, which are precursors to heme. Tetracycline can cause a rare form of phototoxicity that mimics porphyria and is called pseudoporphyria (but does not involve porphyrins).
image Four other ribosomal proteins (S3, S8, S14, and S19) are important for tetracycline binding, but these are low affinity binding.
image Stenotrophomonas is a genus of bacteria that was originally classified as Pseudomonas. It is usually susceptible to sulfa antibiotics, but if it is resistant to sulfa antibiotics it is sometimes susceptible only to minocycline.
image With respect to mechanisms of resistance, there are at least 23 genes for energy-dependent efflux proteins, 11 genes for ribosomal protection proteins, three genes for an inactivating enzyme, and one gene with an unknown mechanism of resistance.
image Proteus and Pseudomonas constitutively produce an efflux pump for which all tetracyclines are substrates; therefore these microbes are universally resistant to all tetracyclines.

FYI

image The class of tetracyclines was first discovered in the 1940s, but tetracycline itself was not the first drug in this class.
image Chlortetracycline was the first tetracycline (and thus the true prototype). However, it is no longer used clinically.
image A modification of tetracyclines has resulted in a new class of antibiotic called glycylcyclines (tigecycline). These chemicals contain an N-O-N group added to the tetracycline. They were introduced in 2006, and this class of antibiotics can overcome some forms of tetracycline resistance.
image Humans carry a 30S ribosome subunit within their mitochondria. However, the side effects of tetracyclines do not involve the mitochondria.
image Tetracycline is produced by Streptomyces bacteria. Some tetracyclines are natural, and some are modified or synthetic.
image The S in 50S and 23S refers to Svedberg units. A Svedberg unit is a measurement of time and equals 10-13 seconds. It is used to describe speed of sedimentation during centrifuging. Combining two molecules (30S + 50S) and predicting the combined Svedberg units are not simply an additive process because the surface area changes. Thus in the bacterial ribosome, 30S + 50S = 70S (and not 80).

Macrolides

Description

Macrolides are antibacterial agents that contain a large macrolide ring.

Prototype and common drugs

image Prototype: erythromycin
image Others: azithromycin, clarithromycin

MOA (Mechanism OF Action)

image The production of proteins from mRNA is called translation; this step requires ribosomes, transfer RNA (tRNA), and messenger RNA (mRNA) (Figure 18-14).
image mRNA contains the sequencing code based on DNA; tRNA contains single amino acids and binds to a three-base sequence of mRNA; ribosomes are like assembly line processing machinery, bringing the mRNA and tRNA together to assemble sequences of amino acids.
image The ribosomes are different sizes:

image Prokaryotes (bacteria) have 70S ribosomes made of a small (30S) and a large (50S) subunit.

• The 50S subunit is composed of a 5S and a 23S subunit plus 34 other proteins.

image Eukaryotes (humans) have 80S ribosomes, composed of a small (40S) and a large (60S) subunit.

image Ribosomes have different binding sites, named:

image Aminoacyl (A): Incoming tRNA binds to this site.
image Peptidyl (P): This is where the existing amino acid chain (connected to tRNA) is elongated when the incoming amino acid is transferred to it through the action of peptidyl transferase.
image Exit or egress (E): After the tRNA gives up the amino acid chain, it must leave so that new tRNA can take its place.

image Macrolides bind the 23S rRNA molecule of the 50S RSU and inhibit peptidyl transferase, blocking the transfer of the new amino acid onto the growing chain.
image Inhibition of protein synthesis does not typically kill bacteria cells, so these agents are generally bacteriostatic, but in high concentrations they can be bactericidal.
image Macrolides are phagocytosed by macrophages, which is a benefit because WBCs preferentially travel to sites of infection, thereby theoretically delivering the drug to the site at which it is needed. This is very convenient.
image

Figure 18-14

Motility

image Erythromycin also stimulates motilin receptors on the GI smooth muscle. This results in increased GI muscular activity, leading to increased forward transit of GI contents.

Mechanisms of Resistance

image Modification of the RSU binding site either by chromosomal mutation or through methylation via methylase greatly decreases the efficacy of macrolides; bacterial methylase can be produced constitutively (all the time) or can be induced.
image Reduced intracellular concentrations are found within the bacterium, through either reduced permeability of cell membrane to macrolides or, probably more important, increased efflux of macrolides via active pumps.
image A third, and maybe least prominent, method of resistance is through the production of esterases that hydrolyze macrolides; this is more common with gram-negative enteric bacteria (bacteria that colonize the GI tract).
image Cross-resistance is complete among all macrolides; if a bacterium is resistant to one, it will be resistant to all others in this class.

Pharmacokinetics

image Half-lives of erythromycin, clarithromycin, and azithromycin are 1.5, 6, and 68 hours, and administration is four times daily, twice daily, and once daily, respectively. At high doses, clarithromycin is sometimes administered once a day.
image Azithromycin contains an additional nitrogen molecule in the macrolide ring to make it a 15-atom ring. This imparts increased stability of the ring. A very high amount of drug is distributed intracellularly; although distribution into tissues is excellent, it is not distributed into CNS (and therefore is not useful for CNS infections). The intracellular distribution contributes to its long half-life.
image Erythromycin and clarithromycin are significant CYP450 enzyme inhibitors and are metabolized by the liver. Drug interactions with other CYP450 inhibitors should be monitored.
image Azithromycin is metabolized by the liver but is not an enzyme inhibitor.
image Erythromycin is unstable in gastric acid and therefore must be administered with salts or esters or via enteric-coated tablets when administered orally.
image The addition of a methyl group to erythromycin creates clarithromycin, and the addition of a methylated nitrogen to erythromycin creates azithromycin; both are stable in gastric acid and very well absorbed orally.
image Because of the long duration of action of azithromycin, a 5-day, oral, once-a-day course for most sensitive infections is considered a treatment of adequate duration.

Spectra at a Glance

image Gram-positive: very good (but resistance to erythromycin has developed)
image Gram-negative: very good
image Anaerobes: resistant
image Resistant organisms:

image MRSA: resistant
image VRE: resistant
image Pseudomonas: resistant

image Special sensitivities:

image Atypical bacteria (many of which are intracellular organisms): Mycoplasma, Rickettsia, Chlamydia, Legionella

Indications

image In addition to antibacterial activity, erythromycin specifically is used to enhance GI motility. Through direct stimulation of the GI tract, this mechanism is responsible both for the enhanced motility that is of benefit in patients who have dysmotility and also, unfortunately, for the GI intolerance (side effects) in patients who have normal motility.

image Examples of conditions associated with dysmotility include diabetes (gastroparesis), scleroderma, and ileus.

image Clarithromycin and azithromycin are commonly used in sexually transmitted infections when chlamydia or gonorrhea is suspected and are also commonly used for treatment of pneumonias.

Contraindication

image Previous liver complications with a macrolide are likely to recur and therefore should be considered a contraindication to macrolide use.

Side Effects

Erythromycin

image GI: Significant GI upset because of increased gut motility
image Acute cholestatic hepatitis: Likely hypersensitivity-related, this side effect can lead to fever, jaundice, and impaired liver function. Abdominal pain, especially right upper quadrant pain, should lead to the suspicion of liver involvement.

Azithromycin and Clarithromycin

image These agents are better tolerated but can also cause liver impairment.

Important Notes

image The short duration of treatment, good oral absorption, once-a-day administration, and low side effect profile are all favorable characteristics for an antibiotic and have contributed to azithromycin’s popularity.
image Scleroderma results in severe esophageal disease that frequently leads to acid reflux; increasing motility helps to empty the stomach and reduce (in part) reflux of acid and stomach contents into the esophagus.
image Gastroparesis (decreased motility or even paralysis of the stomach) in diabetes is a result of autonomic dysfunction. This occurs because small nerves become glycosylated in patients with diabetes, leading to neuropathy.

FYI

image A macrolide ring is a 12-, 14-, or 16-atom ring made of 11 carbon and three oxygen molecules. Two sugar molecules are attached to the macrolide ring. Erythromycin is shown in Figure 18-15.
image Nomenclature of macrolides is similar to that of aminoglycosides (gentamicin) except that for macrolides, thro precedes the mycin.
image Tacrolimus is technically also a macrolide, but it is not an antibiotic. It is an immunosuppressive.
image Erythromycin is produced by Saccharopolyspora erythraea bacteria. The 14-member ring is difficult to synthesize. It was isolated in the Philippines in 1949.
image The GI motility profile was discovered through the observation of the multitude of GI side effects.
image

Figure 18-15

Oxazolidinones

Description

Oxazolidinones form a newer class of antibiotics that are ribosomal inhibitors.

Prototype

image Linezolid

MOA (Mechanism of Action)

image The production of proteins from mRNA is called translation; this step requires ribosomes, transfer RNA (tRNA), and messenger RNA (mRNA) (Figure 18-16).
image mRNA contains the sequencing code based on DNA; tRNA contains single amino acids and binds to a three-base sequence of mRNA; ribosomes are like assembly line processing machinery, bringing the mRNA and tRNA together to assemble sequences of amino acids.
image The ribosomes are different sizes:

image Prokaryotes (bacteria) have 70S ribosomes made of a small (30S) and a large (50S) subunit.

• The 50S subunit is composed of a 5S and a 23S subunit plus 34 other proteins.

image Eukaryotes (humans) have 80S ribosomes, composed of a small (40S) and a large (60S) subunit.

image Ribosomes have different binding sites, named:

image Aminoacyl (A): Incoming tRNA binds to this site.
image Peptidyl (P): This is where the existing amino acid chain (connected to tRNA) is elongated when the incoming amino acid is transferred to it through the action of peptidyl transferase.
image Exit or egress (E): After the tRNA gives up the amino acid chain, it must leave so that new tRNA can take its place.

image Linezolid blocks the translocation step of protein synthesis by binding the 23S rRNA of the 50S RSU.
image It is therefore bacteriostatic.
image Mitochondrial and bacterial ribosomes are similar, and therefore bacterial ribosomal suppression can also result in human mitochondrial suppression. Linezolid is therefore a mitochondrial inhibitor, which is probably the cause of some rare but very serious side effects.
image

Figure 18-16

Mechanism of Resistance

image Mutation of the 23S binding site

Pharmacokinetics

image Linezolid has 100% oral bioavailability, so the oral and intravenous doses are the same.
image Linezolid is a weak monoamine oxidase inhibitor (MAOI); this could result in increased sensitivity to sympathomimetic drugs.

Spectra at a Glance

image Gram-positive: very good
image Gram-negative: resistant
image Anaerobes: resistant
image Resistant organisms:

image MRSA: very good
image VRE: very good
image Pseudomonas: resistant

image Special sensitivities:

image Mycobacterium tuberculosis

Contraindications

image None of significance

Side Effects

image The side effects, although very serious, are rare.
image Serotonin syndrome is a condition characterized by high levels of serotonergic activity in the brain. It occurs in patients who are taking drugs that increase the amount of available serotonin in the brain. Drugs in the selective serotonin reuptake inhibitor (SSRI) class of antidepressants are the most common offenders, but drugs that possess MAOI activity can also produce the syndrome.
image Hyperlactatemia and metabolic acidosis are probably caused by mitochondrial inhibition. The lactate is produced by the cells that cannot undergo aerobic metabolism because of the mitochondrial suppression, and the accumulation of lactate, which is an acid, produces metabolic acidosis.
image Nerve damage: Central and peripheral neuropathies have been reported. The nerve damage has occurred at the same time as the lactic acidosis and therefore could also be mediated by mitochondrial suppression.
image Hematologic: Bone marrow suppression (myelosuppression) characterized by low blood counts (platelets, RBCs, or WBCs) has been reported in patients treated with linezolid for at least 21 days. It is usually mild and is reversible within 4 weeks of stopping the drug. It is not common and usually occurs around 1 month after a patient begins to take the drug.

Important Notes

image Linezolids were approved in 2000, and linezolid resistance was first reported in 2001. New drugs often have low rates of resistance, but over time, increased evolutionary pressure from exposure of the drug to bacteria results in increased levels of resistance.
image Currently their use is generally limited to infections caused by multidrug-resistant gram-positive bacteria. Liberal use of antibiotics is associated with resistance, and therefore antibiotics that are effective against resistant organisms should not be used against organisms that are still sensitive to other antibiotics:

image VRE
image MRSA

Advanced

image Patients who are on long-term treatment with linezolid may develop optic neuropathy (in other words, a peripheral neuropathy), resulting in symmetric painless decreased vision.
image Myelosuppression risk is 1/750 in exposed patients, specifically those with the following:

image Low platelet count (thrombocytopenia)
image Low RBC count (anemia)
image Pancytopenia (all three blood cell lines)

Sulfonamides and Other Folate Synthesis Inhibitors

Description

The sulfonamides are antibacterial agents that are inhibitors of folate synthesis. They are frequently also referred to as sulfa antibiotics.

Prototype and common drugs

image Prototype: sulfamethoxazole

image Others: sulfadiazine, sulfanilamide, sulfacytine, sulfamethizole

image Topical: silver sulfadiazine, sulfacetamide
image Nonsulfas: trimethoprim, pyrimethamine

MOA (Mechanism of Action)

image Most bacteria must synthesize their own folate for survival; they cannot use external sources. In contrast, humans do not synthesize folate but rather obtain it through the diet.
image Sulfonamides are inhibitors of folate synthesis.
image A few steps are required in the synthesis of folate. Specifically, sulfonamides are competitive inhibitors with p-aminobenzoic acid (PABA) in the first reaction of the folate synthesis pathway, catalyzed by the enzyme dihydropteroate synthase. Inhibiting the synthesis of tetrahydrofolate (THF) results in reduced DNA synthesis, which stops bacterial growth (a bacteriostatic effect).
image Trimethoprim inhibits the last reaction of folate synthesis (catalyzed by dihydrofolate reductase) and is commonly administered in conjunction with sulfonamides for greater antibiotic efficacy. Inhibition of the folate synthesis pathway at two different steps results in a bactericidal action and is the reason why trimethoprim and sulfamethoxazole (TMP-STP) are combined and commonly used clinically for many infections.

Mechanisms of Resistance (Figure 18-17)

image Bacteria that do not synthesize their own folate (similar to humans) are inherently completely resistant to sulfonamides.
image Overproduction of PABA by bacteria can overcome the action of competitive inhibition of sulfas.
image Enzyme mutation of dihydropteroate synthase leads to reduced affinity for sulfas and results in resistance.
image Lower levels of drug inside bacterial cells because of either decreased membrane permeability to sulfas or active efflux of the drug also confer resistance to organisms.
image An alternative metabolic pathway for synthesis of folate within bacteria has also been postulated as a method of resistance.
image

Figure 18-17

Pharmacokinetics

image Metabolism of sulfonamides is via the liver and excretion by the kidney. In patients with advanced renal dysfunction, doses should be reduced.
image Sulfadoxine has a long half-life (7 to 9 days), whereas the half-life of sulfamethoxazole, a commonly prescribed sulfa drug, is 10 to 12 hours.

Spectra at a Glance

image Gram-positive: good
image Gram-negative: good
image Anaerobes: resistant
image Resistant organisms:

image MRSA: resistant
image VRE: resistant
image Pseudomonas: resistant

image Special sensitivities:

image Pneumocystis jiroveci causes P. jiroveci pneumonia (PJP) (the older name is Pneumocystis carinii pneumonia or PCP)
image Toxoplasma
image Nocardia
image Stenotrophomonas

Contraindications

image Allergy to sulfa antibiotics
image Glucose-6 phosphate dehydrogenase deficiency (a rare enzyme deficiency)

Side Effects

image Precipitation in urine: Sulfa molecules might precipitate at neutral or acidic pH, leading to crystalluria (crystals in the urine), and possibly hematuria (blood in urine secondary to reaction from crystals).
image Nausea, vomiting, diarrhea
image Photosensitivity
image Hypersensitivity: Cross-reactivity can occur with other sulfone-containing drugs, including hydrochlorothiazide and sulfonylureas. There is little evidence to support cross-reactivity, which is usually not severe and limited to rash.

Rare and Serious

image Stevens-Johnson syndrome is a rare but very serious (life-threatening) hypersensitivity reaction involving skin and mucous membranes.
image Blood cell problems include hemolytic anemia (red cell destruction), aplastic anemia (absence of red cell production), granulocytopenia, and thrombocytopenia.

image A rare condition glucose-6—phosphate dehydrogenase deficiency increases the risk of hemolytic anemia

image Kernicterus: Sulfa antibiotics compete with bilirubin binding sites on albumin, leading to increased free bilirubin and jaundice in the newborn.

Important Notes

image TMP-SMX is a very common preparation used clinically.
image Common clinical infections treated by sulfonamides include the following:

image Urinary tract infections (UTIs)
image Respiratory tract infections (including community-acquired pneumonia)
image PJP prophylaxis and treatment

• Pneumocystis is a fungus, and although technically only one organism infects humans, it was originally thought to be a different species and so is referred to by two names:

image P. jiroveci (the proper name) and P. carinii (the original name)
image Pneumonia caused by Pneumocystis is therefore abbreviated as both PJP and PCP.

• PJP only occurs in patients who are immunocompromised.

image Topical application for infection prevention:

• Burns
• Severe blistering diseases of the skin (pemphigus)

image Sulfasalazine contains a sulfa component but is used clinically as an antiinflammatory (because of the salicylate component) for the GI tract (because it is very poorly absorbed and thus has exposure only to the GI tract). It is described in the section on salicylates.

Advanced

image Other drugs that contain a sulfone group include the following:

image Sulfonylureas (oral hypoglycemics)
image Thiazides (diuretics)
image Sumatriptan (for migraines)
image Sulfasalazine (an antiinflammatory salicylate)
image Probenecid (a uricosuric drug used for treatment of gout and for prolonging the half-life of penicillin)

FYI

image A sulfone is an 0=S=0 group connected to two R groups. A sulfonamide is created when one of the R groups is an amide (NH2). Sulfonamides are also called sulfa drugs.
image Sulfonamides are technically derivatives of p-aminobenzene sulfonamide (Figure 18-18).
image Sulfa drugs were discovered in the 1930s and were the only antibiotics available before penicillin. They were therefore the first antibiotics.
image Other drugs that interfere with the folate synthesis pathway include:

image Methotrexate (used for cancer therapy and treatment of autoimmune diseases)

image PABA was found in sunscreens but has been replaced largely by padimate O, a derivative of PABA. It is interesting that the sulfonamides increase the risk of photosensitivity and that PABA was used to protect the skin, despite their similar chemical structures.
image Folate deficiency causes megaloblastic anemia: big RBCs (contrast this with iron deficiency, which causes microcytic anemia: small RBCs). The cells cannot divide in the absence of folate, but they can continue to produce RNA and protein; hence they grow large, but their numbers are low.
image

Figure 18-18

Metronidazole

Description

Metronidazole is an antibiotic that is a member of the imidazoles, a class of drug usually associated with antifungals. However, the antiinfective activity of metronidazole is limited to anaerobic bacteria and protozoa but not fungi.

Prototype

image Metronidazole

MOA (Mechanism of Action)

image Metronidazole is a prodrug. The nitrogen group must be reduced (addition of electron) before the chemical obtains its antiinfective function. It is reduced by a nitroreductase enzyme called a ferredoxin (an iron- and sulfur-containing enzyme). The extra nitrogen side chain is reduced in this reaction.
image With aerobic bacteria the electron transport chain does not require these special enzymes because oxygen is the terminal electron acceptor; therefore the prodrug is not converted to the active form of the drug. However, with anaerobic bacteria, with which oxygen is absent, these special enzymes are present. Therefore metronidazole is not activated with aerobic bacteria but is particularly effective against anaerobic bacteria.
image Reduction of the prodrug metronidazole results in the production of toxic products (hydroxylamine) and other free radicals that damage DNA.

Mechanisms of Resistance

image Some bacteria are facultatively anaerobic (can live with or without oxygen) or are microaerophiles (can live in the presence of very little oxygen). In these bacteria, the genes required to produce ferredoxin can be switched off; this would result in metronidazole not becoming reduced, and therefore it would remain in the inactive prodrug state.

Pharmacokinetics

image Oral administration results in nearly complete absorption.
image Metronidazole is metabolized by the liver. Dose adjustments are not required in patients with renal dysfunction but are required in those with hepatic dysfunction.

Spectra at a Glance

image Gram-positive: poor (if aerobic)
image Gram-negative: poor (if aerobic)
image Anaerobes: very good (for both gram-positive and gram-negative organisms)

image Microaerophilic bacteria (limited activity): Propionibacterium, Actinomyces

image Resistant organisms:

image MRSA: resistant
image VRE: resistant
image Pseudomonas: resistant

image Special sensitivities:

image C. difficile
image Protozoa: (Trichomonas, Giardia, Entamoeba)

Contraindications

image Ethanol: Metronidazole can have a disulfuram-like effect: ingestion with alcohol can lead to severe nausea and vomiting. This results from inhibition of the enzyme acetaldehyde dehydrogenase, leading to increased levels of acetaldehyde, which are toxic.
image Pregnancy (first trimester in particular): Metronidazole causes tumor growth in laboratory rats and readily crosses the placenta. It should be used only in extreme situations in pregnancy, after risks have been weighed against benefits.

Side Effects

image GI: nausea
image Metallic taste: common, harmless
image CNS toxicity: rare, manifests as ataxia, encephalopathy, or seizure.
image Rare:

image Neutropenia
image Pancreatitis
image Peripheral neuropathy
image Hepatitis

Important Notes

image For treatment of C. difficile infection, oral administration is the preferred route because the infection is inside the GI tract.

FYI

image Metronidazole contains the five-member imidazole ring (three carbons + two nitrogen atoms), but there is a nitrogen side chain; it is therefore a nitroimidazole. It is in a drug category all on its own (Figure 18-19).
image Imidazole rings are present in a number of biologically important molecules, including:

image Histamine
image Theophylline (airway medication)
image Antifungals

image The first ferredoxin enzyme was isolated from Clostridium (a genus of anaerobic bacteria) in 1964.
image Metronidazole causes mutation in bacteria and is tumorigenic in laboratory animals, suggesting that large doses over long periods of time might be associated with a risk of cancer.
image

Figure 18-19

Introduction to Antimycobacterials

A tubercle is a nodule or wartlike projection, depending on the context in which the term is being used. Therefore the name tuberculosis means a condition of having nodules. One of the many chest x-ray findings of TB is the presence of nodules (round shadows) in the lungs.

TB is hard to kill because it grows very slowly. Effective treatment requires multiple antibiotics for prolonged periods of time, up to as long as 12 months and even longer for resistant strains.

The main anti-TB drugs and their abbreviations include the following:

image First-line agents

• Ethambutol (EMB or E)
• Isoniazid (INH or H)
• Pyrazinamide (PZA or Z)
• Rifampin (RMP or R)
• Streptomycin (STM or S)

image Second-line agents (in preferred order)

• Aminoglycosides: kanamycin, amikacin
• Polypeptides: capreomycin, viomycin, enviomycin
• Fluoroquinolones: moxifloxacin
• Thioamides: ethionamide, prothionamide
• Cycloserine
• p-Aminosalicylic acid (PAS or 4-ASA)

Second-line agents are either less effective or more toxic than first-line agents. Other drugs are even less effective against TB than second-line agents. They are sometimes called third-line drugs. They are not listed here.

There are now many resistant strains of TB, including multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB).

image Criteria for MDR-TB:

• Isoniazid resistant and
• Rifampin resistant

image Criteria for XDR-TB:

• Isoniazid resistant and
• Rifampin resistant and
• Aminoglycoside resistant and
• Fluoroquinolone resistant

MDR-TB and XDR-TB should be treated with five drugs simultaneously (excluding the drugs to which they are resistant). Resistant TB strains should be treated by physicians who are experienced in the treatment of TB. Treatment for MDR-TB must be given for a minimum of 18 months and cannot be stopped until the patient has been culture negative for a minimum of 9 months. Some patients have been treated for longer than 2 years.

Mutation Rate

image The rate of mutations in TB resulting in drug resistance is:

image 3 in 107 for EMB (relatively high)
image 2.5 in 108 for STM and INH
image 2 in 1010 for RMP (quite low)

image Severe, advanced pulmonary TB has approximately 1012 bacteria in the body, resulting in approximately:

image 105 EMB-resistant bacteria
image 104 STM-resistant bacteria
image 104 INH-resistant bacteria
image 102 RMP-resistant bacteria

image The mutations occur independently of one another. Chances of harboring a bacterium that is resistant to:

image INH and RMP is 1 in 106
image All four drugs is 1 in 1011

image The high rate of mutations and the low probability of bacteria with resistance to four drugs is the rationale for using multiple drugs in the treatment of TB.

Standard Regimen

image Treatment involves an induction phase (high dose, more drugs) followed by a maintenance phase (fewer drugs).
image Abbreviations are used to denote drugs, duration of treatment, and frequency of administration: (months)(single letter drug abbreviations)(times per week). For example:

image The current standard regimen is 2HREZ/4HR, which means:

• 2 months of isoniazid + rifampin + ethambutol + pyrazinamide
• Followed by 4 months of isoniazid + rifampin
• When there is no subscript times per week, the drugs are to be taken daily.

image 2SHRZ/4HR is an alternate to the standard regimen (replaces streptomycin for ethambutol).
image If patients are still culture positive 2 months after finishing the full regimen (about 15% of patients), then another 6HR is required (6-month extension of the maintenance portion), and testing for resistance is also required in case the drugs being used are no longer effective.

Ethambutol

Description

Ethambutol is a first-line drug for treatment of TB. It is used in combination with other antituberculous drugs.

Prototype

image Ethambutol

MOA (Mechanism of Action) (Figure 18-20)

image The mycobacterial cell wall is composed of a peptidoglycan–arabinogalactan–mycolic acid structure.
image Ethambutol disrupts formation of the tuberculous cell wall by blocking arabinosyl transferases. These enzymes attach the arabinose residue of arabinogalactan to mycolic acid.
image Ethambutol is bacteriostatic; it suppresses the growth of TB but does not kill TB.
image

Figure 18-20

Mechanisms of Resistance

image The emb (A, B, and C) genes code for arabinosyl transferases. Mutations in these genes affect binding of ethambutol and can result in ethambutol being ineffective.
image Resistance to ethambutol develops quickly when the drug is used as a solo medication; therefore it is always used in combination with other agents.

Pharmacokinetics

image Ethambutol is cleared primarily by the kidneys, and doses need to be adjusted downward in patients with moderate to severe renal dysfunction.

Indication

image TB: first-line drug, given in combination with other anti-TB medications

Contraindication

image Age <5: It is difficult to test vision in young children, and therefore toxicity relating to vision cannot be assessed in these patients.

Side Effects

image In general, ethambutol is minimally toxic (<2% incidence of side effects)
image Neurologic:

image Optic neuritis: <1% occurrence. Inflammation of the optic nerve results in decreased visual acuity (blurred vision). Recovery usually occurs after discontinuation of the drug. This is a dose-related effect and occurs more commonly with higher doses. One theory for the MOA of ocular toxicity is related to its zinc chelating effect, but the mechanism has not been fully established.

• Permanent blindness can occur if the drug is not stopped early enough.

image Red-green color blindness can also occur.
image Peripheral neuropathy causes numbness and tingling of fingers and feet.

image Rash
image Fever

Important Notes

image Vision tests for acuity and color discrimination should be performed at the start of administration of ethambutol and should be repeated periodically, or immediately if visual problems are reported.
image Renal dysfunction leads to increased levels of ethambutol; therefore patients with renal dysfunction should be monitored more closely for visual changes.

Advanced

image Ethambutol can result in increased urate in the urine. This makes it a uricosuric drug, which is beneficial to patients with elevated blood uric acid but detrimental to patients with a tendency to form renal stones.

FYI

image Ethambutol is abbreviated as EMB or simply E.

Isoniazid

Description

Isoniazid is a first-line anti-TB drug. It is used in combination with other anti-TB drugs.

Prototype

image Isoniazid

MOA (Mechanism of Action) (Figure 18-21)

image Isoniazid passively enters mycobacterial cells and kills rapidly dividing cells.
image In short, isoniazid inhibits mycobacterial cell wall synthesis.
image The chemical steps are a bit complicated; the following is a simplified version:

image Isoniazid is a prodrug activated by the mycobacterial enzyme katG.
image The activated compound reacts with nicotinamide adenine dinucleotide (NAD) to form an INH-NAD complex.
image The INH-NAD complex inhibits one of the final steps of mycolic acid synthesis via the enzyme that is abbreviated InhA.
image The net results are accumulation of long-chain fatty acids, decreased production of mycolic acid, and cellular death.

image

Figure 18-21

Mechanisms of Resistance

image As a result of the MOA being multistepped, there are many opportunities for TB to develop isoniazid resistance:

image Mutation leading to overexpression of InhA (the enzyme that needs to be inhibited)
image Mutation leading to underexpression of katG (the enzyme that converts the prodrug to the active form)

Pharmacokinetics

image Isoniazid is distributed in serum, in cerebrospinal fluid (CSF), and within caseous granulomas (which often surround TB). Caseous means having a cheeselike consistency.
image Isoniazid is metabolized in the liver via acetylation.

image There are two forms of acetylation enzymes. Therefore some patients metabolize INH faster than others.

image Isoniazid is a hepatic enzyme inducer. It will decrease the serum levels of other drugs that are hepatically cleared.

Side Effects

image Hepatitis, which can be initially asymptomatic and detected only by hepatic enzyme elevation. Significant enzyme elevation might mandate that isoniazid be discontinued in that patient. Note that the term hepatitis here does not refer to viral hepatitis, but rather a noninfectious inflammation of the liver that is directly drug induced.
image Peripheral neuropathy—dysesthesia (tingling), hyperesthesia (pain), or anesthesia (loss of sensation) commonly present in the hands or feet—is believed to be mediated by a drug-induced vitamin B6 deficiency, which is prevented by administering pyridoxine (vitamin B6).
image Mild CNS effects may occur.
image Rash may be present.

Important Notes

image Baseline measurements of hepatic enzymes are required because of the risk of hepatitis. Repeat measurements as follows:

image At regular intervals
image If baseline results are abnormal
image If the patient has signs or symptoms of hepatitis

Advanced

image Deficiency mutations cause loss of an enzyme. Therefore if two genes (one normal and one mutated) are present, the mutated gene will be recessive because the normally functioning gene will replace the missing enzyme. Recessive INH-resistant genes include katG, ndh, msh, and nat.
image Overexpression mutations cause too much enzyme. Therefore if two genes (one normal and one mutated) are present, the mutated gene will be dominant because the mutated gene will continue to pump out excessive enzyme even in the presence of the normal gene. Dominant INH-resistant genes include InhA, which is inhibited by INH-NAD. It is more difficult to inhibit an enzyme that is produced in high quantity.
image There are more mechanisms of isoniazid resistance not listed here.

FYI

image Isoniazid was the first anti-TB drug and was discovered in 1952. The name isoniazid is derived from isonicotinic acid hydrazide.
image Isoniazid is often abbreviated as INH or simply H.
image Isoniazid is a pyridine (five carbon plus one nitrogen ring). Pyridine is a component of nicotinamide, which in turn is a component of nicotinamide adenine dinucleotide (NAD).
image Nicotinamide is the amide of nicotinic acid.

image Nicotinic acid is incorporated into NAD.
image Nicotinic acid is also known as niacin (vitamin B3), a drug used to lower cholesterol.

Pyrazinamide

Description

Pyrazinamide is an antituberculous drug. It is an analog of nicotinamide. It is abbreviated PZA or simply Z.

Protoype

image Pyrazinamide

MOA (Mechanism of Action) (Figure 18-22)

image Pyrazinamide is a prodrug. It must first be converted to pyrazinoic acid by a mycobacterial enzyme called pyrazinamidase.
image Pyrazinoic acid probably exerts its antituberculous activity via inhibition of an enzyme called fatty acid synthase I that is involved in cell wall synthesis.
image Fatty acid synthase I activity is required for fatty acid synthesis, but the exact role that it plays in mycobacterial growth and structure is not fully elucidated.
image Pyrazinamide is active only if the bacterium is in an acidic environment; pyrazinoic acid appears to accumulate in higher levels.
image

Figure 18-22

Indications

image The only use for pyrazinamide currently is part of a multidrug treatment of M. tuberculosis infection.
image It is not effective against other strains of Mycobacteria.
image It is never used as a single drug; resistance develops very quickly when it is used alone.

Contraindication

image Preexisting hepatic dysfunction

Side Effects

Serious

image Hepatic injury: Drug-induced hepatitis is the most serious side effect of PZA.

image Hepatic enzymes must be measured while patients are taking PZA.
image If signs or symptoms of hepatitis occur, then the drug must be stopped immediately.

More Common (Less Serious)

image Arthalgia (joint pain) occurs in approximately 1% of patients.
image Increased uric acid: PZA inhibits the excretion of urate (uric acid salt) and therefore increases the probability of precipitating gout (which causes joint pain and inflammation via deposition of uric acid crystals in joints, especially the great toe).
image Anorexia (loss of appetite): This effect is not to be confused with anorexia nervosa, which is a psychiatric condition. Anorexia (not the psychiatric type) can occur with many diseases and in fact can be a symptom of hepatic disease.
image Nausea and vomiting are also signs of hepatic disease but can be isolated side effects of PZA.

Important Notes

image The dose of PZA used to be higher (40 to 50 mg/kg, whereas it is now 15 to 30 mg/kg). The incidence of hepatic injury used to be as high as 15%, with 2% to 3% of patients demonstrating jaundice and with deaths from liver disease also being reported.

FYI

image PZA is structurally similar to vitamin B3 but is not itself a vitamin.
image A pyrizine molecule is a six-membered ring with two nitrogens at opposite ends, producing a symmetrical molecule.
image Pyrazinamide also has an amide group attached to the side chain, hence its name.
image Note the common denominator of nicotinamide among INH and PZA.

Rifamycins

Description

Rifamycins are antibiotics that are well known for their anti-TB activity. They are also active against other bacteria.

Prototype and common drugs

image Prototype: rifampin (also known as rifampicin)
image Others: rifabutin, rifapentine

MOA (Mechanism of Action) (Figure 18-23)

image RNA polymerase reads DNA to produce an mRNA copy of the genetic code. Without RNA, protein synthesis cannot occur.
image Rifampin inhibits bacterial RNA synthesis by binding prokaryotic (bacterial) RNA polymerase. It prevents initiation of RNA synthesis (but not elongation of RNA).
image Rifampin does not bind human RNA polymerase, so its action on RNA synthesis is limited to bacterial RNA, which serves to limit its side effects.
image Rifampin is bactericidal for extracellular and intracellular bacteria, but despite this, it is not commonly used as a solo agent for treatment of established infections because of the high rates of resistance that develop.
image Rifampin is highly lipophilic. This is extremely important because it confers the property that the drug can easily cross lipophilic membranes:

image Mycobacterial cell walls contain mycolic acids, which are long fatty acids and therefore lipids. Rifampin therefore easily and readily enters mycobacterial cells.
image Biofilms (inert films that bacteria can live in) created by some bacteria generate a barrier that antibiotics generally cannot enter. However, rifampin can enter the biofilms because of its lipophilic nature.
image CNS distribution is high (and therefore rifampin is effective for CNS infections such as bacterial meningitis).
image Rifampin enters phagocytic cells and therefore can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and organisms inside abscesses, which do not have good blood supplies.

image

Figure 18-23

Mechanisms of Resistance

image Mutations to the gene rpoB, which gives rise to bacterial RNA polymerase, confer resistance to rifampin.
image Resistance occurs in about 1 in 106 bacteria, and therefore when rifampin is used as a solo agent, resistant strains are preferentially selected for and resistance is quickly established.

Pharmacokinetics

image Rifamycins are primarily metabolized by the liver and eliminated in the bile. Does adjustments are not required in liver or renal dysfunction.
image Rifamycins are potent inducers of a number of CYP enzymes. Therefore patients on drugs broken down by CYP enzymes will require higher doses of these drugs. Important examples include warfarin, an anticoagulant; human immunodeficiency virus (HIV) medications (protease inhibitors and nonnucleoside reverse transcription inhibitors); and methadone.

image HIV medications and methadone are relevant because patients who are HIV positive or abusers of intravenous narcotics have a higher likelihood of contracting mycobacteria and requiring rifampin.

image Aminosalicylic acid may delay the absorption of rifampin and cause inadequate plasma concentrations. If both drugs need to be administered, it is important to space out administration by as many hours as possible.
image Rifampin is distributed widely in body fluids and tissues, and adequate CSF concentrations are achieved, but only in the presence of meningeal inflammation (which occurs with bacterial meningitis).

Spectra at a Glance

image Gram-positive: good
image Gram-negative: moderate
image Anaerobes: resistant
image Resistant organisms:

image MRSA: good
image VRE: resistant
image Pseudomonas: moderate

image Special sensitivities:

image Mycobacteria (TB)
image N. meningitidis

Contraindications

image None of major significance

Side Effects

Common and Mild

image Discoloration of secretions: Because of its lipophilic nature, it enters secretions readily and colors them orange or red. Such secretions include tears, urine, sweat, stool, sputum, and saliva. Contact lenses can be stained. Patients should be warned about this so that they do not become unnecessarily alarmed when it happens.
image Cholestatic jaundice and hepatitis: Levels of liver enzymes such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin can be elevated. Elevations in bilirubin usually resolve after 10 days. Rifampin blocks bilirubin excretion, and liver enzyme production increases to compensate. Isolated mild elevations in bilirubin are not an indication to stop treatment.
image Rash occurs rarely.

Rare but Serious

image Acute interstitial nephritis (AIN): inflammation of the renal interstitium caused by an allergic-type reaction
image Thrombocytopenia: a decreased platelet count

Important Notes

image Staphylococcal infections (S. epidermidis and S. aureus) are commonly associated with biofilm production. Because of the lipophilic nature of rifampin, it absorbs into and crosses biofilms and can be more effective against these infections.
image Rifampin is commonly coadministered for the following serious infections:

image Meningitis
image Osteomyelitis
image TB
image Endocarditis
image Joint hardware (joint replacement) infections (poor access because of no blood supply)
image Resistant strains of S. aureus (MRSA)

image Rifampin is indicated as a prophylactic measure in the case of exposure to a patient with meningitis caused by N. meningitidis.

Advanced

image Many guidelines recommend rifampin as a second drug to be used in combination for some staphylococcal and streptococcal infections. However, a meta-analysis found that only orthopedic infections (bone, joint, or joint hardware) with Staphylococcus showed a significant improvement in cure rates with combination treatment.
image Rifampin is an inducer of the P-glycoprotein (Pgp) transport system. This can result in decreased efficacy of other drugs that are transported by the Pgp system.
image Examples of clinically relevant interactions (reduced levels because of P-450 enzyme induction) demonstrated by recent reports include (in addition to the drugs mentioned previously) everolimus, atorvastatin, rosiglitazone and pioglitazone, celecoxib, clarithromycin, caspofungin, and lorazepam.
image Rifampin is a strong inducer of the enzyme UGT1A1 and can thus reduce levels of the HIV agents atazanavir and raltegravir. This is clinically relevant because patients with HIV often develop infections that are treated with rifampin.

FYI

image Rifamycin B was the first rifamycin to be introduced commercially.
image Mycobacterial cell walls are very lipophilic because of the mycolic acid content and therefore hydrophilic attacks by hydrophilic antibiotics are ineffective, thereby making mycobacteria difficult to kill.

CCR5 Antagonists

Description

CCR5 antagonists are a newer class of drugs that inhibit HIV by preventing its entry into human cells.

Prototype

image Prototype: maraviroc

MOA (Mechanism of Action)

image Several steps are involved in the replication of HIV. The virus must fuse to the host cell, uncoat, enter and be transcribed by reverse transcriptase, become incorporated into the host genome, and be transcribed to viral RNA, which is then translated into polyproteins (Figure 18-24).
image Entry of HIV into the host cell begins with the attachment of the HIV envelope glycoprotein (gp120) to the CD4 T-cell receptor. This interaction produces a conformational change in gp120 that allows it to bind to a chemokine co-receptor, either CCR5 or CXCR4.
image Once gp120 is bound to either CCR5 or CXCR4, further conformational changes occur that allow the HIV envelop gp41 fusion peptide to insert into the cell membrane, causing the virion to fuse with the cell membrane.
image The CCR5 antagonists block the interaction of gp120 with CCR5, thus preventing viral entry.
image Some patients express CCR5, some express CXCR4, and some express a mixture of the two (“dual-mixed”). The CCR5 antagonists are typically reserved for patients expressing CCR5. Use of CCR5 antagonists in dual-mixed patients leads to selection of CXCR4 and resistance.
image

Figure 18-24 (Modified from Pommier Y, Johnson AA, Marchand C: Integrase inhibitors to treat HIV/AIDS, Nat Rev Drug Discov 4(3):236, 2004. Reprinted by permission from Macmillan Publishers.)

Mechanisms of Resistance

image Switching of CCR5 to CXCR4 or dual-mixed population of CCR5 and CXCR4

Pharmacokinetics

image Maraviroc is eliminated primarily by hepatic metabolism.
image Maraviroc is a CYP3A4 substrate and a substrate for Pgp. However, it does not appear to either inhibit or induce CYP3A4.
image With the exception of tipranavir and ritonavir, concomitant use with protease inhibitors will require a maraviroc dose reduction because of their ability to act as CYP inhibitors.

Indication

image HIV-1 in patients in whom prior therapies have failed with evidence of CCR5 tropism

Contraindications

image None of major significance

Side Effects

image Antiretrovirals are typically administered in combination regimens, which can make it unclear how each individual drug contributes to side effects.
image Postural hypotension and syncope: Caution is advised in patients taking antihypertensives or who have a history of syncope. The mechanism is not established.

Rare

image Hepatotoxicity: There were more hepatic adverse events with maraviroc-treated patients during clinical trials. The mechanism was not established.
image Cardiovascular events: Myocardial ischemia and infarction were reported in clinical trials, although infrequently. The mechanism was not established.

Important Notes

image In clinical trials, virologic failure typically occurred in patients exhibiting a switch in HIV-1 from CCR5 to CXCR4 or dual-mixed. However, once patients had discontinued maraviroc, they typically reverted back to CCR5.
image The switching of HIV-1 to CXCR4 after therapy with CCR5 antagonists has prompted the search for CXCR4 antagonists. These agents have not been successfully brought to market yet, because of concerns over toxicity and lack of response.

Advanced

image There is a theoretical concern that CCR5 antagonism may interfere with the body’s response to infection and predispose patients to cancer. To date, there is no obvious indication from clinical trials that maraviroc increases the incidence of infection or cancer versus placebo.

Pregnancy

image Typical of antiretroviral agents, the safety of maraviroc in pregnancy has not been established. Animal studies do not indicate any obvious potential harm; however, these data cannot be reliably generalized to humans.

Lactation

image Maraviroc is secreted into breast milk in animals, but this observation has not been established in humans.

FYI

image The development of CCR5 antagonists was inspired by the observation that individuals who did not express CCR5 because of a gene deletion were resistant to HIV infection.
image The name chemokine comes from the ability of these agents to act as chemotaxic cytokines. Chemokines induce chemotaxis in responding cells and thus direct the movements of various cells within the body. Once a chemokine binds to a chemokine receptor, that cell begins to migrate toward a site of injury or maturation. Certain viruses, including HIV, also bind to chemokine receptors, as a means for gaining entry into host cells.
image CCR5 receptors are targets of drug development for a variety of other indications involving an inflammatory component, including cancer, rheumatoid arthritis, and chronic obstructive pulmonary disease (COPD).

Fusion Inhibitors

Description

Fusion inhibitors block fusion of the HIV virus to the human cell and thereby reduce entry of the virus into the CD4 cell. They are also called entry inhibitors.

Prototype and common drugs

image Prototype: enfuvirtide
image Others: PRO 140, ibalizumab

MOA (Mechanism of Action) (Figure 18-25)

image Several steps are involved in the replication of HIV. The virus must fuse to the host cell, uncoat, enter and be transcribed by reverse transcriptase, become incorporated into the host genome, and be transcribed to viral RNA, which is then translated into polyproteins.
image Enfuvirtide mimics the HIV machinery required to fuse to the CD4 cell. It competes with the HIV proteins and prevents entry of the virus into the CD4 cell:

image Glycoprotein gp120 binds HIV and activates gp41.
image Glycoprotein gp41 changes conformation and creates an entry channel (pore) into the cell.
image Specifically, enfuvirtide binds gp41 and prevents conformation change.

image

Figure 18-25 (Modified from Pommier Y, Johnson AA, Marchand C: Integrase inhibitors to treat HIV/AIDS, Nat Rev Drug Discov 4(3):236, 2004. Reprinted by permission from Macmillan Publishers.)

Pharmacokinetics

image Enfuvirtide is injected only. It is an amino acid sequence and therefore would be enzymatically degraded if taken orally.

Indications

image Fusion inhibitors are used in multiple-drug–resistant HIV patients, already on multiple HIV medications, as part of a combination therapy.
image These are not first-line medications to treat HIV.

Side Effects

image Injection site irritation
image Peripheral neuropathy (can cause pain, numbness, or weakness in extremities)

Important Notes

image When added to an existing drug regimen in patients who had high HIV levels and had already been treated for many years, enfuvirtide resulted in lower HIV levels.

Integrase Inhibitors

Description

Integrase inhibitors are a newer class of drugs for HIV infection that inhibit HIV by preventing the virus from incorporating its DNA into the host genome.

Prototype

image Prototype: raltegravir

MOA (Mechanism of Action)

image Several steps are involved in the replication of HIV. The virus must fuse to the host cell, uncoat, enter and be transcribed by reverse transcriptase, become incorporated into the host genome, and be transcribed to viral RNA, which is then translated into polyproteins (Figure 18-26).
image The integrase enzyme incorporates viral DNA into the host genome.
image Specifically, integrase binds to viral DNA and joins it with host DNA. The divalent cations in the catalytic core of integrase enable it to form covalent bonds with DNA. This is followed by cellular repair activities that seal the viral DNA into the chromosome.
image Integrase inhibitors prevent the formation of covalent bonds with host DNA. This prevents incorporation of HIV into the host genome.
image

Figure 18-26 (Modified from Pommier Y, Johnson AA, Marchand C: Integrase inhibitors to treat HIV/AIDS, Nat Rev Drug Discov 4(3):236, 2004. Reprinted by permission from Macmillan Publishers.)

Mechanisms of Resistance

image Raltegravir is considered to have a low genetic barrier to resistance, as a single point mutation in HIV can lead to a change in sensitivity of integrase to inhibition.
image Cross-resistance among integrase inhibitors may occur, but there is not yet enough experience with these agents to confirm this.

Pharmacokinetics

image The main route of elimination for raltegravir is hepatic; however, dose adjustments are not required in patients with mild to moderate hepatic impairment. Adjustments in severe hepatic impairment have not been studied. Because renal elimination plays a relatively minor role, no adjustments are required in patients with renal impairment.
image Raltegravir is not a substrate for CYP450 enzymes. It also does not inhibit or induce CYP450 enzymes. It is primarily metabolized by glucuronidation (UGT1A1), and it is a Pgp substrate.

Indication

image HIV-1 infection in patients who have tried other therapies with continued viral replication and multidrug resistance

Contraindications

image None of major significance

Side Effects

image Because the antiretrovirals are typically administered in combination regimens, it is difficult to determine the side effects that are associated with a specific class or drug within that class.
image Generally well-tolerated: In controlled trials, raltegravir did not elicit more adverse effects than placebo.

Important Notes

image At present, integrase inhibitors are active against HIV-2.
image During clinical trials, there was a slight, non–statistically significant increase in the incidence of cancer in patients treated with raltegravir versus placebo-treated patients. Although these differences were not statistically significant and raltegravir is not considered to be a carcinogen, rates of cancer are being monitored closely in the postmarketing period.

Advanced

Drug Interactions

image Atazanavir is a UGT1A1 inhibitor, and concomitant administration of raltegravir and atazanavir has been shown to elevate raltegravir levels.
image Rifampin is a strong inducer of UGT1A1; therefore concomitant administration of these two agents can significantly reduce raltegravir levels.

Pregnancy

image As with most antiretrovirals, the safety of integrase inhibitors in pregnancy has not been established.

FYI

image An assay (PhenoSense Integrase Assay) has been developed to measure the susceptibility of HIV-1 to integrase inhibitors.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Description

image Nucleoside reverse transcriptase inhibitors (NRTIs) are agents used in the treatment of HIV infection that inhibit HIV by preventing its transcription.

Prototype and Common Drugs

image Prototype: zidovudine
image Others: didanosine, lamivudine, stavudine, zalcitabine, emtricitabine
image Nucleotide reverse transcriptase inhibitor: tenofovir

MOA (Mechanism of Action)

image Several steps are involved in the replication of HIV. The virus must fuse to the host cell, uncoat, enter and be transcribed by reverse transcriptase, become incorporated into the host genome, and be transcribed to viral RNA, which is then translated into polyproteins.
image Reverse transcriptase is an enzyme that transcribes viral RNA into viral DNA (hence the term reverse).
image Once they have entered the host cell, NRTIs are converted to nucleotides by host cell kinases. These nucleotides then compete with endogenous nucleosides for incorporation into viral DNA in the reaction catalyzed by reverse transcriptase (Figure 18-27).
image NRTIs therefore act as competitive inhibitors of reverse transcriptase. Once they incorporate themselves into DNA, NRTIs cause termination of the DNA chain, in a manner analogous to that seen with the nucleoside analogues such as acyclovir. Chain termination halts the process of viral replication.
image NRTIs also inhibit host cell DNA polymerase, although this likely contributes more to their toxic effects than their efficacy. Inhibition of DNA polymerase in mitochondria leads to depletion of mitochondrial DNA and subsequent depletion of mitochondrial RNA and peptides involved in oxidative phosphorylation. This leads to mitochondrial dysfunction, and this is believed to be the cause of several of the important toxicities associated with drugs of this class.
image Unlike nonnucleoside reverse transcriptase inhibitors (nNRTIs), in which binding to the reverse transcriptase is very specific, NRTIs indirectly inhibit reverse transcriptase and are therefore not specific for HIV-1. nNRTIs act specifically on the HIV-1 strain and lack activity against HIV-2.
image

Figure 18-27 (Modified from Pommier Y, Johnson AA, Marchand C: Integrase inhibitors to treat HIV/AIDS, Nat Rev Drug Discov 4(3):236, 2004. Reprinted by permission from Macmillan Publishers.)

Mechanisms of Resistance

image Mechanisms of resistance include mutations in reverse transcriptase.
image Stavudine, didanosine, and zidovudine have the same resistant mutations.

Pharmacokinetics

image Zidovudine can be given orally or IV, whereas the rest of the NRTIs are available only in oral dosage forms.
image Zidovudine and didanosine are metabolized by the liver, whereas the others rely on the kidneys for their elimination, therefore dose adjustments for these agents should be considered in patients with renal impairment.
image The NRTIs have a short elimination half-life (t1/2); however, their intracellular t1/2 tends to be a lot longer. Early in the history of NRTIs, before a more complete understanding of their pharmacokinetics, this led to overdoses of NRTIs.
image Food also decreases the bioavailability of didanosine, so it should be administered on an empty stomach. Because most protease inhibitors must be taken with food, this complicates the use of these combinations.

Indication

image HIV

image Treatment of infection
image Prevention of transmission from mother to child
image Postexposure prophylaxis

Contraindications

image Avoid in patients with history of pancreatitis or neuropathy: particularly true with didanosine, stavudine, and zalcitabine (see later).

Side Effects

image Myalgia: One of the most common and earliest side effects associated with NRTIs, myalgia was also the first indication of the mitochondrial toxicity that has become associated with these agents. The mitochondrial toxicity is believed to be caused by the inhibition of DNA polymerase by the NRTI.
image Headache
image Diarrhea is most associated with didanosine, likely as a result of the buffers used in oral formulations, some of which contain magnesium, a known laxative.

Serious

image Lactic acidosis: The impairment of mitochondrial function leads to a reliance on anaerobic metabolism, which produces excessive amounts of lactate.
image Lipodystrophy is most associated with stavudine.
image Peripheral neuropathy (didanosine, stavudine, zalcitabine) is likely caused by mitochondrial toxicity. Typically this effect will improve or resolve completely as long as the drug is stopped as soon as the symptoms appear.
image Pancreatitis (didanosine, stavudine, zalcitabine) is a rare but potentially fatal adverse effect, likely caused by mitochondrial toxicity. It is more common with didanosine and particularly common when two of these agents are combined.
image Hepatotoxicity (didanosine, zidovudine) is rare but potentially fatal.
image Bone marrow suppression is likely the result of toxic effects on erythroid stem cells.

Unique

image Hypersensitivity (abacavir), characterized by fever, GI problems including abdominal pain, rash, malaise, and fatigue may occur. If fever, abdominal pain, and rash occur within 6 weeks of initiation of therapy, the drug should be discontinued.
image Acute renal failure (tenofovir) is a rare side effect, and although tenofovir is an antiviral nucleotide like cidofovir and adefovir, it is not believed to share their nephrotoxic effects.
image Stomatitis and oral ulcers (zalcitabine): Zalcitabine may be toxic to rapidly dividing cells, but the mechanism is unclear.

Important Notes

image Lamivudine, emtricitabine, and tenofovir are also active against hepatitis B virus. This presents an opportunity to treat two indications (HIV and hepatitis B) with one drug, but also means that care must be taken when withdrawing these agents from hepatitis B co-infected patients. These patients may experience a rebound and worsening of hepatitis B.
image Lamivudine and abacavir do not share many of the serious mitochondrial toxicities associated with other NRTIs. This is thought to result from the fact that they are weak DNA polymerase inhibitors.
image Antiretrovirals are typically used in combination with one another, referred to as highly active antiretroviral therapy (HAART). The most common combinations are an NRTI with an nNRTI, and an NRTI with a ritonavir-boosted protease inhibitor. Two NRTIs are typically used in these regimens.

Advanced

Pharmacogenetics

image The hypersensitivity reaction to abacavir is more common in those with the HLA-B*5701 allele. This allele is more common in Caucasians and to a lesser extent Hispanics.

Drug Interactions

image Didanosine is easily degraded in an acidic environment and is therefore formulated with buffers such as calcium carbonate and magnesium hydroxide. Agents that bind to divalent cations (e.g., calcium and magnesium) should be administered separately from didanosine. Examples of these agents include fluoroquinolones such as ciprofloxacin. The same is true for agents whose dissolution is pH dependent, such as itraconazole.
image Stavudine and zidovudine compete for intracellular phosphorylation and should not be used in combination with each other.

FYI

image A few NRTIs share the same nomenclature (i.e., end in -vir) as the protease inhibitors.
image Individual antiretrovirals are commonly referred to by three letter or digit acronyms. Aside from the fact that the abbreviation of drug names can lead to dispensing errors, the acronyms typically reflect the chemical rather than the generic name of the drug and are thus very confusing. See examples in Table 18-1.

TABLE 18-1 Origins of the Abbreviations for Various Antiretrovirals

Generic Name Chemical Name Abbreviation
Zidovudine Azidothymidine AZT
Lamivudine 3-Thiacytidine 3TC
Emtricitabine Fluorothiacytidine FTC
Didanosine Dideoxyinosine ddI

Nonnucleoside Reverse Transcriptase Inhibitors (nNRTIs)

Description

nNRTIs, used in the treatment of HIV infection, inhibit HIV by preventing its transcription.

Prototype and Common Drugs

image Prototype: nevirapine
image Others: delavirdine, efavirenz
image Second-generation: etravirine

MOA (Mechanism of Action)

image Several steps are involved in the replication of HIV. The virus must fuse to the host cell, uncoat, enter and be transcribed by reverse transcriptase, become incorporated into the host genome, and be transcribed to viral RNA, which is then translated into polyproteins (Figure 18-28).
image Reverse transcriptase is an enzyme that transcribes viral RNA into viral DNA (hence the term reverse).
image The nNRTIs bind to a site distant from the active site of the reverse transcriptase, and induce a conformational change in the enzyme. This conformational change greatly reduces the activity of the enzyme.
image Unlike the NRTIs, the nNRTIs have no activity against DNA polymerase.
image Also, because the binding of nNRTIs to the reverse transcriptase is very specific, nNRTIs act specifically on the HIV-1 strain and lack activity against HIV-2. Conversely, the NRTIs indirectly inhibit reverse transcriptase and are therefore not specific for HIV-1.
image

Figure 18-28 (Modified from Pommier Y, Johnson AA, Marchand C: Integrase inhibitors to treat HIV/AIDS, Nat Rev Drug Discov 4(3):236, 2004. Reprinted by permission from Macmillan Publishers.)

Mechanisms of Resistance

image Mutations occur in the binding site on the reverse transcriptase.

image A single amino acid change can make the virus resistant to nNRTIs; thus this class as a whole tends to be more susceptible to drug resistance.

Pharmacokinetics

image Nevirapine crosses the placenta and is therefore recommended for prevention of mother-child transmission of HIV.
image The nNRTIs are all metabolized in the liver.
image Because nevirapine is both a substrate and an inducer of CYP3A4, it is able to induce its own metabolism. This means that the dose of nevirapine typically must be adjusted upward after 2 weeks of therapy.
image Optimal absorption of delavirdine is achieved at low pH (<2); thus administration of agents that raise the pH (antacids, proton pump inhibitors, H2 antagonists) may interfere with absorption.

Indication

image HIV-1

image Treatment of infection
image Prevention of transmission from mother to child
image Postexposure prophylaxis

Contraindications

image Pregnancy (efavirenz): Of all the antiretrovirals, efavirenz carries the clearest risk in pregnancy, as it has demonstrated teratogenicity in primates.

Side Effects

image Rash: Macular or papular rash, often pruritic and also self-limiting, may occur with continued drug administration. In a minority of individuals, rash can progress to more serious Stevens-Johnson syndrome.

Serious

image Hepatitis can be severe and fatal; it is more common in female patients, especially during pregnancy. Most cases are the result of a hypersensitivity reaction. Delavirdine has not been associated with fatal hepatitis.
image Neutropenia is a rare effect.

Unique

image CNS (efavirenz): The mechanism has not been established. These side effects are typically transient, resolving after a few hours or up to several weeks.

image Dizziness
image Impaired concentration
image Psychiatric: dysphoria, vivid dreams, psychosis, insomnia

Important Notes

image The nNRTIs do not inhibit DNA polymerase and therefore do not exhibit the same mitochondrial toxicities as the NRTIs. Inhibition of DNA polymerase in mitochondria leads to depletion of mitochondrial DNA and subsequent depletion of mitochondrial RNA and peptides involved in oxidative phosphorylation. This leads to mitochondrial dysfunction, and this is believed to be the cause of several of the important toxicities associated with the NRTIs.
image Etravirine is the first of the second-generation nNRTIs. It was developed through rational drug design, by testing a variety of compounds against known mutations of the HIV-1 reverse transcriptase. This means that etravirine was designed to exhibit minimal cross-resistance with existing nNRTI mutants. However, unique resistant mutations to etravirine have developed.

Combination Therapy

image The nNRTIs as a class are particularly prone to resistance (see MOA for explanation). Therefore it is important that the nNRTIs be given in combination with other antiretrovirals in order to reduce the development of resistance.
image Antiretrovirals are typically used in combination with one another (HAART). The most common combinations are an NRTI with an nNRTI, and an NRTI with a ritonavir-boosted protease inhibitor. Two NRTIs are typically used in these regimens.

Advanced

Drug Interactions

image Many of the nNRTIs are CYP3A4 substrates (nevirapine, delavirdine, efavirenz, and etravirine). Given the number of CYP3A4 inducers and inhibitors, these drugs might be more likely to have their metabolism inhibited or induced by other drugs.
image CYP450 inducers:

image Efavirenz, nevirapine, and etravirine are moderate inducers of CYP3A4.

image CYP450 inhibitors:

image Delavirdine (CYP3A4)
image Etravirine (CYP2C9 and CYP2C19)

FYI

image Efavirenz was the first once-daily drug approved for HIV. Now once-daily formulations are commonplace and are an expectation of new agents.

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