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.

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