Antimicrobial agents

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CHAPTER 14

Antimicrobial agents

Objectives

After reading this chapter, the reader will be able to:

1. Define terms that pertain to antimicrobial agents

2. Define antibiotic

3. Describe the process involved in bacterial susceptibility testing

4. Discuss possible outcomes of antimicrobial combinations

5. List the various classes of the penicillins

6. List the various classes of the cephalosporins

7. Recognize similarities between members of the macrolides

8. Recognize similarities between members of the quinolones

9. List four mechanisms of action of antibacterials

10. List five commonly used antimycobacterials

11. Describe the commonly used azole antifungals and how they differ in spectrum of activity

12. Discuss similarities between members of the echinocandins

13. Describe the mechanism of action of the antiretrovirals

Key terms and definitions

Antagonism 

Antibiotic combination in which the activity of one antibiotic interferes with the activity of the other (block receptor site, enzymatic inactivation), resulting in less activity with the combination than with the individual drugs (i.e., 1 + 1 < 1).

Antibiotics 

Substance derived or produced from a microorganism that inhibits or kills other microorganisms.

Antimicrobials 

Natural and synthetic compounds that either inhibit or kill microorganisms.

Synergy 

The combined effect of two antimicrobials is greater than their added effect (i.e., 1 + 1 > 2).

The antimicrobial properties of fermented beverages, moldy soybean curd, and spices were first described by the Chinese more than 2500 years ago.1 However, dissemination and acceptance of such knowledge did not take root until the early 1900s. The discovery of microscopic “little animals” by van Leeuwenhoek paved the way for Koch to validate that these “little animals,” or germs, caused disease. Before Koch’s work, almost no one believed that germs caused human disease. Despite the discovery of this important relationship, it would take numerous paradigm shifts and incredible luck before the discovery and usage of antimicrobials transpired.2

The sulfanilamides, azo compounds used in the German dye industry, were the first class of agents discovered to have antibacterial activity. These compounds were initially unsuccessful and required multiple modifications to reduce their unpleasant side effects. In 1928, Fleming discovered the first antibiotic, which he named penicillin. Fleming, similar to other scientists of the time, did not realize the utility of penicillin for systemic infections, however. A 1940 publication entitled “Penicillin as a Chemotherapeutic Agent” by Chain and colleagues3 set into motion what we now refer to as the “golden age” of antimicrobial chemotherapy.

The realization that living organisms may produce compounds that kill microbes is a relatively new concept. Since this realization, more than 30 classes of compounds have been identified from natural sources or created synthetically to treat infections resulting from bacteria, fungi, protozoa, and viruses. Techniques to identify organisms and to determine their susceptibility have also evolved over the years and are vital to the choice of the proper antimicrobial agent. In addition, other factors, such as the host, antimicrobial pharmacodynamics, antimicrobial combinations, and methods of monitoring therapy, are important parameters that need consideration before selecting an antimicrobial agent. This chapter focuses on these basic principles of antimicrobial therapy, provides a synopsis of mechanism of action and adverse effects, and emphasizes the clinical use of the various antimicrobial classes for the treatment of respiratory illnesses.1

Principles of antimicrobial therapy

Several factors require careful consideration before choosing a particular antimicrobial agent. Identification of the organism or organisms responsible for the infection is the first step toward treatment. Once the organism is isolated, antimicrobial susceptibility is determined according to standardized methods that can be replicated between laboratories. The susceptibility pattern of the organism narrows the choice of potential agents. Consideration must be given to host factors such as age, pregnancy, organ function, and site of infection. In addition, drug factors, such as available dosage forms, ease of administration, pharmacokinetics, potential adverse events, and cost, influence the choice of a specific agent.4

Identification of pathogen

The first step toward identification of the organism is the collection of potentially infected material for culture. Specimens commonly collected for culture include blood, urine, sputum, cerebrospinal fluid, pleural fluid, synovial fluid, and peritoneal fluid. Several methods are employed to identify the pathogens rapidly, using various chemical stains, immunologic assays, and microscopic examination. The simplest and most common preparation is Gram stain. This stain designates bacteria into two major classes: gram-positive (stain purple) or gram-negative (stain pink). Bacteria stain differently depending on the structural components of their cell wall. These structural components also affect their susceptibility to antimicrobials. Other bacteria, such as Mycobacterium tuberculosis, require the use of an acid-fast stain to penetrate their waxlike cell walls. Mycobacteria require up to 6 weeks for growth on cultures, which makes the acid-fast stain vital for the rapid diagnosis of tuberculosis. Immunologic methods such as enzyme-linked immunosorbent assay (ELISA) and latex agglutination have also been developed to identify pathogens including viruses, molds, certain bacteria, and protozoa.

In many clinical cases, the exact identity of the infecting organism is unknown. As a result, patients are treated empirically with an antimicrobial agent active against the organism or organisms that are most likely causing the infection. For example, 30% to 40% of patients with community-acquired pneumonia (CAP) fail to expectorate sputum, which prevents identification of a specific pathogen. However, research has shown, that the most common pathogens responsible for CAP include Streptococcus pneumoniae; Haemophilus influenzae; and atypical (intracellular) organisms such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. As a result, empiric therapy for CAP involves antimicrobials active against this spectrum of organisms. Conversely, identification of an organism from culture material does not always indicate an infection. For example, hospitalized patients often have growth of gram-negative bacilli (rods) in sputum samples. However, these organisms may represent colonization only, and not hospital-acquired (nosocomial) pneumonia. Common pathogens and treatment of specific respiratory infections are listed in Table 14-1.5

TABLE 14-1

Common Pathogens and Treatment of Respiratory Infections in Adults*

RESPIRATORY INFECTION COMMON PATHOGENS POTENTIAL ANTIBIOTIC REGIMENS
Sinusitis    
Acute (community acquired) Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis Amoxicillin-clavulanate or cefuroxime axetil or respiratory quinolone (levofloxacin or moxifloxacin or gemifloxacin) or macrolide/ketolide or TMP-SMX
Acute (hospital acquired) Pseudomonas aeruginosa, Acinetobacter spp., Staphylococcus aureus Ceftazidime or cefepime or aztreonam or a carbapenem and vancomycin
Chronic Bacteroides spp., Peptostreptococcus spp., Fusobacterium spp. Antibiotics are usually unsuccessful; sinus drainage may be required
Bronchitis    
Acute Mycoplasma pneumoniae, Chlamydia pneumoniae, Bordetella pertussis Antibiotics are usually not indicated; however, doxycycline or macrolide may be considered
Exacerbation of chronic bronchitis S. pneumoniae, H. influenzae, M. catarrhalis Value of antibiotics is controversial; doxycycline or macrolide may be considered
Pneumonia
Community acquired S. pneumoniae, H. influenzae, M. catarrhalis, M. pneumoniae, C. pneumoniae, Legionella pneumophila Azithromycin, clarithromycin, telithromycin, or respiratory quinolone, or doxycycline or β-lactam (ceftriaxone, cefuroxime, amoxicillin-clavulanate) and a macrolide
Hospital acquired (nonneutropenic patient) S. pneumoniae, P. aeruginosa Cefepime, ceftazidime, or aztreonam or a carbapenem or piperacillin-tazobactam ± an aminoglycoside or ciprofloxacin ± vancomycin
Hospital acquired (neutropenic patient) As listed for nonneutropenic patients and fungi such as Aspergillus spp., Pneumocystis carinii (especially if HIV positive) Cefepime, a carbapenem, ceftazidime, or piperacillin-tazobactam + an aminoglycoside or ciprofloxacin ± vancomycin ± amphotericin B ± TMP-SMX
Aspiration suspected S. pneumoniae, Bacteroides fragilis, Peptostreptococcus spp., Fusobacterium spp. Amoxicillin-clavulanate, ampicillin-sulbactam, piperacillin-tazobactam, clindamycin ± quinolone
Patient with cystic fibrosis S. aureus, P. aeruginosa, Burkholderia cepacia Aminoglycoside + piperacillin-tazobactam or ceftazidime, cefepime ± TMP-SMX (B. cepacia)
Empyema    
  Streptococcus milleri, B. fragilis, Enterobacteriaceae, Mycobacterium tuberculosis Piperacillin-tazobactam or third-generation cephalosporin + clindamycin†

image

HIV, Human immunodeficiency virus; TMP-SMX, trimethoprim-sulfamethoxazole.

*The potential treatments listed here are not listed in order of superiority. Choice of antimicrobials depends on the individual susceptibility pattern of the suspected organisms within the specific institution.

†See Table 14-7 for antimycobacterial regimens.

Susceptibility testing and resistance

! KEY POINT

The susceptibility of an organism to an antimicrobial is quantified as the minimal inhibitory concentration (MIC) and the minimal bactericidal concentration (MBC). The science of understanding the optimal effect of an antimicrobial as a function of its concentration to the MIC against the microorganism is known as pharmacodynamics.

Once an organism is isolated, susceptibility test results can usually be obtained within 24 hours. Several methods are commonly used to determine the susceptibility of isolated pathogens. The Kirby-Bauer disk diffusion test involves the use of antibiotic-impregnated disks that are placed on an agar plate heavily inoculated (105 colony-forming units [cfu]/mL) with the isolated bacteria. If the organism is susceptible to the antibiotic, a clear zone of inhibition (no growth of the organism) develops around the disk. The degree of susceptibility or resistance of the organism depends on the diameter of this circular zone of inhibition; that is, a larger diameter indicates greater sensitivity. Another disk diffusion test is the elliptical test, or E-test. The E-test strip is placed on an agar plate heavily inoculated with the isolated organism. The strip creates an antimicrobial gradient, which results in a clear elliptical zone of inhibition. This method allows the determination of the minimal inhibitory concentration (MIC). MIC is defined as the least concentration of antimicrobial that prevents visible growth. The Kirby-Bauer and E-test methods are illustrated in Figure 14-1.

image
Figure 14-1 Disk diffusion test and E-test methods.

Other methods include inoculation of the organism into serial dilutions of an antimicrobial in agar or, more commonly, in broth culture media (Figure 14-2). Automated systems such as Vitek (bioMérieux, Durham, N.C.) and MicroScan (Dade Behring, West Sacramento, Calif.) take advantage of broth microdilution methods to provide efficient and rapid susceptibility results. When susceptibility testing is performed in broth media, a small sample can be removed from the test tubes or microwells with no growth and used to inoculate agar plates. The lowest concentration of antimicrobial agent that prevents growth of the organism on the agar plate after a 24-hour incubation is termed the minimal bactericidal concentration (MBC). Drugs that inhibit the growth of bacteria but do not kill them are termed bacteriostatic. A bactericidal drug is one that kills the bacteria. Examples of bacteriostatic and bactericidal drugs are listed in Box 14-1.

BOX 14-1   Examples of Bactericidal/Fungicidal and Bacteriostatic/Fungistatic Antimicrobials

“Cidal”

*Agents that are bactericidal against Staphylococcus aureus but bacteriostatic against Enterococcus species.

image
Figure 14-2 Minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) by broth macrodilution.

Susceptibility testing is a crucial part of antimicrobial therapy because the empiric regimen may fail when used to treat infections with resistant organisms. Microorganisms, similar to all living things, have genetic variability that affects their susceptibility to antimicrobials. Selective pressure from extensive clinical and agricultural use of antibiotics is thought to play a primary role in the emergence of resistant bacteria. Mechanisms of bacterial resistance include the production of enzymes that degrade or modify antibiotics, alteration of bacterial cell walls or membranes, upregulation of antimicrobial efflux pumps, and alteration of the site of antimicrobial action. Table 14-2 lists important emerging resistant bacteria.4

Gram negative

image

ESBL, Extended-spectrum β-lactamase; MDR, multidrug-resistant; MRSA, methicillin-resistant Staphylococcus aureus; VISA, vancomycin-intermediate S. aureus; VRE, vancomycin-resistant Enterococcus; VRSA, vancomycin-resistant S. aureus.

Host factors

! KEY POINT

The outcome of antimicrobial therapy depends on host factors, susceptibility or resistance to the antimicrobial, and pharmacodynamics.

The safety and efficacy of an antimicrobial agent vary, based on the population of patients being treated.5 For example, bone marrow transplant recipients with an active infection may not improve despite use of the ideal antimicrobial agent because of their impaired immune function. Similarly, other immunocompromised hosts, such as patients with acquired immunodeficiency syndrome (AIDS), recipients of cancer chemotherapy or steroids, and solid organ transplant recipients, are also at risk of failing to improve on antimicrobial therapy. Other factors such as the altered pharmacokinetics of an antimicrobial can affect response to therapy. For example, the absorption of certain antimicrobials such as itraconazole (an antifungal agent) is increased in the presence of gastric acid; others, such as penicillin G, are degraded in the presence of acid. The pH of the stomach varies with age; older patients tend to have achlorhydria, and young children tend to have a higher gastric pH. As a result, these two populations may have enhanced absorption of penicillin and decreased absorption of itraconazole relative to the rest of the population.

The function of the liver and the kidney also changes with age. These two organs play a major role in the metabolism and elimination of drugs from the body. Premature and newborn infants have diminished renal function at birth. Drugs such as β-lactams and aminoglycosides that are eliminated unchanged in the urine require less frequent dosing because of their reduced clearance. Similarly, renal function declines with age, necessitating dosage reductions in elderly patients to prevent potential toxicities from antimicrobial accumulation.

Prevention of toxicity to the fetus or infant while treating a pregnant or nursing mother is also a crucial consideration. Generally, most β-lactams and macrolides seem to be safe in pregnancy. The teratogenic potential of most other antimicrobials is unknown. However, the tetracyclines have been shown to affect fetal dentition and to affect pregnant women adversely. Antimicrobials are often eliminated in breast milk and so have the potential to affect nursing infants adversely. For example, premature infants are often jaundiced at birth because they are unable to conjugate and eliminate bilirubin efficiently. Even a small dose of sulfonamides ingested through breast milk from a treated mother can displace the albumin-bound bilirubin and predispose the infant to kernicterus. Kernicterus is marked by a pattern of cerebral palsy with uncoordinated movements, deafness, disturbed vision, and speech difficulties resulting from deposition of bilirubin in the developing brain.

Antimicrobials concentrate in varying degrees within organ systems and can influence the outcome of therapy. Clindamycin achieves excellent bone concentrations and is very useful for treatment of osteomyelitis resulting from susceptible organisms. Similarly, drugs such as the aminoglycosides, most fluoroquinolones, and penicillins achieve very high concentrations in the urine and are useful for the treatment of urinary tract infections (UTIs). Conversely, certain drugs, although active against the organism in vitro, cannot achieve adequate concentrations at the site of infection. For example, aminoglycosides cannot penetrate the blood-brain barrier to treat meningitis adequately in adults. The blood-brain barrier represents tight junctions between the epithelial cells of the capillary wall that prevent drugs from entering the central nervous system.4

Pharmacodynamics

Pharmacodynamics refers to the science of understanding the optimal effect of a drug as a function of its concentration and the in vitro activity (MIC) against an organism. The pharmacodynamic properties of an antimicrobial are measured in vitro by using time-kill studies. These studies measure the rate and extent of microorganism killing when exposed to varying concentrations of antimicrobials. If the microbial kill rate increases proportionally with drug concentration, the antimicrobial is said to have a concentration-dependent effect. If the microbial kill rate is influenced by the time of drug concentration above the MIC, the antimicrobial is defined as time-dependent (or concentration-independent). Another pharmacodynamic phenomenon exhibited by antimicrobials is known as the postantibiotic effect (PAE). The PAE refers to the sustained suppression of bacterial growth even after the concentration of the antibiotic declines below detectable levels. The length of the PAE varies by the type of organism and the drug. Generally, time-dependent drugs, such as β-lactams, have short PAEs, whereas concentration-dependent drugs, such as aminoglycosides, metronidazole, and quinolones, have longer PAEs. Agents with a short PAE should be dosed frequently, and longer dosing intervals should be used for antimicrobials having a long PAE. These pharmacodynamic properties have been shown in vitro and in numerous animal studies. Clinical trials validating these principles are ongoing, and practical guidelines to incorporate pharmacodynamics in clinical practice are under study.4

Antimicrobial combinations

Empiric regimens must often cover a broad spectrum of organisms, which occasionally requires the use of two or more classes of antimicrobials. Ideally, the regimen should be narrowed after the specific organism has been isolated and susceptibilities are determined. Certain infections are polymicrobial, and in certain settings the use of antimicrobial combinations is justified. When antimicrobials are used in combination, it is important to know whether these agents act synergistically or are antagonistic. Synergy is shown in vitro when the combined effect of two antimicrobials is greater than their added effect (i.e., 1 + 1 > 2). Antagonism occurs when the effect of the combined drug is lower than the effect expected from either agent alone (i.e., 1 + 1 < 1). Antagonism may result in an unfavorable response, and such drug combinations should be avoided. A classic example of antagonism was the use of tetracycline and penicillin in children with pneumococcal meningitis. The mortality associated with the use of combination therapy was three times higher than the use of penicillin alone. Conversely, synergistic combinations have played a vital role in the treatment of resistant Pseudomonas infections in patients with cystic fibrosis. These patients have recurrent bouts of pseudomonal pneumonia and are often colonized with resistant species. Certain synergistic combinations of β-lactams and aminoglycosides have been shown to curb the development of resistance and to improve outcomes.4

Monitoring response to therapy

! KEY POINT

Treatment failure may manifest as continued fever spikes, elevated white blood cell count (WBC), repeated positive cultures, and nonresolution of symptoms.

Certain laboratory parameters can be monitored to assess the efficacy of an antimicrobial regimen, but ultimately the clinical assessment of the patient is the best measure of response to therapy. Treatment failure may manifest as continued fever spikes, elevated white blood cell count (WBC), repeated positive cultures, or nonresolution of symptoms. The reasons for failure can be multifactorial and require consideration of all the aforementioned factors. In addition, noncompliance with the treatment regimen can play a significant role in treatment failure.

The use of antimicrobials can be associated with significant toxicities. The agent amphotericin B, which is used to treat fungal infections such as pulmonary aspergillosis, can cause significant renal dysfunction. Similarly, other agents can have adverse effects on the liver, gastrointestinal tract, neuromuscular system, hematologic system, heart, and lungs. The incidence of these adverse events varies among agents and is often reversible. Careful monitoring of patients receiving antimicrobials can prevent serious and potentially life-threatening adverse events.4

Antibiotics

Numerous antibiotics, a substance inhibiting or killing other microorganisms, have been discovered and developed over the last 50 years. A synopsis of the mechanism of action, clinical uses, and adverse reactions of each class is described in the following sections.

Penicillins

! KEY POINT

The β-lactams are a large class of antibiotics that includes penicillins, cephalosporins, carbapenems, and monobactams (aztreonam).

The discovery of penicillin in 1928 by Fleming ultimately led to the creation of a broad class of antibiotics commonly referred to as β-lactams. β-lactam antibiotics include the penicillins, cephalosporins, monobactams, and carbapenems.6 The main constituent of these antibiotics is the β-lactam ring structure. Chemical manipulation of β-lactam side chains led to the development of new agents with enhanced spectra of antimicrobial activity compared with penicillin. Specific side-chain modifications of penicillin have resulted in a broad class that includes the natural penicillins, aminopenicillins, penicillinase-resistant penicillins, carboxypenicillins, and ureidopenicillins (Table 14-3). Penicillins have also been combined with β-lactamase inhibitors to overcome a common mechanism of bacterial resistance.

TABLE 14-3

Classification and Clinical Uses of Penicillins

β-LACTAM CLASS (GENERIC NAME) BRAND NAME ROUTE COMMON USES (MICROORGANISM)
Natural Penicillins
Penicillin G (potassium) Pfizerpen IM, IV Streptococcus pyogenes, Neisseria meningitidis, Bacillus anthracis (anthrax), Clostridium perfringens (gangrene), Pasteurella multocida, Treponema pallidum (syphilis)
Penicillin G (procaine) Wycillin IM
Penicillin G (benzathine) Bicillin L-A IM
Penicillin V (potassium) Pen-Vee K PO
Penicillinase-Resistant Penicillins
Oxacillin Prostaphlin PO, IM, IV MSSA, MSSE
Nafcillin Unipen PO  
Dicloxacillin Dynapen PO  
Aminopenicillins      
Ampicillin Omnipen PO, IM, IV Listeria monocytogenes, Proteus mirabilis, Eikenella corrodens, Borrelia burgdorferi
Amoxicillin Amoxil, Wymox PO  
Carboxypenicillins      
Carbenicillin Geopen PO, IM, IV Pseudomonas aeruginosa, Enterobacteriaceae
Ticarcillin Ticar IV, IM  
Ureidopenicillins      
Piperacillin Pipracil IM, IV P. aeruginosa, Enterobacteriaceae
Penicillin plus β-lactamase Inhibitors
Amoxicillin–clavulanic acid
Ampicillin-sulbactam		 Augmentin
Unasyn		 PO
IM, IV		 Increased activity against β-lactamase–producing strains S. aureus, Haemophilus influenzae, Moraxella catarrhalis, Proteus spp., Bacteroides spp.
Ticarcillin–clavulanic acid Timentin IV P. aeruginosa, Enterobacteriaceae
Piperacillin-tazobactam Zosyn IV  

image

IM, Intramuscular; IV, intravenous; MSSA, methicillin-sensitive Staphylococcus aureus; MSSE, methicillin-sensitive Staphylococcus epidermidis; PO, oral.

The penicillins generally are widely distributed throughout the body and are associated with relatively low levels of toxicity. Most penicillins are acid-labile (destroyed in the stomach) and therefore are poorly absorbed after oral administration. Most agents in this class are not metabolized but are excreted unchanged in the urine. Therefore, most penicillins require reductions in dosage for patients with renal dysfunction.7

Clinical uses

Natural penicillins.

Benzylpenicillin (penicillin G) is the parent compound of this class. This agent may be administered by the parenteral (intravenous [IV]) or intramuscular (IM) route. Penicillin G procaine is used for intramuscular dosing only and provides a less painful alternative when sustained serum concentrations are required. Phenoxymethyl penicillin (penicillin V) resists degradation by gastric acid and can be administered orally (PO). Natural penicillins are effective primarily against gram-positive bacteria and anaerobes. Penicillin G is the drug of choice for the treatment of primary and secondary syphilis (Treponema pallidum) and pharyngitis caused by group A streptococci (Streptococcus pyogenes). Because of the increasing frequency of resistance in Staphylococcus aureus, S. pneumoniae, and Neisseria gonorrhoeae, penicillin G should no longer be considered the agent of choice for infections caused by these organisms.7

Penicillinase-resistant penicillins.

In an attempt to overcome the emergence of penicillinase-producing (β-lactamase–producing) staphylococci, semisynthetic penicillinase-resistant antibiotics were developed. These agents are commonly referred to as antistaphylococcal agents because of their excellent activity against S. aureus. Methicillin was the first agent in this class of antibiotics, followed by oxacillin, nafcillin, cloxacillin, and dicloxacillin. Chemical modification of penicillin by the addition of an acyl side chain prevents hydrolysis of the agents in the presence of penicillinase. This class has activity against gram-positive cocci (staphylococci and streptococci) and is routinely used in skin and soft tissue infections. These agents are ineffective in the treatment of infections caused by gram-negative organisms or anaerobes. Until the 1980s, these antibiotics were the mainstay of treatment against staphylococci. However, the emergence of methicillin-resistant staphylococci has greatly reduced the clinical effectiveness of these agents.7

Carboxypenicillins.

With the emergence of more resistant gram-negative bacilli, penicillins with increased gram-negative activity were needed. Carbenicillin was the first penicillin to have activity against Pseudomonas aeruginosa. It was also active against most members of the family Enterobacteriaceae, including E. coli, Enterobacter, Proteus, Morganella, and Serratia. Subsequent modification of carbenicillin resulted in ticarcillin, which has even greater in vitro activity against P. aeruginosa and members of Enterobacteriaceae (including Klebsiella). Neither of these agents is considered to have appreciable activity against gram-positive organisms (staphylococci or streptococci). These agents are administered primarily in the intravenous form because high serum concentrations cannot be achieved with the oral formulations.7

Adverse reactions and precautions

The most common adverse reaction to penicillins is hypersensitivity. Approximately 3% to 10% of the population are allergic to penicillin. Reactions vary in severity from a mild rash to life-threatening anaphylaxis. Patients allergic to a penicillin could be potentially allergic to all classes of β-lactams (cephalosporins, carbapenems). In addition to allergic reactions, hematologic reactions such as thrombocytopenia and increased bleeding times have been reported. Hematologic disturbances are thought to be greater with carboxypenicillins than with ureidopenicillins. Gastrointestinal disturbances (nausea, vomiting, and diarrhea) are more common with oral dosage forms of penicillins, especially ampicillin. Interstitial nephritis has occurred most commonly with methicillin (not commercially available) but may occur with other penicillins as well. Central nervous system toxicities (i.e., seizures) have been reported with penicillins. Patients with an underlying seizure disorder and patients with renal insufficiency are at greatest risk for developing this complication.7

Cephalosporins

! KEY POINT

Cephalosporins have been loosely grouped into “generations” based on their spectrum of activities. At present, there are four generations (classes) of cephalosporins.

The cephalosporins include a large group of antimicrobials that are structurally related to the penicillins. Discovered in the 1940s as a microbial by-product of the fungus Cephalosporium acremonium, this class is now widely used in clinical practice. Similar to the penicillins, this class exhibits bactericidal activity, is distributed throughout the body, and produces relatively few adverse effects. Cephalosporins are used for various clinical indications and are available in oral and intravenous formulations (Table 14-4). Agents from this class have been loosely grouped into “generations” based on their spectrum of activities. At present there are four generations (classes) of cephalosporins.

TABLE 14-4

Classification and Clinical Uses of Cephalosporins

CEPHALOSPORIN (GENERIC NAME) BRAND NAME ROUTE COMMON USES (MICROORGANISM)
First Generation      
Cefadroxil Duricef PO MSSA, streptococci
Cephalexin Keflex, Biocef PO  
Cefazolin Ancef, Kefzol IM, IV  
Second Generation      
Cefaclor Ceclor PO MSSA, MSSE, Streptococcus pneumoniae, Klebsiella spp., Escherichia coli, Proteus spp., Haemophilus influenzae
Cefprozil Cefzil PO
Cefuroxime axetil Ceftin PO
Cefuroxime Zinacef, Kefurox IM, IV
Cefotetan Cefotan IM, IV As above and Bacteroides fragilis
Cefoxitin Mefoxin IM, IV  
Third Generation      
Cefixime
Cefpodoxime proxetil		 Suprax
Vantin		 PO
PO		 Better activity than second-generation cephalosporins against Klebsiella, E. coli, Proteus spp., H. influenzae, Enterobacter spp.
Ceftibuten Cedax PO
Cefdinir Omnicef PO
Cefotaxime Claforan IM, IV
Ceftriaxone Rocephin IM, IV
Ceftizoxime Cefizox IM, IV
Ceftazidime Fortaz, Tazidime IM, IV As above and P. aeruginosa
Cefoperazone Cefobid IM, IV  
Fourth Generation      
Cefepime Maxipime IM, IV MSSA, S. pneumoniae, Klebsiella, E. coli, Proteus spp., H. influenzae, P. aeruginosa, Enterobacter spp.

image

IM, Intramuscular; IV, intravenous; MSSA, methicillin-sensitive Staphylococcus aureus; MSSE, methicillin-sensitive Staphylococcus epidermidis; PO, oral.

Clinical uses

As a class, cephalosporins are active against a wide variety of organisms. Because of their broad spectrum of activity and low level of toxicity, these agents are commonly used for a wide variety of infections. The spectrum of activity differs for each cephalosporin generation. All cephalosporins are ineffective against enterococci.9

First-generation cephalosporins.

The first-generation cephalosporin agents are very active against a wide variety of gram-positive organisms, including methicillin-sensitive S. aureus (MSSA) and streptococci. They have moderate activity against community-acquired, gram-negative organisms such as E. coli, Klebsiella pneumoniae, H. influenzae, M. catarrhalis, and some Proteus species. They are also considered effective against many oral anaerobes (e.g., Peptostreptococcus). Commonly used agents within this class are cephalexin, cefazolin, and cefadroxil. These agents are not active against Bacteroides fragilis, P. aeruginosa, and most members of Enterobacteriaceae. Generally, first-generation cephalosporins are appropriate for treatment of infections of skin and soft tissue, uncomplicated community-acquired UTIs, streptococcal pharyngitis, and surgical prophylaxis.

Second-generation cephalosporins.

Second-generation cephalosporins comprise two groups: true cephalosporins and synthetic cephamycins. Cefuroxime and cefaclor are among the more widely used true cephalosporins. In contrast to first-generation cephalosporins, these agents display enhanced gram-negative activity while maintaining comparable gram-positive activity. This group provides improved activity against H. influenzae, M. catarrhalis, Neisseria meningitidis, N. gonorrhoeae, and some members of Enterobacteriaceae. These agents are considered effective in treating CAP, otitis media, pharyngitis, skin and soft tissue infections, and uncomplicated UTIs.

Cephamycins, consisting of cefotetan and cefoxitin, have enhanced activity against gram-negative members of Enterobacteriaceae and anaerobic activity against many Bacteroides species. They are not considered effective against gram-positive organisms such as staphylococci and streptococci. Cephamycins are also useful in the treatment of intraabdominal, pelvic, and gynecologic infections; decubitus ulcers; diabetic foot; and mixed aerobic-anaerobic soft tissue infections.

Third-generation cephalosporins.

Commonly used third-generation cephalosporins are cefixime, cefpodoxime, ceftibuten, cefoperazone, cefotaxime, ceftazidime, ceftriaxone, and ceftizoxime. These agents are active against most gram-negative organisms. However, only ceftazidime and to a lesser extent cefoperazone have activity against P. aeruginosa. Third-generation cephalosporins show excellent activity against S. pneumoniae, S. pyogenes, H. influenzae, N. meningitidis, N. gonorrhoeae, and M. catarrhalis. Although activity varies with individual agents, this group is not considered to have significant activity against anaerobes. Ceftriaxone, cefotaxime, and to a lesser extent ceftizoxime achieve clinically significant concentrations within the meninges, making them ideal agents for the treatment of meningitis. In addition, ceftriaxone has replaced penicillin as the agent of choice in treating all forms of gonococcal (N. gonorrhoeae) infection because of the increased prevalence of β-lactamase–producing strains. Third-generation cephalosporins are commonly used to treat nosocomial pneumonia, bacteremia, UTIs, osteomyelitis, and soft tissue infections.

Adverse reactions and precautions

Similar to penicillins, the cephalosporins as a group are well tolerated. Hypersensitivity reactions occur in 1% to 3% of patients, with cross-reactivity of cephalosporins in patients with penicillin allergy ranging from 5% to 15%. Generally, patients with a penicillin allergy (limited to a rash) may be challenged with a cephalosporin. Cephalosporin use is contraindicated, however, in patients with a history of anaphylaxis to β-lactams.10 Desensitization should be performed if no therapeutic alternative exists for the use of a cephalosporin. Oral cephalosporins have been associated with minor gastrointestinal complaints such as nausea, vomiting, and diarrhea. Hypoprothrombinemia has been reported, especially with agents (cefotetan and cefoperazone) with a methylthiotetrazole (MTT) side chain. The MTT side chain may also induce a disulfiram-like reaction in patients who concurrently ingest alcohol (disulfiram inhibits the metabolism of alcohol). The symptoms of this uncomfortable reaction include flushing, nausea, thirst, palpitations, chest pain, vertigo, and death in some cases. Most cephalosporins are eliminated through the kidneys and require dosage adjustment in the presence of renal insufficiency.11

Carbapenems

The carbapenems are the newest class of β-lactam antibiotics. At present, four carbapenems—imipenem-cilastatin, meropenem, doripenem, and ertapenem—are available for use in the United States. Cilastatin is used to inhibit the metabolism of imipenem within the kidney to prolong the half-life of this agent. Carbapenems are broad-spectrum antibiotics, displaying activity against a wide variety of gram-positive, gram-negative, and anaerobic bacteria.12

Clinical uses

Imipenem, meropenem, and doripenem all are active against P. aeruginosa, multidrug-resistant (MDR) gram-negative bacilli, and most anaerobes. Ertapenem differs from other carbapenems in that it possesses no activity against P. aeruginosa.13 All four carbapenems have activity against gram-positive organisms such as MSSA and Streptococcus species, including pneumococci (S. pneumoniae). Imipenem, meropenem, and doripenem have been used clinically for empiric treatment of bacteremia and sepsis, community-acquired and nosocomial pneumonia, skin and skin structure infections, complicated UTIs, intraabdominal infections, obstetric and gynecologic infections, osteomyelitis, and infections in patients with cancer and neutropenia. Because ertapenem is ineffective against P. aeruginosa, it should not be used in the treatment of nosocomial pneumonia, neutropenic fever, or any other infection in which P. aeruginosa is a likely pathogen.13 Because of their excellent in vitro activity and broad spectrum of coverage, these agents are often reserved to treat infections that are caused by bacteria resistant to most other agents.

Monobactams (aztreonam)

Aztreonam is a synthetic monocyclic β-lactam antibiotic. It is the only commercially available agent belonging to the class of antibiotics known as the monobactams.14

Aminoglycosides

Streptomycin was discovered in 1943 and was the first antimicrobial agent available to treat tuberculosis. Numerous other aminoglycosides have been developed since and include gentamicin, tobramycin, netilmicin, and amikacin. These agents are used for gram-negative infections, including infections caused by P. aeruginosa. These antimicrobials have poor gastrointestinal absorption and require parenteral administration.15 Table 14-5 lists aminoglycosides and their clinical uses.

TABLE 14-5

Clinical Uses of Aminoglycosides*

GENERIC NAME (TRADE NAME) BRAND NAME MOST COMMON CLINICAL USES
Streptomycin   Brucellosis, tuberculosis, endocarditis caused by gentamicin-resistant enterococci
Gentamicin Garamycin Nosocomial Enterobacteriaceae and Pseudomonas aeruginosa infections, tularemia, brucellosis; endocarditis caused by susceptible enterococci or viridans streptococci, Staphylococcus aureus, Corynebacterium spp., penicillin-susceptible Streptococcus
Tobramycin Nebcin
Amikacin Amikin Similar to gentamicin and tobramycin but useful against Acinetobacter spp., Nocardia spp., Mycobacterium avium-intracellulare, Mycobacterium chelonae, Mycobacterium fortuitum
Neomycin Neosporin Prevention of wound infections, preoperative gastrointestinal sterilization
Netilmicin Netromycin Similar to gentamicin and tobramycin
Paromomycin Humatin Intestinal amebiasis, tapeworm infestation, Cryptosporidium diarrhea

image

*The aminoglycosides (most commonly gentamicin and tobramycin) are used to treat infections caused by gram-negative bacteria.

Clinical uses

Gentamicin, tobramycin, and amikacin all have been used for nosocomial gram-negative infections, such as ventilator-associated pneumonias. However, aminoglycosides do not achieve high concentrations in bronchial secretions when administered systemically; this is thought to be particularly problematic for patients infected with resistant gram-negative organisms. As a result, aminoglycosides (particularly tobramycin and now amikacin) have been administered by inhalation to control P. aeruginosa infections in patients with cystic fibrosis (see Chapter 13). Amikacin is currently more expensive and is generally reserved for organisms resistant to other aminoglycosides. Aminoglycosides are used synergistically with β-lactams when treating endocarditis caused by Streptococcus species and Enterococcus species. Aminoglycosides are also used extensively to treat intraabdominal infections. Streptomycin is used in combination with other antitubercular antimicrobials, especially for MDR tuberculosis.

Adverse reactions and precautions

! KEY POINT

Primary toxicities associated with the use of aminoglycosides are nephrotoxicity and ototoxicity.

The primary toxicities associated with the use of aminoglycosides are nephrotoxicity and ototoxicity. Nephrotoxicity usually develops after at least 5 to 7 days of therapy and occurs more commonly in patients with hypotension, liver disease, advanced age, and coadministration of other nephrotoxic agents. Ototoxicity (both cochlear toxicity and vestibular toxicity) may be irreversible because significant damage must occur before it can be detected. The most common symptoms associated with the development of cochlear toxicity include tinnitus (ringing in the ears); vestibular toxicity manifests as dizziness and nausea. Another serious but rare toxicity is neuromuscular blockade associated with peritoneal irrigation and rapid high-dose aminoglycoside use. Underlying conditions such as myasthenia gravis or concomitant use of neuromuscular blockers may potentiate this side effect, requiring supportive measures such as intubation and possible ventilation support.17

Tetracyclines

! KEY POINT

Tetracyclines are broad-spectrum antibiotics with activity against gram-positive and gram-negative microorganisms and many rickettsiae, chlamydiae, mycoplasmas, spirochetes, protozoa, and mycobacteria.

Tetracyclines are broad-spectrum antibiotics with activity against gram-positive and gram-negative microorganisms and many rickettsiae, chlamydiae, mycoplasmas, spirochetes, protozoa, and mycobacteria. The most commonly used agent in this class is doxycycline because it can be administered twice daily and is relatively inexpensive. Other available tetracyclines include minocycline and tetracycline. The agents are available in oral and parenteral formulations.18

Adverse reactions and precautions

Gastrointestinal symptoms such as nausea, vomiting, and diarrhea are the most common side effects associated with tetracyclines. Tetracyclines bind to growing bone and can temporarily inhibit their growth. Because of the latter side effect, use of tetracyclines is contraindicated in women during pregnancy and when breastfeeding and in children younger than 8 years of age. Tetracyclines bind to divalent and trivalent cations (calcium, magnesium, aluminum, and iron), which decrease their gastrointestinal absorption when given with antacids, iron supplements, and dairy products. Avoiding the coadministration of tetracyclines with these agents by 1 to 2 hours can prevent this interaction. The prolonged use of minocycline has been associated with vestibular side effects, a blue-black oral pigmentation, and lupus-like symptoms.

Tigecycline

Tigecycline, a glycylcycline antibiotic, is similar in structure to tetracycline antibiotics. Because of substitution of a central four-ring carbocyclic nucleus, tigecycline has a greater spectrum of activity than tetracyclines. Tigecycline is active against most gram-positive bacteria, including S. pneumoniae, vancomycin-susceptible enterococci, vancomycin-resistant enterococci, coagulase-negative staphylococci, MSSA, and methicillin-resistant S. aureus (MRSA). Tigecycline also has activity against most gram-negative bacteria, including H. influenzae, M. catarrhalis, most members of the Enterobacteriaceae family (including extended-spectrum β-lactamase [ESBL]–producing organisms), and Acinetobacter species. It is also active against many anaerobic bacteria. However, tigecycline is not active against P. aeruginosa and Proteus species.19

Macrolides

! KEY POINT

Macrolides exhibit activity against gram-positive bacteria (streptococci, methicillin-sensitive Staphylococcus aureus [MSSA]), gram-negative bacteria (Haemophilus influenzae and Moraxella catarrhalis), and atypical bacteria (mycoplasmas, rickettsiae, Legionella, and Chlamydia).

Erythromycin was introduced in 1952 and was the first agent of this class to be used for infections with atypical organisms and for infections in patients intolerant to penicillin G. Early work with erythromycin involved production of various salt derivatives to improve its gastrointestinal tolerability and absorption. In the last decade, clarithromycin and azithromycin (an azalide) have been introduced. Macrolides exhibit activity against gram-positive bacteria (streptococci, MSSA), gram-negative bacteria (H. influenzae, M. catarrhalis), and atypical bacteria (mycoplasmas, rickettsiae, Legionella, and Chlamydia). Clarithromycin and azithromycin are also active against Mycobacterium avium and other mycobacterial species.21

Clinical uses

Macrolides are considered the drug of choice for the treatment of pneumonia caused by the atypical pathogens C. pneumoniae, M. pneumoniae, and L. pneumophila. Macrolides are considered a safer alternative to tetracyclines for the treatment of chlamydial (C. trachomatis) pelvic infections in pregnant women. Clarithromycin is the preferred agent in combination with ethambutol or rifabutin for the treatment of M. avium complex (MAC) in patients with human immunodeficiency virus (HIV) infection. Azithromycin has a superior pharmacokinetic profile compared with the latter agents because it maintains prolonged intracellular concentrations (long half-life). As a result, azithromycin can be administered once weekly for prophylaxis of MAC in patients with HIV, whereas clarithromycin must be administered twice daily. Similarly, 3-day and 5-day regimens of azithromycin have been found to be as effective as a 10-day regimen of erythromycin for the treatment of CAP.

Adverse reactions and precautions

! KEY POINT

Clinically significant drug interactions may occur with erythromycin and clarithromycin and other drugs metabolized by the same hepatic enzymes, resulting in potentially life-threatening complications (i.e., arrhythmias and seizures with high serum concentrations of theophylline, bleeding with high concentrations of warfarin).

Clarithromycin and azithromycin are generally better tolerated than erythromycin. The most common adverse reactions of macrolides include gastrointestinal complaints such as nausea, vomiting, abdominal cramps, and diarrhea (30% of patients taking erythromycin). The use of intravenous erythromycin is associated with thrombophlebitis. Ventricular tachycardia and Q–T interval prolongation have been reported with the use of the macrolides. Erythromycin and clarithromycin are potent inhibitors of the hepatic drug metabolism system known as the cytochrome P450 (CYP) system. As a result, erythromycin and clarithromycin can increase the systemic concentrations of drugs metabolized through the CYP system. For drugs with narrow therapeutic indices, such as theophylline, warfarin, and triazolam, this interaction can lead to potential life-threatening complications. Abnormalities in liver function, tinnitus, dizziness, and reversible hearing loss also have been associated with the use of macrolides.22

Telithromycin

Telithromycin is the first member of the ketolide group of antimicrobials, which are structurally related to the macrolide antibiotics. It has good antimicrobial activity against respiratory pathogens typically responsible for CAP, such as S. pneumoniae, H. influenzae, M. pneumoniae, C. pneumoniae, L. pneumophila, and M. catarrhalis. Telithromycin has improved acid stability compared with erythromycin and therefore has good oral absorption.23

Clinical uses

At present, telithromycin is indicated for the treatment of acute exacerbation of chronic bronchitis (AECB), acute bacterial sinusitis, and CAP. For AECB and acute bacterial sinusitis, a 5-day course of telithromycin was shown to have comparable efficacy to comparator agents (amoxicillin-clavulanate, cefuroxime, or clarithromycin). Longer courses of telithromycin (7 to 10 days) are required for treatment of CAP. It is not currently approved for the treatment of streptococcal pharyngitis; however, it has been shown to be equally as effective as clarithromycin or penicillin V. Telithromycin may serve as an alternative agent for patients at risk of infection with penicillin-resistant or macrolide-resistant S. pneumoniae.23 It is also an alternative treatment in patients with penicillin allergies. Telithromycin is available only in oral formulation and is typically dosed as 800 mg daily.

Adverse reactions and precautions

Telithromycin is generally well tolerated, with most side effects being mild to moderate. The most commonly occurring adverse effects were gastrointestinal, with nausea and diarrhea occurring in 7% to 13% of patients. Visual disturbances (blurred vision, difficulty focusing, and diplopia) were reported in slightly more than 1% of patients. These effects often occurred after the first or second dose and resolved on discontinuation of the medication. Telithromycin has the potential to prolong the Q–T interval; however, clinical trials to date have not reported a significant incidence. Telithromycin is a competitive inhibitor of certain CYP enzymes including 3A4 and 2D6. Care should be exercised when administering other medications metabolized through these pathways.

Quinolones (fluoroquinolones)

The quinolones, also known as fluoroquinolones (Table 14-6), are a semisynthetic group of antimicrobials structurally related to nalidixic acid (quinolone), one of the by-products of chloroquine synthesis. They are widely distributed into most body fluids and tissues (achieving high respiratory tract concentrations). Quinolones are eliminated primarily through the kidneys and achieve high concentrations in the urine. Agents from this class have variable activity against gram-negative bacteria, gram-positive bacteria, anaerobes, atypical bacteria, and mycobacteria.24 Ciprofloxacin, levofloxacin, and moxifloxacin are the most commonly used fluoroquinolones in the United States. Gatifloxacin was removed from the market in 2006 because of the high incidence of diabetes and other blood glucose irregularities.

TABLE 14-6

Classification and Clinical Uses of Quinolones

GENERIC NAME BRAND NAME ROUTE COMMON USES (MICROORGANISM)
Ciprofloxacin Cipro IV, PO Pseudomonas aeruginosa, Enterobacteriaceae, Neisseria gonorrhoeae, Mycoplasma pneumoniae, Legionella pneumophila
Ofloxacin Oflox IV, PO P. aeruginosa, Enterobacteriaceae, N. gonorrhoeae, M. pneumoniae, Chlamydia pneumoniae, L. pneumophila
Levofloxacin Levaquin IV, PO P. aeruginosa, Enterobacteriaceae, S. pyogenes, MSSA, Haemophilus influenzae, Moraxella catarrhalis, penicillin-resistant Streptococcus pneumoniae, M. pneumoniae, C. pneumoniae, L. pneumophila
Moxifloxacin Avelox PO Enterobacteriaceae, S. pyogenes, MSSA, H. influenzae, M. catarrhalis, penicillin-resistant S. pneumoniae, M. pneumoniae, C. pneumoniae, L. pneumophila
Gemifloxacin Factive PO H. influenzae, C. pneumoniae, Klebsiella pneumoniae, S. pneumoniae, M. catarrhalis, M. pneumoniae, L. pneumophila, S. pyogenes, S. aureus, Klebsiella oxytoca
Trovafloxacin Trovan IV, PO Enterobacteriaceae, S. pyogenes, MSSA, H. influenzae, M. catarrhalis, penicillin-resistant S. pneumoniae, M. pneumoniae, C. pneumoniae, L. pneumophila, Bacteroides fragilis
Norfloxacin Noroxin PO Enterobacteriaceae (used only in treatment of urinary tract infections)

image

IV, Intravenous; MSSA, methicillin-susceptible Staphylococcus aureus; PO, oral.

Clinical uses

Most quinolones (excluding norfloxacin) have activity against the common respiratory pathogens, including S. pneumoniae, H. influenzae, M. catarrhalis, C. pneumoniae, M. pneumoniae, and L. pneumophila. Quinolones have been shown to be effective in the treatment of upper and lower respiratory tract infections, genitourinary tract infections, and skin and skin structure infections, with results comparable to other antiinfective agents, such as cephalosporins, macrolides, and trimethoprim-sulfamethoxazole (TMP-SMX). The currently available quinolones (except trovafloxacin) do not penetrate the cerebrospinal fluid to any significant extent. Ciprofloxacin has been shown to have the best in vitro activity of the quinolones against P. aeruginosa and other gram-negative aerobes. Ciprofloxacin and levofloxacin have been used for the treatment of nosocomial pneumonia.

Adverse reactions and precautions

Quinolones are well tolerated and are considered one of the safest antimicrobial classes. Gastrointestinal side effects such as nausea, vomiting, and diarrhea occur in less than 5% of patients treated with quinolones. Prolongation of the Q–T interval (especially in female patients) has been reported with the use of quinolones. Seizures have been reported with ciprofloxacin in elderly patients and those with diminished renal function. Trovafloxacin use has been associated with fatal cases of liver toxicity. At present, trovafloxacin use outside the hospital setting for longer than 14 days is not recommended. Studies in immature laboratory animals have shown changes in weight-bearing joints after quinolone exposure. Although quinolone-induced arthropathy has not been documented in humans, use of quinolones in children (18 years old or younger) should be reserved for cases in which the benefits outweigh the risks. Dosage adjustment of quinolones (except moxifloxacin and trovafloxacin) is necessary in the presence of renal insufficiency. Concomitant use of antacids and iron supplements reduces the absorption of quinolones (as with tetracyclines).

Other antibiotics

The following agents belong to various classes of antimicrobials with different mechanisms of action and spectra of activity. Individual agents are discussed as they represent the clinically used agents of their antimicrobial class.

Chloramphenicol

Chloramphenicol has been available for use in the United States since 1949. This agent has a broad spectrum of activity against gram-positive, gram-negative, and anaerobic bacteria. Chloramphenicol distributes well into various tissues including the brain. Use of this antibiotic has declined with the availability of less toxic agents.25

Adverse reactions and precautions.

Because of the possibility of irreversible bone marrow suppression that may lead to serious and fatal blood dyscrasias (aplastic anemia), chloramphenicol has little place in the antimicrobial armament at the present time. Aplastic anemia is a life-threatening complication reported in 1 of every 20,000 patients treated with chloramphenicol. Chloramphenicol should not be used in premature and newborn infants, who cannot adequately metabolize this drug. The decreased metabolism of chloramphenicol results in high serum concentrations that can lead to gray baby syndrome (vomiting, pallor, cyanosis, circulatory collapse), which has an attributable mortality of 60%. The prolonged use of chloramphenicol in children with cystic fibrosis has been associated with optic neuritis leading to blindness.

Colistin (colistimethate)

Colistin, a member of the polymyxin family, was used in the early 1960s for serious gram-negative infections, including infections caused by P. aeruginosa. It was approved in 1968 by the U.S. Food and Drug Administration (FDA) but was later abandoned for drugs with similar gram-negative efficacy and more favorable side-effect profiles.26 However, there has been a resurgence in the use of colistin, because of the emergence of MDR gram-negative bacteria including P. aeruginosa and Acinetobacter species.

Daptomycin

! KEY POINT

Daptomycin is a novel cyclic lipopeptide that has activity against a wide range of gram-positive bacteria, including multidrug-resistant staphylococci and enterococci.

Daptomycin is a novel cyclic lipopeptide that has activity against a wide range of gram-positive bacteria, including MDR staphylococci and enterococci. However, daptomycin is inactive against gram-negative bacteria.

Clinical uses.

Daptomycin is currently approved for use in complicated skin and skin structure infections caused by susceptible gram-positive bacteria and S. aureus bacteremia. It has excellent activity against resistant staphylococci and enterococci, including vancomycin-resistant strains, although it is not approved for this use. In a phase 3 trial involving daptomycin for the treatment of CAP, daptomycin was inferior to the comparator agent (ceftriaxone), especially in patients with more serious infections. This poor response in pulmonary infections has been attributed to inactivation of daptomycin by pulmonary surfactants.27 Consequently, daptomycin is not indicated for use in the treatment of pneumonia. Daptomycin is typically dosed at 4 to 6 mg/kg every 24 hours. It is available only as an intravenous infusion.

Adverse reactions and precautions.

In earlier clinical studies involving daptomycin dosed every 8 to 12 hours, creatine phosphokinase (CPK) elevations and myalgias were noted that resulted in temporary suspension of drug development of this agent in the early 1990s. Once-daily administration of daptomycin has minimized these abnormalities noted in earlier studies. Clinical data have reported CPK elevations as a rare occurrence; however, the manufacturer recommends stopping hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors and other drugs associated with rhabdomyolysis during daptomycin therapy. In addition, daptomycin should be discontinued in patients with myalgias associated with CPK elevations or in asymptomatic patients with CPK elevations greater that 10 times the upper limit of normal.

Trimethoprim-sulfamethoxazole

Sulfamethoxazole belongs to the class of antibiotics known as the sulfonamides. Trimethoprim is a pyrimidine found to potentiate the activity of sulfamethoxazole. The combination of trimethoprim and sulfamethoxazole (TMP-SMX; Bactrim) was introduced in 1968 and has since gained a place in the treatment of numerous infections. This combination is active against gram-positive bacteria (streptococci, MSSA, MRSA) and gram-negative bacteria (H. influenzae, Burkholderia cepacia, Stenotrophomonas maltophilia). In addition, it is active against Pneumocystis jiroveci (formerly known as Pneumocystis carinii).28

Clinical uses.

TMP-SMX is used for the treatment and prophylaxis of Pneumocystis pneumonia (PCP) in patients infected with HIV. TMP-SMX is widely distributed in the body, achieving detectable levels in most tissues. High concentrations are achieved in the urine, making it an ideal agent for the treatment of UTIs. In addition, TMP-SMX has been used for treatment of acute exacerbations of bronchitis, traveler’s diarrhea caused by enterotoxigenic E. coli, otitis media, and shigellosis. In recent years, bacterial resistance to TMP-SMX has increased, creating controversy over the continued use of this combination as a first-line agent for UTIs. TMP-SMX also displays good activity against MRSA, including community-acquired strains, which gives practitioners an effective oral option for treatment.

Adverse reactions and precautions.

TMP-SMX is relatively well tolerated; nausea, vomiting, diarrhea, and hypersensitivity are the most common adverse effects. In addition, sulfamethoxazole has side effects that are common to all sulfonamides, including neutropenia, thrombocytopenia, hemolytic anemia, jaundice, hepatic necrosis, and drug-induced lupus. TMP-SMX should be avoided in all patients with “sulfa” allergies or hypersensitivities. Patients who are deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD) should not receive TMP-SMX because this combination can increase the risk of hemolytic anemia. The daily dosage of TMP-SMX should be reduced in the presence of renal insufficiency because both agents are eliminated through the kidneys. Patients should be advised to take TMP-SMZ with 8 oz of water to prevent acute interstitial nephritis.

Clindamycin

Clindamycin, a member of the lincosamide class of antibiotics, has activity against gram-positive and anaerobic bacteria. In addition, this agent is active against Toxoplasma gondii and P. carinii.25,29

Metronidazole

Metronidazole is a nitroimidazole that was used initially for its antiprotozoal effects against pathogens such as Trichomonas vaginalis, Giardia lamblia, and Entamoeba histolytica. Its anaerobic properties were discovered after an observation that acute ulcerative gingivitis improved in patients being treated for trichomonal vaginitis.25

Clinical uses.

Anaerobic infections have been implicated in abscesses within the brain, lung, and intraabdominal cavity. Metronidazole is often added as an adjunct, especially when surgical drainage of the abscess is impossible. In contrast to clindamycin, metronidazole penetrates well into the central nervous system and is useful for the treatment of brain abscesses. A key anaerobic pathogen, B. fragilis is part of the normal enteric flora and can contribute to sepsis in the event of gastrointestinal disease, surgery, or penetrating trauma. Metronidazole is often added to treat polymicrobial infections, especially when B. fragilis is suspected. Bacterial vaginosis caused by Gardnerella, Trichomonas, and Bacteroides species is also treated with metronidazole. In addition, diarrhea caused by C. difficile can be treated with metronidazole.

Nitrofurantoin

Multiple nitrofuran compounds have been synthesized since their discovery in the early 1940s. The most widely used agent of this class has been nitrofurantoin. This antibacterial does not achieve therapeutic concentrations in body tissues other than the kidney. As a result, it is used only for UTIs.30

Adverse reactions and precautions.

Nausea and vomiting are common side effects that can require cessation of therapy. Hypersensitivity syndromes such as skin rashes, drug fever, and asthma have been observed. Nitrofurantoin can accumulate in patients with renal dysfunction and result in serious complications such as peripheral neuritis. In addition, pneumonitis mimicking acute respiratory infection has been reported, but is rapidly reversible with discontinuation of this drug. Chronic pulmonary disease marked by interstitial fibrosis has been reported. This reversible condition may occur in patients who receive nitrofurantoin for longer than 6 months. Hemolytic anemia in patients with G6PD deficiency can be precipitated with this agent. A disulfiram-like reaction can also occur in patients who consume alcohol while being treated with nitrofurantoin.

Vancomycin

Vancomycin is a glycopeptide antibiotic with activity against gram-positive bacteria. It is not active against gram-negative bacteria. Its use in recent years has increased as a result of the emergence of MRSA.31

! KEY POINT

Vancomycin is a glycopeptide antibiotic with activity against gram-positive bacteria. It is not active against gram-negative bacteria.

Quinupristin and dalfopristin

Quinupristin and dalfopristin are streptogramins that act synergistically when used together (as in the product Synercid). These agents are active against gram-positive bacteria and are used primarily to treat infections caused by vancomycin-resistant Enterococcus faecium (VREF).31

Linezolid

The antibiotic linezolid belongs to a novel class of antibiotics known as the oxazolidinones. Linezolid, similar to quinupristin-dalfopristin, is active against gram-positive bacteria and is approved for the treatment of severe life-threatening VREF infections. In contrast to vancomycin and quinupristin-dalfopristin, linezolid is available as an oral formulation that is completely absorbed from the gastrointestinal tract.32

Antimycobacterials

Tuberculosis has received heightened attention largely because of the increase in cases attributed to the HIV epidemic. Each year, millions of individuals are exposed to tuberculosis, many through casual contact. More than one third of the world’s population has contracted tuberculosis. The U.S. Centers for Disease Control and Prevention (CDC) makes annual recommendations for the prevention and treatment of tuberculosis infection. Nosocomial transmission can be prevented by placing patients with suspected or confirmed tuberculosis in respiratory isolation (negative-pressure room) until they are (1) determined not to have tuberculosis, (2) discharged from the hospital, or (3) confirmed to be noninfectious. Other measures such as use of fitted respiratory masks (by health care personnel) can prevent transmission of Mycobacterium tuberculosis by aerosolization to caregivers.

Treatment consists of multiple antibiotic regimens for 6 to 12 months in duration. Single-agent regimens should never be used for treatment because the likelihood of developing resistance is high. Treatment failures often result from poor patient compliance and from resistance to antibiotics. Drugs used in the treatment of tuberculosis can be categorized as either first-line or second-line agents depending on their efficacy and side-effect profiles. Initial therapy generally involves a combination of isoniazid, pyrazinamide, rifampin, and ethambutol. Table 14-7 summarizes clinically used antimycobacterial agents, doses, routes of administration, and side effects. Addition or subtraction of agents from this regimen is usually based on culture and sensitivity data, along with patient response to treatment. Guidelines for the treatment of active pulmonary tuberculosis are provided in Table 14-833,34 or may be viewed directly at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm.

TABLE 14-7

Dose, Route, and Side-Effect Profile of Commonly Used Antimycobacterials

ANTIMYCOBACTERIAL ADULT DOSE ROUTE SIDE EFFECTS
Isoniazid 5 mg/kg/day; maximum 300 mg/day PO, IM Hepatotoxicity (symptoms include nausea, loss of appetite, abdominal pain), peripheral neuritis, rash, fever, anemia
Rifampin 10 mg/kg/day; maximum 600 mg/day PO, IV Hepatotoxicity, flulike symptoms, discolorations of body secretions to an orange color
Rifabutin 300 mg/day PO Hepatotoxicity, flulike symptoms, discolorations of body secretions to an orange color
Pyrazinamide 15-30 mg/kg/day; maximum 2000 mg/day PO Hepatotoxicity, arthralgia, hyperuricemia
Ethambutol 15-25 mg/kg/day; maximum 2500 mg/day PO Optic neuritis (greater incidence in patients receiving >15 mg/kg/day)
Streptomycin 15 mg/kg/day; maximum 1000 mg/day IM Ototoxicity (high-frequency hearing loss, vertigo), nephrotoxicity

image

IM, Intramuscular; IV, intravenous; PO, oral.

INH + RIF (or RFB) + PZA + B6 daily for 2 months, then INH + RIF (or RFB) + B6 daily for additional 4 months

INH + RIF (or RFB) + PZA + ETB or SM + B6 daily for 2 months, then INH + RIF or unknown (or RFB) + B6 daily for additional 4 months Requires DOT INH + RIF (or RFB) + PZA + ETB + B6 or SM daily for 2 weeks, then 2-3 times/week for 6 weeks, then INH + RIF (or RFB) + B6 2-3 times/week for 6 months DOT RIF (or RFB) + PZA + ETB daily for 6 months INH + FQN + ETB + B6 daily for 12-18 months; supplement with PZA first 2 months INH + RIF + ETB daily for 9 months Treatment as in clinical scenarios 1 and 2 for the first 2 months, then extend INH + RIF (or RFB) + B6 daily for additional 7 months

image

AIDS, Acquired immunodeficiency syndrome; B6, pyridoxine; DOT, directly observed therapy; ETB, ethambutol; FQN, fluoroquinolone; HIV, human immunodeficiency virus; INH, isoniazid; PZA, pyrazinamide; RFB, rifabutin; RIF, rifampin; SM, streptomycin.

Data from American Thoracic Society, CDC, Infectious Diseases Society of America: Treatment of tuberculosis, MMWR Recomm Rep 52(RR-11):1-77, 2003.

! KEY POINT

The most commonly used antimycobacterials in the treatment of tuberculosis include isoniazid, rifampin, rifabutin, pyrazinamide, ethambutol, and streptomycin.

Isoniazid

Isoniazid (INH) is well absorbed orally and is distributed throughout the body, especially in the cerebrospinal fluid. Isoniazid is metabolized by the liver, and its metabolite is eliminated by the kidneys.

Adverse reactions and precautions

An elevation in liver enzymes has been reported in patients receiving isoniazid and is reversible with discontinuation of the drug. Rare cases of serious hepatitis and death also have been reported. Hepatotoxicity usually occurs between the 4th and 8th weeks of treatment but may occur at any time. Tests used to measure hepatocellular injury should be performed and include monitoring liver transaminases such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In addition, patients should be monitored for the development of symptoms of hepatitis, such as nausea, loss of appetite, and abdominal pain. Neurotoxicity has also been reported and occurs more frequently in patients receiving higher dose therapy. Supplementation with pyridoxine (vitamin B6) has been shown to reduce the frequency of this adverse reaction. Rare miscellaneous reactions, such as rash, anemia, and fever, also have been reported.

Rifampin and rifabutin

Rifampin and rifabutin are semisynthetic antibiotics referred to as rifamycins. Rifampin and rifabutin have similar structures and spectra of activity. They are well absorbed orally, with good penetration into most tissues. These agents do not penetrate the central nervous system well in the absence of inflammation. Rifampin is extensively metabolized through the liver and is an inducer of the CYP system. Rifabutin is also metabolized hepatically; however, it is a weaker enzyme inducer than rifampin. CYP induction is known to decrease plasma concentrations of drugs hepatically metabolized; therefore dosage adjustments of agents metabolized by this system are necessary.

Pyrazinamide

Pyrazinamide is a nicotinic acid derivative that is well distributed into most tissues, including the cerebrospinal fluid. Pyrazinamide is hepatically metabolized and excreted by the kidneys.

Ethambutol

Ethambutol is a synthetic, orally administered agent that distributes extensively throughout the body, including the cerebrospinal fluid. Most of it is eliminated unchanged in the urine.

Antifungals

! KEY POINT

Use of antifungals, such as polyenes, azoles, and echinocandins, is increasing with the number of immunocompromised patients.

The incidence of fungal infections has increased dramatically. Candida species are now the fourth most commonly isolated bloodstream pathogens. Candidemia has a mortality rate of 40%. The number of patients immunocompromised as a result of AIDS, cancer chemotherapy, and organ transplantation has been increasing. These patient populations have diminished cell-mediated immunity and are predisposed to numerous fungal pathogens that vary in incidence geographically. The treatment of choice for most fungal infections has been the polyene amphotericin B. The high incidence of nephrotoxicity associated with this agent served as the impetus for the development of the azoles. Ketoconazole was the first agent of this class, but it has largely been replaced by the triazoles fluconazole and itraconazole. Newer triazoles with improved activity against molds are being developed. In addition, a new class of antifungals known as the echinocandins is now available. Systemically used antifungals, including route and clinical uses, are summarized in Table 14-9.35–37

TABLE 14-9

Classification of Systemically Used Antifungals

ANTIFUNGAL CLASS AND GENERIC NAME BRAND NAME ROUTE COMMON USES (MICROORGANISM)
Polyenes      
Amphotericin B Fungizone IV, PO* Candida spp., Aspergillus spp., Cryptococcus neoformans, Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis
Amphotericin B colloidal dispersion Amphotec IV Candida spp., Aspergillus spp., mucormycosis, C. neoformans
Amphotericin B lipid complex Abelcet IV Candida spp., Aspergillus spp., mucormycosis, C. neoformans
Liposomal amphotericin B AmBisome IV Candida spp., Aspergillus spp., mucormycosis, C. neoformans, leishmaniasis
Azoles      
Ketoconazole Nizoral PO Candida spp.†, C. neoformans, H. capsulatum, B. dermatitidis
Fluconazole Diflucan IV, PO Candida spp.†, C. neoformans
Itraconazole Sporanox PO Candida spp.†, Aspergillus spp., C. neoformans, H. capsulatum, B. dermatitidis, C. immitis, Sporothrix schenckii
Voriconazole Vfend IV, PO Candida spp.†, Aspergillus spp., C. neoformans, C. immitis, H. capsulatum, B. dermatitidis, Fusarium spp., Scedosporium spp.
Posaconazole Noxafil PO Candida spp.†, Aspergillus spp., C. neoformans, C. immitis, H. capsulatum, B. dermatitidis, Fusarium spp., Scedosporium spp.
Echinocandins      
Caspofungin Cancidas IV Aspergillus spp., Candida spp.
Micafungin Mycamine IV Aspergillus spp., Candida spp.
Anidulafungin Eraxis IV Aspergillus spp., Candida spp.
Other Antifungals      
Flucytosine Ancobon PO Aspergillus spp., Candida spp., C. neoformans
Griseofulvin Fulvicin PO Tinea corporis, tinea cruris, tinea barbae, tinea capitis, and tinea unguium
Terbinafine Lamisil PO, TOP Tinea corporis, tinea pedis, tinea manuum, tinea cruris, tinea imbricata, tinea capitis, and tinea unguium

image

IV, Intravenous; PO, oral; TOP, topical.

*The oral form of amphotericin B is not absorbed through the gastrointestinal tract.

†Candida krusei is intrinsically resistant to all azoles.

Polyenes

Polyenes include amphotericin B and nystatin. Amphotericin B has been available for more than 50 years and remains the drug of choice for most systemic fungal infections. More recently, amphotericin B has been formulated into lipid-based products. These lipid-based products alter the distribution of amphotericin B, resulting in a higher uptake of the agent into the reticuloendothelial system (liver, spleen, lymphatics) relative to the kidneys.38 The net effect of this shift in distribution has been shown to reduce the incidence of nephrotoxicity. Nystatin is used only topically for oral and intertriginous (between skin surfaces) candidiasis. A lipid-based formulation of nystatin is currently under investigation.

Azoles

Systemically used azoles include ketoconazole, fluconazole, itraconazole, voriconazole, and posaconazole. Ketoconazole was the first oral agent available to treat systemic fungal infections. This agent is poorly absorbed from the gastrointestinal tract (when an acidic environment is not present) and has potential for substantial toxicity. As a result, ketoconazole has largely been replaced by the newer triazoles fluconazole, itraconazole, and voriconazole. Fluconazole is available in oral and intravenous formulations, is widely distributed into the tissues, and is relatively nontoxic. Compared with ketoconazole, it has a narrow spectrum of activity. Itraconazole has an enhanced spectrum of activity compared with fluconazole but slightly less than that of voriconazole. Voriconazole is also available in oral and intravenous forms. Posaconazole was approved more recently for prophylaxis of invasive aspergillosis and disseminated candidiasis in severely immunocompromised hosts and for the treatment of refractory oropharyngeal candidiasis. Use of posaconazole is intended for patients failing or refractory to other therapies and has been documented to be active against Zygomycetes.37

Clinical uses

Ketoconazole has largely been replaced by the more potent and better tolerated triazoles. The primary indication for fluconazole is for candidiasis (nonneutropenic patients) and as suppressive therapy for patients with cryptococcal meningitis, but it may also be used to treat coccidioidomycosis. Itraconazole is considered the drug of choice for the treatment of cutaneous and lymphangitic sporotrichosis. Itraconazole is also used as prophylaxis and suppressive therapy for pulmonary aspergillosis, histoplasmosis, blastomycosis, cryptococcosis, coccidioidomycosis, paracoccidioidomycosis, and candidiasis. Voriconazole is considered the drug of choice as primary therapy for invasive aspergillosis and has been approved for the management of candidemia and infections caused by rare pathogens such as Fusarium and Scedosporium apiospermum. Candidiasis caused by Candida krusei (which lacks the CYP system) may be intrinsically resistant to this class of agents, although in vitro activity has been documented with voriconazole and posaconazole.

Adverse reactions and precautions

Fluconazole is well tolerated and has minimal side effects. Common adverse effects with ketoconazole, itraconazole, and voriconazole are anorexia, nausea, and vomiting. In addition, transaminase and bilirubin elevations have been reported. Impotence, decreased libido, and gynecomastia are also known to occur with ketoconazole and are attributed to its inhibition of sex steroid synthesis, and consequently it is used clinically for certain endocrine disorders. Voriconazole can cause visual disturbances such as photopsia and chromatopsia, which can occur in 30% of patients.36,39 Ketoconazole, itraconazole, and voriconazole are metabolized in the liver and are potent inhibitors of the CYP 3A4 system, so each has a significant potential for drug interactions. Conversely, fluconazole does not undergo significant hepatic metabolism and has the lowest drug interaction potential of the triazoles. Fluconazole is, however, eliminated unchanged in the urine and so dosage adjustment is required in patients with impaired renal function. Renal function is also important when administering the intravenous formulations of itraconazole and voriconazole. These drugs should be avoided in patients with creatinine clearance values less than 30 mL/min to prevent the accumulation of cyclodextrin, an intravenous solubilizing agent. Cyclodextrin is also used to formulate oral itraconazole solution and has been cited as the cause of the high incidence of adverse gastrointestinal intolerance relative to itraconazole capsules, which do not contain this agent.

Echinocandins

Caspofungin was the first echinocandin to receive FDA approval in early 2001. Micafungin and anidulafungin received FDA approval in 2004 and 2006, respectively. These agents have similar pharmacokinetic and pharmacodynamic properties. They have poor gastrointestinal absorption, and all require parenteral administration.40

Mode of action

Echinocandins inhibit fungal cell wall synthesis by inhibiting (1,3)-β-d-glucan synthase.37 These agents may be either fungicidal or fungistatic against fungi depending on the isolate.

Adverse reactions and precautions

Echinocandins seem to be well tolerated, although most of the safety data are for caspofungin and micafungin. In most studies, common adverse reactions were infusion-related and included fever, rash, flushing, and thrombophlebitis. Infusion-related reactions were approximately 10% for caspofungin and slightly less for micafungin. Anidulafungin has produced infusion-related reactions in 15% of patients. Nausea and vomiting were also frequently reported for all three agents. Elevations in liver transaminase (AST and ALT) levels and hyperbilirubinemia were noted with echinocandins, but these were mild and reversible on drug discontinuation. Echinocandins are not metabolized through the CYP system, reducing the potential for drug interactions.41 All echinocandins can increase the area under the curve (AUC) of cyclosporine when coadministered, with caspofungin creating the most significant changes in AUC. The mechanism of this interaction is unknown. Concurrent use of cyclosporine and echinocandins may warrant careful monitoring.

Flucytosine

Flucytosine acts as an antimetabolite and is used primarily as adjunctive therapy for susceptible fungal pathogens. It is active against Candida, Cryptococcus, and Aspergillus.35

Griseofulvin and terbinafine

Griseofulvin was one of the first antifungals discovered; however, only dermatophytes (skin fungi) are susceptible to this agent. The absorption of this agent is greatly increased when taken with a high-fat meal. Terbinafine, which was developed more recently, has shown more potent activity against dermatophytes. Terbinafine is a highly lipophilic allylamine that concentrates in the stratum corneum, sebum, and hair follicles. This property makes it an excellent agent for cutaneous dermatophytosis (e.g., ringworm infection, athlete’s foot) and onychomycosis (fungal infection in nails).35

Antiviral agents

! KEY POINT

Antivirals (excluding antiretrovirals) mimic nucleosides and inhibit DNA synthesis.

Several agents are available for treating viral infections (Table 14-10). All of these agents act by inhibiting steps involved in viral replication; none of the agents inhibit nonreplicating viruses. Antivirals (excluding antiretrovirals) mimic nucleosides and inhibit DNA synthesis. Agents used to treat HIV are not discussed here.42

TABLE 14-10

Classification of Antivirals

GENERIC NAME BRAND NAME ROUTE COMMON USES (MICROORGANISM)
Acyclovir Zovirax IV, PO, TOP HSV-1, HSV-2, HZV, VZV
Valacyclovir Valtrex PO HSV-1, HSV-2, HZV, VZV
Penciclovir Denavir TOP HSV-1, HSV-2, HZV, VZV
Famciclovir Famvir PO HSV-1, HSV-2, HZV, VZV
Ganciclovir Cytovene IV, PO, IO CMV
Valganciclovir Valcyte PO CMV
Cidofovir Vistide IV CMV
Foscarnet Foscavir IV HSV-1, HSV-2, VZV, CMV that are suspected to be resistant to acyclovir and ganciclovir
Fomivirsen Vitravene IVit CMV
Amantadine Symadine PO Influenza A
Rimantadine Flumadine PO Influenza A
Oseltamivir Tamiflu PO Influenza A and B

image

CMV, Cytomegalovirus; HSV-1, -2, herpes simplex virus type 1, 2; HZV, herpes zoster virus; IO, intraocular; IV, intravenous; IVit, intravitreal injection; PO, oral; TOP, topical; VZV, varicella-zoster virus.

Acyclovir and valacyclovir

Acyclovir is available in intravenous, oral, and topical formulations. Oral acyclovir is not readily absorbed and requires frequent daily dosing. Valacyclovir, a prodrug of acyclovir, was developed to improve gastrointestinal absorption of acyclovir. Valacyclovir is available only in oral formulation.42

Penciclovir and famciclovir

Penciclovir and famciclovir are similar in structure and activity to acyclovir. Famciclovir, the prodrug of penciclovir, is converted to its active form (penciclovir) in the gastrointestinal tract. Famciclovir is available in oral formulation, and penciclovir is available only in a 1% topical cream. Penciclovir and famciclovir seem to have greater in vitro activity against HSV and VZV than acyclovir.42

Ganciclovir and valganciclovir

Ganciclovir is a guanine nucleoside analogue with a mechanism of action similar to acyclovir. Valganciclovir is a newly approved prodrug of ganciclovir that improves ganciclovir absorption. Ganciclovir has a higher affinity for DNA transferase than acyclovir, which increases the intracellular half-life of the drug and allows less frequent dosing. Valganciclovir is available only in oral formulation; ganciclovir is available in oral, intravenous, and intraocular (eye implant) formulations.42

Cidofovir

Cidofovir is an acyclic phosphonate nucleoside analogue that has potent antiviral activity against a wide variety of viruses. In contrast to the guanine nucleoside analogues, cidofovir has enhanced activity against HSV, EBV, VZV, and CMV. Cidofovir is available only in intravenous formulation.42

Foscarnet

Foscarnet is a pyrophosphonate nucleoside analogue that has potent antiviral activity against HSV, EBV, VZV, and CMV. In addition, foscarnet has shown activity against hepatitis B and influenza viruses. It is poorly absorbed, and it is available only in intravenous formulation.42

Fomivirsen

Fomivirsen is the first member of a new class of antiretrovirals termed antisense oligonucleotides. It is available only as an intravitreal preparation.45

Amantadine and rimantadine

Amantadine and rimantadine are closely related antiviral agents with activity against influenza A only. Amantadine has also been used in the treatment of Parkinson disease. Both agents are well absorbed from the gastrointestinal tract and are suitable for oral administration.42

Oseltamivir

Oseltamivir belongs to a new class of antivirals known as neuraminidase inhibitors. Oseltamivir is a prodrug that is converted to its active form (oseltamivir carboxylate) after it is absorbed. It is available only as an oral formulation.42

Adverse reactions and precautions

Oseltamivir is well tolerated; nausea and vomiting are reported as the most frequent adverse reactions. These symptoms usually occur on the first 2 days of therapy. Dosage adjustment is required in patients with renal insufficiency.

imageRESPIRATORY CARE ASSESSMENT OF ANTIBIOTIC THERAPY

imageSELF-ASSESSMENT QUESTIONS

1. What is the difference between bacteriostatic and bactericidal antimicrobial agents?

2. Describe the difference between antimicrobial agents that act in a concentration-dependent manner and agents that act in a time-dependent manner.

3. Describe at least three parameters that may indicate antibiotic failure in a patient.

4. Why is combination antibiotic therapy useful? (Be specific.)

5. Describe the mechanism of action of penicillin antibiotics. Name at least two additional antibiotic classes with similar mechanisms of action.

6. Which β-lactam antibiotic is least likely to cause an allergic reaction in a patient with a penicillin allergy?

7. Name three antimicrobial agents that would be useful in the treatment of community-acquired pneumonia.

8. What is the antimicrobial agent of choice for treatment of Pneumocystis pneumonia (PCP)?

9. What agents are considered first-line therapy for treatment of pulmonary tuberculosis?

10. Which antimicrobial agents are useful for the treatment of nosocomial pneumonia caused by Pseudomonas aeruginosa?

imageCLINICAL SCENARIO

Blade Devero is a 61-year-old white man with a history of chronic obstructive pulmonary disease (COPD) and recurrent pneumonia who is admitted to University Hospital from the community, with complaints of cough productive of yellow-green sputum, fever, chills, and worsening shortness of breath (SOB). The patient states that he has felt relatively well the past 3 to 4 weeks except for occasional night sweats.

COPD was diagnosed in 2005. He also has hypertension (HTN), mild benign prostatic hypertrophy (BPH), and a left below-knee amputation (BKA). Mr. Devero is also allergic to penicillin (anaphylactic reaction).

Mr. Devero’s medications (before admission) are as follows:

His vital signs are as follows: temperature (T) 101.2° F, blood pressure (BP) 158/92 mm Hg, heart rate (HR) 104 beats/min, respiratory rate (RR) 28 breaths/min, weight 130 lb, height 65 inches, oxygen saturation by pulse oximetry (Spo2) 92% on 4 L O2, 68% on room air.

Physical examination revealed the following (remarkable findings): elderly cachectic man in acute distress; tachycardic, with a regular rhythm; bilateral respiratory crackles; and clubbing and cyanotic nail beds.

His white blood cell count (WBC) is 15.6 × 103 cells/mm3. Sputum showed many white blood cells, few epithelial cells, and many gram-positive cocci in chains/pairs; culture is pending. A chest x-ray film revealed left lower lobe infiltrate.

Using the SOAP method, assess this clinical scenario.

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