Antimicrobial agents

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CHAPTER 14

Antimicrobial agents

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

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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

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.

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.

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

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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

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

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

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

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.

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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.