Penicillins

Penicillins were the first agents of the β-lactam class to be developed and can be divided into groups that are based largely on spectrum of activity and chemistry: the natural penicillins (penicillin G, penicillin V), the aminopenicillins (ampicillin and amoxicillin), the penicillinase-resistant penicillins (methicillin, oxacillin, nafcillin), and the extended-spectrum penicillins (carbenicillin, mezlocillin, ticarcillin, piperacillin). Penicillin G was discovered by Alexander Fleming more than a half century ago and is primarily active against gram-positive organisms, both aerobic and anaerobic. The aminopenicillins are more active against gram-negative organisms such as Escherichia coli and Haemophilus influenzae. Penicillinase-resistant penicillins were developed to meet the challenge of the rapid development of penicillinase-mediated resistance in Staphylococcus aureus. These penicillinase-resistant penicillins are all active against S. aureus, except methicillin-resistant S. aureus (MRSA). They are also active against streptococci (except Enterococcus spp.). Nafcillin differs pharmacologically from the others in being excreted primarily by the liver rather than by the kidneys. Nafcillin displays a relative lack of nephrotoxicity compared with methicillin. Oxacillin also has a better renal safety profile than methicillin. Long-term, high-dose use of all β-lactam agents may be associated with reversible neutropenia.

The extended-spectrum penicillins all display enhanced gram-negative activity compared with the aminopenicillins. There are some variations in the activity demonstrated against Klebsiella, Enterobacter, Serratia, Citrobacter, and Pseudomonas. All the agents in this class are susceptible to the type I, chromosomal β-lactamases that are inducible or constitutively produced in strains of Enterobacter, Serratia, Citrobacter, and Pseudomonas. Exposure to the extended-spectrum β-lactams will select out strains that constitutively produce these β-lactamases. These strains are considered antibiotic resistant. Some experts think that the addition of an aminoglycoside to the β-lactam agent will prevent or retard the emergence of β-lactam resistance. In addition, the extended-spectrum penicillins are susceptible to the newly evolving plasmid-mediated extended-spectrum β-lactamases (ESBLs), which are constitutively produced by organisms that harbor them. Piperacillin and ticarcillin are currently the only available extended-spectrum penicillins in the United States and only in fixed combinations with β-lactamase inhibitors.

β-Lactam Antimicrobial plus β-Lactamase Inhibitor Combination

Timentin, (ticarcillin/clavulanate), Zosyn (piperacillin/tazobactam), and Unasyn (ampicillin/sulbactam) are all combinations of two β-lactam drugs. The first β-lactam drug, the true antibiotic, effectively binds to the target site in the bacteria and results in the death of the organism, assuming that the second β-lactam drug neutralizes the organism’s β-lactamase. The second β-lactam drug has poor intrinsic activity as an antibiotic but still displays high affinity to and may bind irreversibly to and neutralize the β-lactamase enzyme the organism has produced. This agent is also known as a β-lactamase inhibitor. The combination adds to the spectrum of the original antibiotic when the mechanism of resistance is a β-lactamase enzyme. Not all β-lactamase inhibitors have an equal ability to inhibit all β-lactamases. Timentin and Zosyn have no significant activity against Pseudomonas beyond that of ticarcillin or piperacillin because their β-lactamase inhibitors do not effectively inhibit the β-lactamases of Pseudomonas. In general, the β-lactamase inhibitors present in the antibiotics Timentin, Zosyn, and Unasyn do not inhibit the adenosine monophosphate 3′5′ (AmpC), type 1 chromosomal β-lactamases present in Enterobacter, Serratia, and Citrobacter. They do, however, inhibit enzymes present in a number of other pathogens, including the β-lactamases often present in strains of H. influenzae, Bacteroides fragilis, and S. aureus.

Cephalosporins

Cephalosporins can be distinguished on the basis of activity against gram-negative pathogens and stability of the antibiotic to a number of the gram-negative β-lactamases. The cephalosporins fall roughly into five categories (“generations”) on the basis of these characteristics. First-generation cephalosporins (cephalothin, cefazolin) are active against most strains of E. coli but are not entirely stable to the β-lactamases produced by some strains of E. coli and H. influenzae. The activity of these antibiotics against gram-positive pathogens such as S. aureus is close to that of oxacillin and nafcillin; however, none of the current cephalosporin antibiotics of any generation displays reasonable activity against the enterococci. Clinically relevant activity against B. fragilis does not exist for the first-generation cephalosporins. The second-generation cephalosporins (cefamandole, cefuroxime) have chemically increased intrinsic activity against gram-negative organisms, including E. coli and Klebsiella. They are also more stable against the principal β-lactamases of E. coli and H. influenzae. Activity against S. aureus is significantly decreased compared with the first-generation cephalosporins but is sufficient to achieve clinical success in many situations and to warrant FDA approval for treatment of these organisms. A slightly different group of antibiotics, the cephamycins (cefoxitin, cefotetan), have activity against the gram-negative enteric bacilli similar to the second-generation cephalosporins but display enhanced anaerobic activity against B. fragilis and may play a role in the treatment of intra-abdominal infections. Their activity against B. fragilis, however, is inferior to metronidazole, clindamycin, or the carbapenems.The third-generation cephalosporins, cefotaxime and ceftriaxone, have enhanced stability against the most prevalent β-lactamases of H. influenzae, E. coli, and Klebsiella and enhanced activity against many of the enterobacteriaceae but are, unfortunately, not stable to the inducible chromosomal β-lactamases (AmpC, type I) of Enterobacter, Serratia, or Citrobacter. Ceftazidime, another third-generation cephalosporin, has far greater intrinsic activity against Pseudomonas aeruginosa than previous cephalosporins, but it too is degraded by the inducible chromosomal β-lactamases of Enterobacter, Serratia, and Citrobacter, as well as the chromosomal β-lactamases of Pseudomonas. None of the third-generation cephalosporins are as active against S. aureus. Cefepime, a fourth-generation cephalosporin, has the best overall activity against both gram-negative and gram-positive pathogens, with activity against P. aeruginosa equivalent to ceftazidime and activity against S. aureus equivalent to second-generation cephalosporins. It is also the most stable to β-lactamase degradation by all but some of the ESBL class of β-lactamases. The novel fifth-generation cephalosporins, ceftobiprole and ceftaroline, are the first β-lactam antibiotics with activity against MRSA. Ceftobiprole was recently approved by the FDA for the treatment of complicated skin and skin structure infections in adults. Ceftaroline is currently in phase III clinical development. In addition to activity against MRSA, the fifth-generation cephalosporins have a spectrum of activity similar to that of third- and fourth-generation cephalosporins. Ceftobiprole also exhibits in vitro activity against enterococci and Pseudomonas. Ceftaroline is not reliably active against ESBLs, whereas ceftobiprole has activity against P. aeruginosa similar to that of cefipime. Although still in phase III trials, ceftobiprole has potential for use as empiric monotherapy for serious infections in the ICU because it has activity against both MRSA and P. aeurignosa.¹²

Carbapenems

Three carbapenems, imipenem (combined with cilastin, an inhibitor of a renal tubular dehydropeptidase enzyme, to avoid nephrotoxicity), meropenem, and ertapenem are currently FDA approved in pediatric patients older than 3 for treatment of complicated skin and skin structure infections (SSI), complicated intra-abdominal infections, and meningitis. Pediatric clinical investigation of doripenem, a fourth-generation carbapenem recently FDA approved for adults, is ongoing. The carbapenems have a β-lactam ring structure that differs slightly from the penicillins and cephalosporins (see Figure 94-1), with chemical modifications to enhance activity and stability similar to those of cephalosporins. The broad antimicrobial spectrum of activity of the carbapenems is similar and includes gram-negative, gram-positive, and anaerobic organisms. Relevant gram-negative pathogens include enteric bacilli such as E. coli, Klebsiella, Enterobacter, and Citrobacter in addition to P. aeruginosa. They are active against gram-positive organisms including S. aureus and streptococci, although activity against the enterococci is substantially less than penicillin G or ampicillin. Meropenem is slightly more active against gram-negative pathogens and imipenem is slightly more active against gram-positive pathogens, although there is probably no clinical significance in these differences for most infections being treated. Although not FDA approved for the treatment of nosocomial pneumonia, meropenem has been shown to be effective in numerous clinical trials. Both agents are active against anaerobes, including β-lactamase–positive strains of B. fragilis. Ertapenem has a similar spectrum of activity to the other carbapenems, although intrinsic activity against P. aeruginosa is less than that of the other carbapenems. Nevertheless, it has a prolonged serum elimination half-life compared with the other agents, allowing for once- or twice-daily therapy compared with three or four times daily. Doripenem was recently approved for the treatment of complicated intra-abdominal and complicated urinary tract infections in adults. Its spectrum of activity is similar to the other carbapenems; however, it appears to have more potent in vitro activity against P. aeruginosa.

With respect to toxicity, the carbapenems are well tolerated, although imipenem displays interference with central nervous system (CNS) γ-aminobutyric acid inhibition of neuron activity and was shown to be associated with an increase in seizure activity in children treated for bacterial meningitis compared with historic controls.¹⁴ On the basis of these observations, meropenem is the preferred carbapenem for children at risk for seizures or with CNS infections and inflammation. Meropenem is well tolerated in children. In pediatric trials, diarrhea and rash occur in less then 5%, and drug-related seizures were not observed in children with meningitis treated with meropenem.

Monobactams

Aztreonam, the only monobactam currently available, has a unique chemical structure in which the β-lactam ring is not attached to an adjacent 5- or 6-membered ring but does have chemical additions to the β-lactam ring that enhance activity and stability to β-lactamases. It displays aerobic, gram-negative activity, including activity against many strains of P. aeruginosa.

Aminoglycosides

Aminoglycoside antibiotics are bactericidal in a concentration-dependent fashion against a wide range of aerobic pathogens. The first antibiotic in this class, streptomycin, was isolated from Streptomyces griseus and was first available in 1944. Subsequently, other aminoglycosides have been isolated from fungi, and chemical modifications to enhance activity and decrease toxicity have been made to older agents. These agents inhibit protein synthesis by irreversible binding to the 30S ribosomal subunit. The gram-negative spectrum of activity is extensive, including enteric bacilli (E. coli, Klebsiella, Enterobacter, Serratia), P. aeruginosa, and many free-living gram-negative bacilli that may only be pathogenic for immunocompromised children or those with trauma in which environmental contamination of deep tissues has occurred. These antibiotics have no clinically relevant anaerobic activity.

Although the first aminoglycosides exhibited substantial renal toxicity and ototoxicity, subsequent agents are significantly safer. With serum concentrations present within the therapeutic range, renal toxicity and ototoxicity are unusual. The most widely available parenteral agents are gentamicin, tobramycin, and amikacin. Because of the relatively low serum concentrations necessary to prevent toxicity and poor penetration into the spinal fluid, these agents are not used as primary therapy of CNS infections. Direct intrathecal instillation should also not be considered routinely for CNS infections because data collected during a prospective study of aminoglycosides as adjunctive therapy in neonatal gram-negative meningitis revealed higher rates of morbidity.¹⁵ Streptomycin, the most toxic of the aminoglycosides, continues to be used infrequently in the treatment of tuberculosis, plague, and tularemia in children.

Caution should be exercised in the use of these agents in undrained abscess infections, including intraabdominal infections. The acidic and anaerobic conditions present in abscesses produce MICs against aerobic gram-negative organisms that are 10 times higher than those documented under ideal laboratory conditions.¹⁶

Aminoglycosides have demonstrated excellent clinical efficacy against susceptible organisms. Nevertheless, the toxicity of the antibiotics may preclude the attainment of serum and tissue concentrations that are severalfold higher than the MICs of the pathogens. Synergy between a β-lactam agent and an aminoglycoside in bacterial killing can be demonstrated against many gram-negative pathogens. For the critically ill or immunocompromised child, a combination of agents is often used to obtain the maximal antibiotic killing. In addition, some experts believe that the combination will retard the emergence of antibiotic resistance in gram-negative organisms containing inducible AmpC, chromosomal β-lactamases.

Glycopeptides

Vancomycin is currently the only available glycopeptide in the United States, although teichoplanin is available in other areas of the world and a new generation of glycopeptides is presently in clinical trials in adults. The glycopeptides are primarily active against gram-positive organisms, both aerobic and anaerobic. This class of antibiotic is cell wall active, as are the penicillins, but has a different mechanism of action in prevention of pentapeptide cross-linking in the formation of cell wall peptidoglycan.

Vancomycin is bactericidal against virtually all strains of staphylococci and against most strains of streptococci, although it is bacteriostatic against the enterococci. Resistance to vancomycin is noted to occur in strains of Enterococcus faecium (vancomycin-resistant enterococcus [VRE])¹⁷ and has now been described in S. aureus.¹⁸

The tissue distribution of vancomycin is extensive, with elimination of unchanged antibiotic by the kidney. Dosage adjustment is required in renal insufficiency. Penetration into the cerebrospinal fluid (CSF) is not well studied and is erratic. Serum concentrations of approximately 40 μg/mL are thought to be necessary to achieve CSF concentrations sufficiently high enough to achieve a reliable microbiologic cure in meningitis or ventriculitis. The toxicities of vancomycin are primarily nephrotoxicity and ototoxicity. As with the aminoglycosides, close attention to serum antibiotic concentrations will avoid clinically significant toxicity.

The new generation glycopeptides, dalbavancin, telavancin, and oritavancin, are undergoing clinical trials. Telavancin, a lipoglycopeptide, was recently FDA approved in adults for the treatment of complicated skin or skin structure infections caused by gram-positive organisms.