Supported by an unrestricted educational grant from Eli Lilly and Company

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Volume II, Issue 2 - May 1996

The cephalosporins resemble penicillins in that they have a b-lactam structure, but the five-member thiazolidine ring characteristic of the penicillins is replaced by a six-member dihydrothiazine ring. This ring provides the molecule with the ability to resist bacterial enzymes. The antibacterial activity comes from the b-lactam ring. Side chains in positions 3 and 7 affect the pharmacokinetic and antibacterial spectrum of the cephalosporins.

The cephalosporins, like all b-lactams, inhibit enzymes that create the cross-linkage of the peptidoglycan polymer leading to interference with the cell wall structure. These enzymes, located beneath the cell wall, are known as penicillin-binding proteins (PBP). b-lactam antibiotics have different binding affinities to the various PBPs. The effect of an antibiotic on a specific microorganism depends on which PBP is bound and inactivated.

Advantages of the cephalosporins have made them a popular choice among physicians in the US. These advantages include a broad range of activity, a safe record in children with almost no dose-related toxicity, and the lack of need to monitor levels. In addition, these drugs can be used safely in most patients with hepatic or renal failure. Adverse reactions are rare and consist primarily of hypersensitivity reactions with urticaria, nonspecific rash, and pruritus. The frequency of skin reactions has ranged in most surveys from 0.9 to 3.2 %.(1) Immediate reactions of anaphylaxis and bronchospasm are rare but have been reported. There appears to be a 5% to 10% cross-reactivity in penicillin-allergic patients but this figure may actually be lower.

One of the limitations of this class of antibiotics is that none of the currently available cephalosporins have reliable activity against methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus, Legionella, Campylobacter organisms, Listeria, and Clostridium difficile.

The cephalosporins are classified into generations based on their general features of antimicrobial activity (Table 1). The first generation of cephalosporins include agents with good activity against Gram-positive bacteria (S aureus, group A streptococci, Streptococcus pneumoniae) and relatively modest coverage for Gram-negative organisms. The second-generation antimicrobials have increased activity against certain Gram-negative pathogens, including Haemophilus influenzae, Neisseria meningitidis, and Moraxella catarrhalis. The cephalosporins included in the third generation are somewhat less active against Gram-positive cocci but much more active against enteric Gram-negative organisms. The currently available oral cephalosporins for pediatric use are listed in Table 2.

The first generation oral cephalosporins are effective alternatives to penicillin for treating staphylococcal and streptococcal infections (Table 3). For this reason they are indicated for skin and soft-tissue infections, as well as for streptococcal pharyngitis. It is important to stress that the members of this generation are not indicated for empiric treatment of otitis media or sinusitis. Although these agents have some activity against Escherichia coli, Klebsiella and Proteus, their use is limited to urinary tract infections caused by susceptible strains of these organisms.

Cephalexin, cefadroxil, cephradine and other first-generation oral cephalosporins have a similar antibacterial spectrum. Cephalexin and cephradine are absorbed well by the gastrointestinal tract but their short half-life requires QID dosing. Cefadroxil has a longer serum half-life that allows for BID administration.

Penicillin and erythromycin remain the drugs of choice for treating streptococcal pharyngitis but the Committee on Infectious Diseases of the American Academy of Pediatrics recently has recognized that the first generation cephalosporins are acceptable alternatives for penicillin-allergic patients and to re-treat patients with recurrent streptococcal pharyngitis.(2) For soft-tissue infections the antistaphylococcal penicillins (cloxacillin and dicloxacillin) are considered the first choice but their bitter taste limits their usefulness in pediatrics, making the first generation cephalosporins an appealing alternative. The second- and third-generation cephalosporins offer no therapeutic advantage in the treatment of these entities and are significantly more expensive.

The oral second-generation cephalosporins have increased activity against Gram-negative bacteria, including H influenzae, N meningitidis and M catarrhalis, making them useful for treating upper and lower respiratory tract infections, sinusitis and otitis media (Table 4). These agents also are active against E coli, Klebsiella and Proteus which makes them potential alternatives for treating urinary tract infections caused by these organisms.

Cefaclor was the first member of this group on the market and remains one of the most widely used cephalosporins. In general, its spectrum of activity is similar to that of the other second generation agents except for somewhat limited activity against S aureus.(3) Based on its half-life the recommended dosing interval is TID although limited clinical trials have shown good response rates with BID dosing to treat acute otitis media. Cefaclor has been associated with an unusual serum-sickness like reaction which is characterized by a generalized pruritic rash, arthritis, arthralgias and fever. These symptoms appear 5 to 15 days after the start of therapy and generally disappear within 5 days after discontinuing the drug. The incidence of such reactions, which has varied from 1 per 200 to 1 per 10,000 antibiotic courses, appears to be due to an inherited defect in the handling of metabolic products of cefaclor.

Cefprozil has a spectrum similar to that of the other second generation cephalosporins with the convenience of BID dosing. Four patients with serum sickness-like reaction associated with cefprozil therapy have been described.(4) The activity of cefprozil against b-lactamase-positive H influenzae is not ideal.

Cefuroxime axetil recently became available in a pediatric suspension with a BID dosing schedule. This compound is formulated as an ester prodrug to facilitate its absorption, but it may cause a metallic aftertaste. The antimicrobial activity is identical to the parenteral cefuroxime formulation, making it the logical agent to complete therapy when patients with pneumonia without a specific pathogen have improved on intravenous cefuroxime.

Loracarbef, although chemically a carbacephem, has a spectrum of activity similar to that of the second generation cephalosporins. It is structurally identical to cefaclor except for a sulfur atom that has been replaced by a methylene group. This change gives greater chemical stability in solution and allows storage at room temperature. The recommended dosing schedule is BID. The serum-sickness-like reaction associated with cefaclor does not appear to be as common with loracarbef.

The currently available third-generation cephalosporins are active against many enteric Gram-negative organisms, including b-lactamase producers, Salmonella and Shigella, but have less activity against Gram-positive bacteria (Table 5). Enterobacter, pseudomonas and serratia generally are resistant to these agents. Indications for this group include respiratory tract infections, acute otitis media, and urinary tract infections due to susceptible organisms. Cefixime and cefpodoxime also are indicated as single-dose oral alternatives for treating uncomplicated urethral or cervical infections due to N gonorrhoeae.

Cefixime has a prolonged half-life that allows for once a day dosing. Its poor activity against S aureus and only moderate activity against S pneumoniae preclude its use as a first choice in the treatment of otitis media or soft-tissue infections.

Cefpodoxime proxetil, unlike cefixime, has good activity against S aureus, S saprophyticus, and the pneumococci. It has a BID dosing schedule and, because it is also an ester prodrug, may have a metallic aftertaste. Recently, a once-a-day indication for otitis media was approved but the available data with this schedule are not convincing.

Ceftibuten, the newest member of this group with once-a-day dosing, has excellent Gram-negative activity but no activity against S aureus and limited clinical efficacy against pneumococci and M catarrhalis.

The second- and third-generation cephalosporins, with the exception of cefixime and ceftibuten, are considered second-line alternatives for treating acute otitis media caused by S pneumoniae, H influenzae, M catarrhalis, and S pyogenes. Cefixime and ceftibuten are not indicated for treatment of otitis media resulting from pneumococcus infection. Most experts agree that amoxicillin remains the first choice for uncomplicated acute otitis media, with trimethoprim-sulfamethoxazole (TMP/SMX) and erythromycin-sulfisoxazole as alternatives in the penicillin-allergic patient.(5) The indications for second line agents include lack of clinical response, reappearance of signs and symptoms, or documented resistance to the initial agent. Other second-line agents used to manage pediatric otitis media include amoxicillin-clavulanate, clarithromycin, and azithromycin. Because all of these second-line agents have produced comparable response rates in the treatment of otitis media, the decision to use a particular one should be based on other factors such as cost, potential for adverse effects, convenient dosing schedule, and acceptability to the patient.

Penicillin-resistant S pneumoniae has emerged as an important pathogen in childhood upper respiratory infections,(6) with some areas of the country reporting rates of resistance >30%. This resistance to penicillin is the result of alterations in the PBP, not because of production of b-lactamase enzymes. While the therapeutic approach to serious infections due to these resistant strains has been established,(7) there is limited data on the management of less serious infections due to these isolates, as in the case of otitis media or sinusitis. In vitro data by Nelson and colleagues(8) demonstrated variable activity of the oral cephalosporins against penicillin-resistant pneumococci, with cefuroxime, cefprozil, and cefpodoxime showing moderate to high activity; loracarbef and cefaclor with poor to moderate activity; and cefixime and ceftibuten with very poor activity against resistant strains. The only cephalosporin that has been evaluated in a clinical trial to date is cefuroxime, which showed a 92.5% success rate for penicillin-susceptible isolates (MIC <0.1 micrograms/mL), 90% for the intermediately-resistant isolates (MIC 0.1 to 1.0 micrograms/mL), and 75% for highly-resistant strains (MIC >1.0 micrograms/mL).(9) Further clinical trials to evaluate other cephalosporins are being conducted and will help define alternatives in the treatment of these infections.

Other drugs that have shown excellent in vitro activity against the resistant pneumococci are clindamycin and rifampin, with modest activity noted for erythromycin and clarithromycin, and poor activity for TMP/SMX, ciprofloxacin and amoxicillin. Clindamycin previously has been found to be effective in treating otitis media caused by S pneumoniae,(10) and a clinical trial in treating resistant strains is warranted. Rifampin should not be used as a single agent in treating these infections due to the rapid emergence of resistance but the combination of rifampin and clarithromycin appears to be synergistic and may prove helpful.(8) In the future, the selection of a particular antimicrobial agent as the first-line drug may be influenced by the increased prevalence of resistant organisms.

Armando G. Correa, M.D.
Assistant Professor of Pediatrics
Baylor College of Medicine
Houston, TX

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