Cefaclor

Abstract

Dermatologists treat a variety of uncomplicated skin and skin structure infections (uSSSIs) such as folliculitis, impetigo, erysipelas, cellulitis, furuncles, carbuncles, and non-perirectal abscesses. Most uSSSIs are caused by Staphylococcus aureus and Streptococcus pyogenes. The new extended-spectrum cephalosporins (cefdinir, cefpodoxime) offer efficacy against most Gram-positive and Gram-negative pathogens.

Despite recently published guidelines, many physicians do not prescribe cephalosporins for uSSSIs out of concern that these agents will produce a hypersensitivity reaction in patients allergic to penicillin. Although the rate of cephalosporin reaction in penicillin-allergic patients is often quoted as up to 10%, this rate does not take into account the 1% to 3% risk for allergy to cephalosporin alone and the nonspecific increased risk of penicillin-allergic patients to develop hypersensitivity to other drugs. When these additional risks are considered, the likelihood of a reaction in known penicillin-allergic patients, especially to most third-generation and extended spectrum cephalosporins, becomes less than 1%.

Cephalosporins with side chains unlike those of penicillin or ampicillin side chains are less likely to result in an allergic reaction in penicillin or ampicillin-allergic patients than cephalosporins with similar side chains. Although both cefdinir and cefpodoxime are considered to carry a very low risk of cross reactivity with penicillin or ampicillin, the former demonstrates better activity against S. aureus. Among the late-generation cephalosporins, cefdinir is the most potent oral agent when tested against oxacillin-susceptible staphylococci, 4- to 16-fold more active than cefprozil and cephalexin, respectively.

Introduction

Skin and skin structure infections (SSSIs) comprise a large component of cutaneous diseases treated by dermatologists in community practice. SSSIs are treated according to whether they are uncomplicated or complicated. (1) Uncomplicated infections include folliculitis, impetigo, erysipelas, cellulitis, furuncles, carbuncles, and non-perirectal abscesses. Complicated infections involve deeper tissue as well as skin; include infected ulcers and infected burns; may include systemic confounders such as neutropenia and immunosuppression; and may occur at high-risk sites (eg, near the anus).

In both pediatric and adult patients, most uncomplicated skin and skin structure infections (uSSSIs) are caused by Staphylococcus aureus and Streptococcus pyogenes. (2) S. aureus is found in 85% and S. pyogenes in 30% of lesions associated with impetigo, the most common superficial skin infection in children. (3,4) Due to the high prevalence of these organisms in pyogenic skin infections, empiric therapy is usually directed against them unless the infection is known to be caused by another pathogen.

When treating bacterial uSSSIs, a variety of antibiotic agents are available from which to choose (Table 1). Efficacy and safety are prime factors, but antibiotic resistance, potential litigation due to unexpected adverse drug reactions, and cost must also be considered. Choices are also based on spectrum of activity, pharmacologic properties, and the potential for complicating pregnancy discovered after antibiotic administration. (5)

Categorized by generation, cephalosporins are the most widely prescribed class of orally administered antibiotics for SSSIs. First-generation members (cephalexin, cefadroxil) have good activity against S. pyogenes and methicillin-susceptible S. aureus (MSSA) and are given once or four times daily. Second-generation members (cefaclor, cefuroxime, cefprozil) have expanded activity against Gram-negative pathogens while retaining good activity against Gram-positive organisms. Their longer half-lives permit less frequent (twice daily) dosing. Third-generation cephalosporins (cefixime, ceftibuten, cefditoren) are effective against Gram-negative pathogens but less effective against Gram-positive organisms when compared with earlier cephalosporins: They are given once or twice daily.

The new extended-spectrum agents (cefdinir, cefpodoxime) offer advantages of broader activity spectrum, showing efficacy against both common Gram-positive and Gram-negative pathogens. These agents are administered twice daily.

The American Academy of Pediatrics (AAP) has issued evidence-based practice guidelines for the use of cephalosporins for certain indications in patients allergic to penicillin. These guidelines were formulated with the assumption that the frequently quoted rates of cross-sensitivity to cephalosporins among patients allergic to penicillin (8%-18%) require revision. (6) The AAP guidelines support (1) the use of cefuroxime, cefpodoxime, and cefdinir in the management of acute bacterial sinusitis for patients with allergy to penicillin, providing the allergic reaction is not severe, (7) and (2) the use of cefuroxime, cefpodoxime, and cefdinir for patients with "non-type I allergy," and parenteral ceftriaxone as a treatment alternative. (8) The types of immunopathologic drug reactions are shown in Table 2. (6,9) Type I reactions may be acutely life threatening, while the others are not. All four types have occurred with penicillin and penicillin derviatives. (10)

Despite these updated guidelines, many physicians hesitate to prescribe cephalosporins due to confusion regarding the definition of a reaction due specifically to penicillin allergy. (6)

This report explores the issue of prescribing cephalosporins to patients with allergies to penicillin, provides updated information on the potency and spectrum of various antibiotics used to treat community-acquired skin and soft-tissue infections (CA-SSTIs), and summarizes the sensitivities of various antibiotics used to treat SSSIs.

Cephalosporins and Penicillin Allergy

When a known penicillin-sensitive patient has an allergic reaction after receiving a cephalosporin, the reaction may not be due to the established allergy to penicillin; it may be caused by an allergy to cephalosporin, which occurs in 1% to 3% of patients regardless of penicillin-allergy status. In addition, penicillin-allergic patients have an increased risk for allergic reaction to any drug. The reported rate of cephalosporin reaction in penicillin-allergic patients is 0.7% to 8.1%, (11,12) but the actual rate is much lower when the generalized risks enumerated above are considered. First- and second-generation cephalosporins have approximately 2% risk and third-generation cephalosporins carry about a 0.6% risk. (6) A detailed review of data on the relationship between penicillin allergy and cephalosporins showed that most penicillin-allergic patients could be given cephalosporin antibiotics safely. (13) This is especially true if one pre-selects the cephalosporin based upon chemical structural considerations (see below).

The Role of Side Chains

Cephalosporins and penicillin are both of low molecular weight, are highly substituted, and possess a [beta]-lactam ring. (14) Representative structures are shown in Figure 1. As the primary antigenic determinant, the [beta]-lactam ring is responsible for antimicrobial activity. (14,15) However, it is not this ring structure which is primarily the determinant of hypersensitivity, but rather the side chains. The cross reactivity between penicillin or ampicillin and cephalosporins with a different side chain appears to be less than that between penicillin/ampicillin and cephalosporins with similar side chains. (15) Therefore, it is important to recognize which cephalosporins "resemble" penicillin or ampicillin in side-chain structure to make logical decisions about potential problems and permissible drug usage despite a history of penicillin allergy.

Figures 2 to 5 illustrate the role of side chains in cross reactivity between penicillins and cephalosporins. The safety of prescribing cephalosporins with side chains dissimilar to those of penicillin is supported by the study of Novalbos and colleagues. (15) In this study, 41 penicillin-allergic patients were challenged with three cephalosporins (cephazoline, cefuroxime, and ceftriaxone) with a side chain unlike that of the specific penicillin derivative that induced the known allergy. When therapeutic doses of the aforementioned cephalosporins were given to these patients, no ill affects were observed. These results are consistent with those of other studies (13,16,17) that suggest markedly reduced cross-reactivity between penicillin and cephalosporins with dissimilar side chains.

Cephalosporins with side chains that are structurally similar to penicillin include cephaloridine, cephalothin, and cefoxitin. The former two agents are no longer available in the US for human use, and thus have no clinical relevance. By contrast, many widely available cephalosporins are structurally similar to, and therefore potentially cross-reactive with, ampicillin (and amoxicillin). Such drugs include cefaclor, cephalexin, cefprozil, cephradine, and cefadroxil. Notably absent from both penicillin and ampicillin structural analogues are the following, presumed safer agents: cefdinir, cefpodoxime, cefditoren, and cefuroxime (oral), as well as ceftriaxone (parenteral).

Clinical Basis for Selecting Antibiotics

A comprehensive study of the comparative potencies and spectra of cefdinir with those of various antibiotics used to treat community-acquired SSSIs has been reported. (18) The data from this study were used to establish a clinical basis for selecting empiric antibiotic therapy for the treatment of uSSSIs. (1) The data are shown in Tables 3 and 4.

Among cephalosporins, cefdinir was the most potent oral cephalosporin (MI[C.sub.90] 0.5 [micro]g/mL) tested against oxacillin-susceptible staphylococci, 4- to 16-fold more active than cefprozil and cephalexin, respectively. Cefuroxime (MIC90 4 [micro]g/mL) and amoxicillin/clavulanate (MI[C.sub.90] 2 [micro]g/ml) also showed excellent activity. Cefpodoxime was notably less effective in vitro against pathogenic staphylococci than cefdinir. With the exceptions of erythromycin and ciprofloxacin, all Group A and B streptococci were 100% susceptible to all tested agents.

Against S. pyogenes, cefdinir (MI[C.sub.90] [less than or equal to]0.03 [micro]g/mL) and cefpodoxime (MI[C.sub.90] [less than or equal to]0.03 [micro]g/mL) were the most active cephalosporins. Cefuroxime (MI[C.sub.90] [less than or equal to]0.06 [micro]g/mL) and amoxicillin clavulanate (MI[C.sub.90] [less than or equal to]0.06 [micro]g/mL) also showed excellent activity.

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In some situations, one may encounter Gram-negative pathogens as etiologic for uSSSIs, particularly Escherichia coli and Klebsiella species. Against these most common Gram-negative etiologies of uSSSIs, cefdinir (MI[C.sub.90] 0.5 [micro]g/mL) and cefpodoxime (MI[C.sub.90] 0.5 [micro]g/mL) are the most active cephalosporins, while cefuroxime is considerably less effective against these microbes.

Taking these recent microbiological data together, one might attempt to identify a cephalosporin which is: (1) easy to administer (orally), (2) considered safe to use in allegedly penicillin or ampicillin allergic patients, (3) expected to be effective against the Gram-positive organisms which typically cause uSSSIs, and (4) expected to be effective against the few Gram-negative organisms which may cause or confound uSSSIs. Cefdinir and cefditoren seem the logical candidates to fulfill these criteria based upon current MIC patterns and our better understanding of the role of chemical structure in penicillin cross-reactivity. It should be noted that the latter drug is not indicated in patients less than 12 years of age.

Updated Uses and Limitations of Antibiotic Classes

Penicillins

S. pyogenes is generally sensitive to penicillins. S. aureus is no longer routinely sensitive due to widespread resistance. [beta]-Lactamase-stable penicillins exhibit good anti-staphylococcal activity and good tissue penetration, but are not effective against Gram-negative organisms. Most penicillins and penicillin derivatives are given twice or four times a day.

Macrolides

Erythromycin is less useful because of selected properties, including frequent gastrointestinal (GI) intolerance, short half-life, increasing resistance of organisms associated with uSSSI, and lack of utility if Gram-negative pathogens cause or complicate the infection. Clarithromycin and azithromycin have fewer GI side effects and longer half-lives but activities against staphylococci and streptococci are largely similar to erythromycin. Cross-resistance will limit utility. (19)

Lincosamides

Lincosamides, clindamycin in particular, have good activity against S. pyogenes and MSSA. They are active against many community-acquired MRSA strains. A resistance to erythromycin may signal inducible resistance to clindamycin. There is, however, an increased risk of gastrointestinal overgrowth of Clostridium difficile, which is associated with pseudomembranous colitis. Although almost any antibiotic can induce pseudomembranous colitis, it appears that clindamycin is particularly likely to cause this severe adverse event. Lincosamides are given twice or four times daily. (19)

Tetracyclines

Tetracycline, doxycycline, and minocycline have also been studied in the management of uSSSIs. Some resistance exists to all three variations. Minocyline covers some MRSA, for example. However, MRSA susceptibility to minocycline may vary from locale to locale, and it is imperative for the clinician to be familiar with resistance patterns inherent to his or her region. Timing is an issue, as both food and cationic minerals may bind tetracyclines. There is a risk of GI intolerance and yeast infections, as well as some concern about administration to a female of child-bearing potential who might become (or might be) pregnant. Studies and clinical experience also suggest variable degrees of photosensitivity; the latter is most severe with the parent molecule (tetracycline) and least severe with minocycline. Doxycycline induces a dose-dependent photosensitivity (none at 40 mg/day and increasing photosensitivity up to the standard 100 mg twice-daily dose).

Fluoroquinolones

Despite a long half-life and efficacy comparable to [beta]-lactams for erysipelas, cellulitis, impetigo, surgical wounds, and diabetic foot infections, fluoroquinolones should be reserved as alternatives to [beta]-lactams. Due to widespread use, resistance among staphylococci, streptococci, and Gram-negative bacilli is increasing. (20) MRSA develops rapid resistance to fluoroquinolones, and for this reason this class has not proven satisfactory for this indication. (21) Animal data suggest some degree of fetal risk should drugs of this class be inadvertently given to a pregnant female. Agitation, nightmares, and insomnia also may rarely complicate fluoroquinolone administration.

Trimethoprim/Sulfamethoxazole

This combination is effective against CA-MRSA but resistance occurs among staphylococci. There is also significant risk of severe hypersensitivity reactions such as erythema multiforme major and toxic epidermal necrolysis. For this reason, this agent is not a first-line therapy for most uSSSIs. Photosensitivity has occurred in rare cases. Trimethoprim/sulfamethoxazole continues as a popular choice for CA-MRSA, however, as most strains will be susceptible throughout the US.

Conclusion

The safety of treating penicillin-allergic patients with cephalosporins with side chains not similar to those of penicillin is supported by numerous studies, as is the superior potency, broad spectrum, and tolerability of later-generation agents (such as cefdinir) in the treatment of uSSSIs. While other classes of antibiotics may be effective, they all manifest some suboptimal properties. Thus, cephalosporins remain an excellent choice for the empiric therapy of most uSSSIs in both adults and children.

Disclosure: Dr. Rosen is a member of the Speakers Bureau of Abbott Laboratories.

References

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Address for Correspondence

Theodore Rosen MD

Professor of Dermatology

Baylor College of Medicine

6620 Main, Suite 1425

Houston, Texas 77030-2725

Phone: 713-794-7129

Fax: 713-794-7863

Theodore Rosen MD

Professor of Dermatology, Baylor College of Medicine, Houston, TX

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