PHARMACOLOCY AND THERAPEUTICS
OELOXACIN VERSUS CEPHALEXIN FOR TREATING SKIN AND SOFT TISSUE INFECTIONS BENJAMIN A. EIPSKY, M . D . , DABNEY R. Y A R B R O U C H III, M . D . , EREDERIC B. WALKER IV, M . D . , ROBERT D. POWERS, M . D . , AND MANUEL R. M O R M A N , M . D . , P H . D .
and safety of ofloxacin in comparison with cephalexin for treating various skin, skin structure, and soft tissue infections in adults.
Abstract Patients with acute localized skin or soft tissue infections were randomized to receive either ofloxacin (300 mg orally, b.i.d.) or cephalexin (500 mg orally, b.i.d.). Among 401 enrolled patients, 382 were evaluable for safety and 148 for microbiologic response. Microbiologic cure occurred in 93.4% of ofloxacin-treated patients and in 94.0% of those treated with cephalexin. Clinical cure or improvement, respectively, was found in 85.2% and 11.1% of patients treated with ofloxacin, and 83.6% and 14.9% of patients receiving cephalexin. Adverse effects (primarily associated with the gastrointestinal tract and central nervous system) were considered to be drug-related in 7.9% of those receiving ofloxacin and 4.8% of those receiving cephalexin. Thus, ofloxacin is as effective and well tolerated as cephalexin and a good alternate antibiotic for treating skin and skin structure infections caused by a variety of pathogens.
Materials and Methods After giving informed consent, patients were enrolled at 18 centers in the United States. Acute skin, skin structure, or soft tissue infections were diagnosed by the presence of localized pain, erythema, swelling, drainage, or other clinical signs. Isolation of a pathogen from a culture of the affected area was required. Patients with secondarily infected ulcers associated with complications of diabetes mellitus, peripheral vascular disease, or those with decubitus ulcers were limited to 20% of the total enrollment. Patients were excluded if they: were pregnant or nursing; were likely to require concomitant parenteral antimicrobial therapy; had osteomyelitis; had significant gastrointestinal problems or surgery that might interfere with the absorption of the drugs; were allergic to any members of the quinolone, cephalosporin, or penicillin classes of antimicrobials; had clinically significant or unstable renal, hepatic, cardiovascular, hematologic, neurologic, psychiatric, respiratory, neoplastic, metabolic, or articular disease; had received ofloxacin or any other investigational agent within 30 days of entry; or had an infection involving more than one anatomic area. Cultures were obtained by swab, needle aspiration, or curettage, as appropriate. An equal number of patients were assigned randomly to receive 10 days of twice-daily oral therapy with either ofloxacin (300 mg) or cephalexin (500 mg). Patients returned for two follow-up evaluations: the first between study days 3 and 5 (during the course of therapy) and the second between study days 11 and 13 (after concluding therapy).
Infections of the skin and soft tissues are common and usually uncomplicated. Some patients, however, develop more serious infections, or infections caused by multiple or antibiotic-resistant pathogens. Furthermore, some patients are allergic or intolerant to (3-lactam antibiotics. In circumstances such as these, commonly used antibiotics may be inadequate. In comparison, the recently introduced fluoroquinolones have more favorable pharmacokinetic properties and a broader spectrum of activity. All of these agents are active against most aerobic gram-negative organisms; for gram-positive organisms, including Stapbylococcus aureus and
Streptococcus pyogenes—the two most common pathogens causing skin and soft tissue infections— ofloxacin may be more active than other available agents. This study was designed to evaluate the efficacy
Efficacy and Safety Determinations: The primary measure of efficacy w a s eradication of the originally isolated pathogen(s) on follow-up culture. Response to antimicrobial treatment was also evaluated by (1) pathogen, (2) infection site, and (3) clinical response. Microbiologic efficacy was classified as cure, failure, cure or failure with superinfection, or not evaluable. Safety evaluation was based on diary cards and detailed questioning at follow-up visits. Drug-related adverse experiences were those assessed by the investigator as being definitely or probably related to the study drug. The distributions of microbiologic and clinical responses were compared for the two antibiotic groups using the Cochran-Mantel-Haenszel procedure. Fisher's exact twosided test was used to compare the eradication rates of pathogens between the two treatment groups and to compare the rate of superinfection between groups. Adverse events were evaluated using Fisher's exact two-sided test.
From the Seattle VA Medical Center, University of Washington School of Medicine, Seattle, Washington, the Department of Surgery, Medical University of South Carolina College of Medicine, Charleston, South Carolina, the Departments of Internal Medicine, and Emergency Medical Services, University of Virginia School of Medicine, Charlottesville, Virginia, and "•private practice. Supported by an educational grant from the Robert Wood Johnson Pharmaceutical Research Institute. Address for correspondence: Benjamin A. Lipsky, M.D., General Internal Medicine Clinic, Seattle VA Medical Center (J1 IM), 1660 S. Columbian Way, Seattle, WA 98108. 443
International Journal of Dermatology Vol. 31, No. 6, June 1992 RESULTS
Table 1. Microbiologic Efficacy hy Pathogen Pathogen
Patient Population Of the 401 patients enrolled, 202 patients were randomized to ofloxacin and 199 patients to cephalexin. Of these, 148 (81 receiving ofloxacin and 67 receiving cephalexin) were evaluable for microbiologic efficacy, and 382 (189 ofloxacin and 193 cephalexin) were evaluable for safety. The only demographic difference among patients evaluable for safety was in gender distribution; 119 (63%) of the ofloxacin-treated patients and 142 (74%) of the cephalexin-treated patients were male (P = .03). The two treatment groups evaluable for efficacy were similar with respect to gender, age, and race.
Ofloxacin (n = 76)
Cephalexin (n = 67)
Proportion Eradicated %
Proportion Eradicated %
Aerobic Gram-positive Staphylococcus aureus 42/47 89.4 Staphylococcus coag. ne^. 10/10 100.0 Staphylococcus epidermidis 616 100.0 Staphylococcus spp — — Streptococcus pyogenes 10/11 90.9 Streptococcus agalactiae — — Streptococcus mitis — — Streptococcus spp 5/5 100.0 Enterococci 1/1 100.0 Diphtheroids 2/2 100.0 Unidentified gram-positive 1/1 100.0 Aerobic Gram-negative Proteus mirabilis 3/3 100.0 Morganella morgaini 1/1 100.0 Escherichia coli 1/1 100.0 Klehsiella oxytoca 1/1 100.0 Citrohacter freundii — — Klebsiella pneumoniae — — Neisseriaspp 1/1 100.0 Hemophilus 1/1 100.0 parainfluenzae Anaerobic Peptostreptococcus 1/1 100.0 anaerohius Bacteroides hivius 1/1 100.0 Genera of uncertain 1/1 100.0 affiliation Total Pathogens 89/95 93.7 Total Infections 71/76 93.4
Efficacy Microbiological Response. The most frequently isolated pathogens were S. aureus (70), coagulase-negative staphylococci (11), Staphylococcus epidermidis (9), and Streptococcus pyogenes (7). Twenty-six pa-
tients (12 receiving ofloxacin and 14 receiving cephalexin) had mixed infections. Of the 143 patients evaluable for comparative efficacy, 93.4% (71/76) of ofloxacin-treated patients and 94.0% (63/67) of the cephalexin patients were microbiologically cured. The bacterioiogic outcome by pathogen is shown in Table 1. Tbere was no statistically significant difference in the microbiologic cure rates between the two treatment regimens (P = .86). Infection persisted in five ofloxacin-treated patients and in three cephalexin-treated patients. The persistent infections were caused by S. aureus alone (in 4 ofloxacin patients and 2 cephalexin-treated patients) and by S. aureus and S. pyogenes (1 patient in each treatment group). Seven (3.8%) of the evaluable patients receiving ofloxacin and three (1.6%) receiving cephalexin developed superinfections. Clinical Response. Among the evaluable patients, abscess was the most frequent diagnosis, followed by cellulitis, impetigo, and "wound infections." A summary of clinical response by diagnosis is presented in Table 2. Among ofloxacin-treated patients, 85.2% were cured, 11.1% improved, and 3.7% were failures. The infections in the 3 patients who failed therapy were caused by S. epidermidis., S. pyogenes, and a mixed infection consisting of S. aureus and S. pyogenes. Among cephalexin-treated patients, 83.6% were cured, 14.9% improved, and 1.5% were failures. The one failure in the cephalexin group was due to Klebsiella oxytoca. Although clinical failures were noted more frequently in the ofloxacin group among patients with cellulitis, impetigo, and wound infections, overall there was no significant difference between treatment groups in the proportion of patients who failed treatment.
38/42 90.5 6/6 100.0 4/4 100.0 1/1 100.0 11/12 91.7 4/4 100.0 1/1 100.0 3/3 100.0 2/2 100.0 — — — — — — 1/1 2/2 1/1 3/3 — —
— — 100.0 100.0 100.0 100.0 — —
Adverse Effects Overall, 104 (55%) of 189 patients treated with ofloxacin and 92 (48.9%) of 188 of those receiving cephalexin reported at least one potential adverse experience during the study. The most frequently reported symptoms for both drugs were nausea, headache, diarrhea, fatigue, dizziness, and gastrointestinal distress. Adverse events that were considered to be drug related were reported for 15 (7.9%) of 189 ofioxacin-treated patients and 9 (4.8%) of 193 cephalexin-treated patients (P = .29). Seven patients in the ofloxacin group (3.7%) and eight in the cephalexin group (4.1%) discontinued therapy because of adverse experiences. Although minor variations were observed in clinical laboratory test values, tbese generally were not considered to be related to drug therapy and showed no clinically relevant trends. DtSCUSSION
This study confirms the effectiveness of ofloxacin for oral therapy of infections of the skin, skin structure, and soft tissue. The microbiologic and clinical cure 444
Ev.i Illation ot Ofk jxncin LJpsk\' cr al.
Table 2. Summary of Glinical Response by Type of Infection Ofloxacin (" =: 76) Type of Infection Gellulitis Abscess Impetigo Wound infection Trophic ulcer Gellulitis and other Wound infection and other Other
Cure Prop. %
Improved Prop. %
14/18 14/15 11/12 9/11
77.8 93.3 91.7 81.8
3/18 1/15 0/12 1/11
Cure Prop. %
Cephalexin (" = 67) impr oved % Prop.
Failure Prop. %
1/18 0/15 1/12 1/11
100.0 88.9 76.9 77.8
16.7 6.7 0.0 9.1
0.0 11.1 23.1 22.2 —
0/9 — 0/1
0.0 — 0.0 0.0
Total patients evaluahle 64/76 for comparative efficacy
rates, respectively, for both ofloxacin (93.4% and 85.2%) and cephalexin (94.0% and 83.6%) were excellent. Ofloxacin was highly effective against the most commonly isolated pathogens, with microbiologic cure rates of 89.4% against S. aureus and 90.9% against S. pyogenes. Ofloxacin was also effective in eradicating mixed infections with Streptococcus and Staphylococcus strains, as well as polymicrobic infections with other bacteria including Neisseria, Hemophilus parainfluenzae, K. pneumoniae, and various strains of Enterobacteriaceae, Acinetobacter, and Proteus. Ofloxacin's efficacy may be based largely on its high penetration into most body tissues and fluids. Serum concentration of ofloxacin after a single oral dose of 300 mg is 4.2 (ig/mL, which exceeds the MlC^o for most common skin and soft tissue pathogens.''- Of 366 pathogens tested in this study, 354 (96.7%) were susceptible to ofloxacin, compared with 316 (86.3%) patbogens in the cephalexin group. Our favorable clinical and microbiologic results are comparable to interim results of this study reported previously.•'"'' While the effectiveness and safety of these two agents have been almost identical in comparative trials with cefaclor and doxycycline, ofloxacin was found to have generally greater microbiologic and clinical efficacy than comparative agents against gram-positive and gram-negative skin and soft tissue pathogens (ofloxacin 83.8% versus cefaclor 69.0%, and ofloxacin 95.2% versus doxycycline 60.0%, respectively).'^~^** In this study, ofloxacin and cephalexin were equally well tolerated. Even though adverse experience information was collected by several methods, patient complaints (mostly nausea, headache, diarrhea) were thought to be drug-related in only 7.9% of those receiving ofloxacin and 4.8% of those receiving cephalexin. The low incidence of probable drug-related side effects offsets the unexpectedly high (almost 50%) overall rate of adverse experiences reported by patients in both groups.
In summary, ofloxacin is a new broad-spectrum oral antimicrobial tbat is highly effective in treating various skin and soft tissue infections. Its efficacy and safety are comparable to those observed with cephalexin. Patients with infections caused by a mixture of organisms, and those allergic to P-lactam antibiotics, may be appropriate candidates for treatment with ofloxacin. DRUG NAMES
cephalexin: Keflex ofloxacin: Eloxin
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