Loracarbef (LY163892) Versus Cefaclor in the Treatment of Bacterial Skin and Skin-Structure Infections in an Adult Population JAMES MCCARTY, M.D., Fresno, California, GARY
E.
RUOFF, M.D., Kalamazoo, Michigan, KIRK
D.
JACOBSON, M.D.,
Eugene, Oregon
Loracarbef (LY163892), a member of the class of fl-lactam antibiotics known as carbacephems, is characterized by a high level of chemical stability and a broad spectrum of antibacterial activity that persists in the presence of fl-lactamase. The efficacy and safety of loracarbef, 200 mg (twice daily), and cefaclor, 250 mg (three times daily) (one patient received 178 mg of cefaclor suspension, three times daily), were compared in a randomized, double-blind, multicenter trial conducted in adults with skin and skin-structure infections due predominantly to Staphylococcus aureus. Examination within 72 hours after the completion of therapy indicated a favorable clinical response in 84 (93.3%) of the 90 loracarbeftreated patients evaluable for efficacy and in 79 (95.2%) of the 83 evaluable patients treated with cefaclor. Pathogens were eradicated in 83 (92.2%) of the patients in the loracarbef group and 74 (89.2%) of those in the cefaclor group. Only four adverse events--headache/migraine, diarrhea, abdominal pain, and nausea-occurred in >2% of the total study population. The overall incidence of adverse events in the 201 loracarbef-treated and 192 cefaclor-treated patients evaluated for safety was 19.9% and 24.5%, respectively. Adverse events that required hospitalization or discontinuation of treatment occurred in four patients in the cefaclor group but in none of those treated with loracarbef. There were no statistically significant differences in the clinical or bacteriologic response or the incidence of side effects between the two treatment groups. These findings indicate that loracarbef given twice daily is comparable in safety and efficacy to cefaclor given three times daily in the treatment of adults with skin and skin-structure infections. From the California Medical Research Group, Fresno, California, the Westside Family Medical Center, Kalamazoo, Michigan, and Patterson Internal Medicine, Eugene, Oregon. This study was supported by grants from Eli Lilly and Company. Requests for reprints should be addressed to James McCarty, M.D., California Medical ResearchGroup, 3636 North 1st Street, Suite 133, Fresno,California 93726. 6A-80S
nfections of the skin and skin structures are comIpractices monly encountered in both general and specialty [1,2]. Although Staphylococcus aureus
and fi-hemolytic streptococci are the most frequent causes of bacterial skin infections, many such infections are caused by multiple pathogens. In addition to staphylococci and streptococci, anaerobic and aerobic gram-negative bacilli may be responsible for bacterial skin infections. The use of topical versus systemic antibiotics for the treatment of skin and skin-structure infections has been a topic of debate; however, the evidence now available suggests the superiority of systemic therapy. For example, a review of the literature conducted by Baltimore [3] showed that antibiotics administered systemically were more effective than those administered topically for the treatment of skin infections. This proved to be the case whether therapeutic outcome was measured by changes in the morphology of the lesions, by the area of involvement, or by eradication of the causative pathogens. Loracarbef is an oral fl-lactam antibiotic of the carbacephem class that has been shown to be active against a broad spectrum of bacteria, including those organisms commonly isolated from patients with skin and skin-structure infections [4-6]. The carbacephems are structurally similar to the cephalosporins but are distinguished by the presence of a methylene group in place of the sulfur atom in the dihydrothiazine ring of the cephalosporin nucleus. This structural difference accounts for the improved chemical stability of carbacephems as compared with corresponding cephalosporins. A double-blind, randomized, multicenter study compared the efficacy and safety of loracarbef with cefaclor, its cephalosporin analogue, in the treatment of skin and skin-structure infections in adults.
STUDY DESIGN Patients ->12 years of age with a clinical diagnosis of a bacterial skin infection, including subcutaneous abscess, cellulitis, impetigo, pyoderma, infected postsurgical or traumatic wound other than a burn wound, infected skin ulcer, lymphangitis, and lymphadenitis, were considered for enrollment in this trial. Pregnant or nursing women, patients
June 22, 1992 The American Journal of Medicine Volume 92 (suppl 6A)
SYMPOSIUM ON ANTIMICROBIALTHERAPY/ MCCARTY ET AL
with a history of renal impairment as indicated by a serum creatinine ->177 tLmol/L (2.0 mg/dL), and individuals with any condition, including significant underlying disease or concomitant infection, that could preclude evaluation of the therapeutic response to the study medication were ineligible for admission. Other exclusion criteria included an anticipated need for systemic or topical antibiotics other than the study agents during the course of the trial, the use of successful or suppressive antimicrobial therapy within 3 days of the pretreatment evaluation, the use of other investigational agents within the previous 28 days, and hypersensitivity to penicillins and/or cephalosporins. Each patient or his or her parent/guardian provided written informed consent for participation in the study. Patients were assigned to treatment with loracarbef or cefaclor, and were given sequentially numbered treatment kits that were randomized at the time of packaging. Treatment was administered in capsule or oral suspension form. The loracarbef dosage was 200 mg twice daily for 7 days, regardless of dosage form. Patients treated with an oral suspension of cefaclor received 20 mg/kg/day, up to a maximum of 534 mg daily, in three divided doses for 7 days. Patients treated with encapsulated cefaclor received 250 mg three times daily for 7 days. In order to maintain the double-blind nature of the study, patients assigned to treatment with loracarbef received placebo at midday. A minimum treatment duration of 5 days was required for patients who responded to antibiotic therapy, but no minimum treatment period was required for nonresponders. Those patients who met the study inclusion criteria provided a complete history and underwent a physical examination within 24 hours prior to administration of the first dose of the assigned medication (day 0). Between days 3 and 5 of treatment, the symptomatic response to the study drug and patient adherence to the prescribed regimen were evaluated. The symptomatic response to therapy was again assessed within 72 hours after the cessation of treatment. Physical examination was repeated to detect possible recurrence of infection 10-14 days after the end of the treatment period. At both posttreatment evaluations (72 hours and 10-14 days following cessation of treatment), the investigators rated the global symptomatic response as cure, improvement (substantial), failure, relapse, or unable to evaluate. Bacteriologic culture of swabs or aspirates taken from study subjects was required prior to treatment. Repeat cultures were performed at the follow-up examinations for those patients who failed to show a clinical response or who demon-
strated clinical relapse. Standardized disk methodology (National Committee for Clinical Laboratory Standards) and/or minimal inhibitory concentration (MIC) determination was used to evaluate the susceptibility of the isolated organisms to both loracarbef and cefaclor. A zone diameter ->18 mm or an MIC -
E.
RUOFF, M.D., Kalamazoo, Michigan, KIRK
D.
JACOBSON, M.D.,
Eugene, Oregon
Loracarbef (LY163892), a member of the class of fl-lactam antibiotics known as carbacephems, is characterized by a high level of chemical stability and a broad spectrum of antibacterial activity that persists in the presence of fl-lactamase. The efficacy and safety of loracarbef, 200 mg (twice daily), and cefaclor, 250 mg (three times daily) (one patient received 178 mg of cefaclor suspension, three times daily), were compared in a randomized, double-blind, multicenter trial conducted in adults with skin and skin-structure infections due predominantly to Staphylococcus aureus. Examination within 72 hours after the completion of therapy indicated a favorable clinical response in 84 (93.3%) of the 90 loracarbeftreated patients evaluable for efficacy and in 79 (95.2%) of the 83 evaluable patients treated with cefaclor. Pathogens were eradicated in 83 (92.2%) of the patients in the loracarbef group and 74 (89.2%) of those in the cefaclor group. Only four adverse events--headache/migraine, diarrhea, abdominal pain, and nausea-occurred in >2% of the total study population. The overall incidence of adverse events in the 201 loracarbef-treated and 192 cefaclor-treated patients evaluated for safety was 19.9% and 24.5%, respectively. Adverse events that required hospitalization or discontinuation of treatment occurred in four patients in the cefaclor group but in none of those treated with loracarbef. There were no statistically significant differences in the clinical or bacteriologic response or the incidence of side effects between the two treatment groups. These findings indicate that loracarbef given twice daily is comparable in safety and efficacy to cefaclor given three times daily in the treatment of adults with skin and skin-structure infections. From the California Medical Research Group, Fresno, California, the Westside Family Medical Center, Kalamazoo, Michigan, and Patterson Internal Medicine, Eugene, Oregon. This study was supported by grants from Eli Lilly and Company. Requests for reprints should be addressed to James McCarty, M.D., California Medical ResearchGroup, 3636 North 1st Street, Suite 133, Fresno,California 93726. 6A-80S
nfections of the skin and skin structures are comIpractices monly encountered in both general and specialty [1,2]. Although Staphylococcus aureus
and fi-hemolytic streptococci are the most frequent causes of bacterial skin infections, many such infections are caused by multiple pathogens. In addition to staphylococci and streptococci, anaerobic and aerobic gram-negative bacilli may be responsible for bacterial skin infections. The use of topical versus systemic antibiotics for the treatment of skin and skin-structure infections has been a topic of debate; however, the evidence now available suggests the superiority of systemic therapy. For example, a review of the literature conducted by Baltimore [3] showed that antibiotics administered systemically were more effective than those administered topically for the treatment of skin infections. This proved to be the case whether therapeutic outcome was measured by changes in the morphology of the lesions, by the area of involvement, or by eradication of the causative pathogens. Loracarbef is an oral fl-lactam antibiotic of the carbacephem class that has been shown to be active against a broad spectrum of bacteria, including those organisms commonly isolated from patients with skin and skin-structure infections [4-6]. The carbacephems are structurally similar to the cephalosporins but are distinguished by the presence of a methylene group in place of the sulfur atom in the dihydrothiazine ring of the cephalosporin nucleus. This structural difference accounts for the improved chemical stability of carbacephems as compared with corresponding cephalosporins. A double-blind, randomized, multicenter study compared the efficacy and safety of loracarbef with cefaclor, its cephalosporin analogue, in the treatment of skin and skin-structure infections in adults.
STUDY DESIGN Patients ->12 years of age with a clinical diagnosis of a bacterial skin infection, including subcutaneous abscess, cellulitis, impetigo, pyoderma, infected postsurgical or traumatic wound other than a burn wound, infected skin ulcer, lymphangitis, and lymphadenitis, were considered for enrollment in this trial. Pregnant or nursing women, patients
June 22, 1992 The American Journal of Medicine Volume 92 (suppl 6A)
SYMPOSIUM ON ANTIMICROBIALTHERAPY/ MCCARTY ET AL
with a history of renal impairment as indicated by a serum creatinine ->177 tLmol/L (2.0 mg/dL), and individuals with any condition, including significant underlying disease or concomitant infection, that could preclude evaluation of the therapeutic response to the study medication were ineligible for admission. Other exclusion criteria included an anticipated need for systemic or topical antibiotics other than the study agents during the course of the trial, the use of successful or suppressive antimicrobial therapy within 3 days of the pretreatment evaluation, the use of other investigational agents within the previous 28 days, and hypersensitivity to penicillins and/or cephalosporins. Each patient or his or her parent/guardian provided written informed consent for participation in the study. Patients were assigned to treatment with loracarbef or cefaclor, and were given sequentially numbered treatment kits that were randomized at the time of packaging. Treatment was administered in capsule or oral suspension form. The loracarbef dosage was 200 mg twice daily for 7 days, regardless of dosage form. Patients treated with an oral suspension of cefaclor received 20 mg/kg/day, up to a maximum of 534 mg daily, in three divided doses for 7 days. Patients treated with encapsulated cefaclor received 250 mg three times daily for 7 days. In order to maintain the double-blind nature of the study, patients assigned to treatment with loracarbef received placebo at midday. A minimum treatment duration of 5 days was required for patients who responded to antibiotic therapy, but no minimum treatment period was required for nonresponders. Those patients who met the study inclusion criteria provided a complete history and underwent a physical examination within 24 hours prior to administration of the first dose of the assigned medication (day 0). Between days 3 and 5 of treatment, the symptomatic response to the study drug and patient adherence to the prescribed regimen were evaluated. The symptomatic response to therapy was again assessed within 72 hours after the cessation of treatment. Physical examination was repeated to detect possible recurrence of infection 10-14 days after the end of the treatment period. At both posttreatment evaluations (72 hours and 10-14 days following cessation of treatment), the investigators rated the global symptomatic response as cure, improvement (substantial), failure, relapse, or unable to evaluate. Bacteriologic culture of swabs or aspirates taken from study subjects was required prior to treatment. Repeat cultures were performed at the follow-up examinations for those patients who failed to show a clinical response or who demon-
strated clinical relapse. Standardized disk methodology (National Committee for Clinical Laboratory Standards) and/or minimal inhibitory concentration (MIC) determination was used to evaluate the susceptibility of the isolated organisms to both loracarbef and cefaclor. A zone diameter ->18 mm or an MIC -
