Drugs 42 (Suppl. 3): 51-56. 1991 0012-6667/91/0300-0051/$3.00/0 © Adis International Limited. All rights reserved. DRSUP3205a
Cefpodoxime Proxetil in the Treatment of Skin and Soft Tissue Infections Kenneth J. Tack,l Nancy E. Wilks,l Gregory Semerdjian,2 Calvin H. Frazier, 3 Kim Shirin,3 Anthony Puopolo,4 Stanley G. Crossland,s Bernard S. Goffe 6 and Larry Millikan 7 Parke Davis, Ann Arbor, Michigan, I San Diego, California,2 Glendale, California,3 Milford, Massachusetts,4 Arlington, Virginia,5 Seattle, Washington,6 Department of Dermatology, New Orleans, Louisiana,7 USA
Summary
Patients with skin and soft tissue infections were enrolled in a study comparing 2 dosage regimens of orally administered cefpodoxime proxetil; 204 patients with mild to moderate infections received cefpodoxime proxetil 200mg twice daily and 47 patients with severe infections received 400mg twice daily. Both dosage regimens were given for 7 to 14 days. 132 of 142 (93.0%) evaluable patients in the 200mg group and 22 of 29 (75.9%) in the 400mg group were clinically cured post-therapy, the remainder in both groups being classified as improved. The pathogen eradication rate at the end of therapy in the 200mg group was 161 of 165 (97.6%), and 38 of 38 (100%) in the 400mg group. Adverse reactions (drug-related) were reported by 20 (8.0%) patients overall, and there was no apparent relationship between the dosage group and the incidence of adverse reactions. The most commonly reported reactions involved the gastrointestinal tract (diarrhoea) or female genital tract (vaginitis). Cefpodoxime proxetil appears to be a useful and safe agent in the therapy of skin and soft tissue infections.
Cefpodoxime proxetil is an orally administered third generation cephalosporin that is broken down by intestinal esterases to the active moiety cefpodoxime (Komai et at. 1988). In vitro susceptibility testing has shown that cefpodoxime is highly active against many species of common bacterial pathogens such as Streptococcus pyogenes and Staphylococcus aureus, as well as many species of Enterobacteriaceae (Jones & Barry 1988). Single oral doses of 200mg achieved a mean peak serum concentration of 2.2 mg/L, and the drug had a half-life of 2.7 hours (Borin et at. 1990). After a 400mg dose, a mean peak concentration of 4.2 mg/L was achieved in healthy subjects (Borin et at. 1990). Tissue penetration, as assessed by a skin blister
technique, was excellent, with penetration from plasma estimated to be 67 to 101% (Borin et at. 1990) or more (O'Neill et at. (990). As cefpodoxime is active in vitro against commonly encountered skin pathogens, and its relatively long half-life permits twice-daily administration, the current study was performed to evaluate its usefulness in skin and skin structure infections.
1. Patients and Methods Written informed consent was obtained from all study patients after the potential risks and benefits of the study had been explained. The protocol and informed consent document were approved by the
52
Drugs 42 (Suppl. J) 1991
Institutional Review Board of each participating institution. Many study sites were outpatient clinic settings.
were planned: (I) on days 7 to 10 of therapy (2) at the end of therapy, up to 6 days after completion of drug, and (3) a long term follow-up, 2 to 3 weeks after completion of therapy.
1.1 Eligibility 1.3 Assessment of Response Patients were recruited at 13 sites throughout the United States. Males and nonpregnant/nonlacTherapeutic outcome was assessed at completating females aged ~ 12 years with skin and soft of therapy. Clinical response was graded as tion tissue infections, such as wound infections, follicure (complete resolution of signs and symptoms culitis, cellulitis, infected ulcers or burns, carbunof infection), improvement (partial resolution), or cles, or infected dermatoses, of < 7 days' duration failure (little or no resolution of signs and sympwere eligible for the study. Patients with a history toms of infection). Microbiological outcome was of allergy to cephalosporins or severe reaction to defined as eradication or persistence of the reother J3-lactams were excluded, as were women of sponsible pathogen(s). Recurrence was defined as childbearing potential not on adequate contracepreappearance of symptoms and signs of the original tion and patients with osteomyelitis, diabetic foot infection between the end-of-therapy visit and the infections, or serious underlying illness. long term follow-up visit. After confirming the diagnosis of skin and/or soft tissue infections and obtaining informed conPatients were considered evaluable for efficacy sent, specimens from the infection sites were obanalysis if (I) a pathogen susceptible to cefpodoxtained for culture and susceptibility testing. Susime was isolated at study admission, (2) the patient ceptibility testing was performed using NCCL~ was compliant with therapy (i.e. took at least 80% approved methodology (National Committee for\ of assigned study medi~ation), (3) returned for the Clinical Laboratory Standards 1990). A IOI-'g \ end-of-therapy evaluatIOn, and (4) took no other cefpodoxime disk was used for disk diffusion sussystemic antimicrobials over the treatment period. ceptibility testing, or minimum inhibitory concenPatients who discontinued the study drug because trations (MICs) were determined using agar plates. of poor clinical response after 48 hours of cefpoThe following breakpoints were used: susceptible, " doxime therapy, but before taking 80% of the inMIC':::; 2 I-'g/ml or disk zone ~ 2lmm; moderately tended course of drug, were considered to be evsusceptible, MIC = 4 I-'g/ml or disk zone 18 to aluable for the efficacy analysis and were classified 20mm; resistant MIC ~ 8 I-'g/ml or disk zone':::; as clinical failures. 17mm (Jones & Barry 1988). All patients who received the study drug were considered evaluable for the safety analysis. Patients were questioned at each visit for possible adverse 1.2 Dosage Regimen events and all such events were recorded. The investigator was required to determine the relationPatients were administered cefpodoxime proxship of each event to the study drug (probably reetil orally, twice daily, and were assigned to I of 2 lated, possibly related, or not related to study drug). treatment regimens depending on the severity of Events considered possibly or probably related to the infection; patients with infections of mild to the study drug were designated drug-related admoderate severity were administered cefpodoxime proxetil equivalent to 200mg cefpodoxime, and verse events (adverse reactions). A battery of patients with severe infections were administered screening laboratory assays was obtained from each cefpodoxime proxetil equivalent to 400mg cefpopatient at admission to the study and repeated at doxime. The duration of therapy was 7 to 14 days the end-of-therapy visit to investigate changes posin both treatment groups. Three follow-up visits sibly indicative of drug toxicity.
Cefpodoxime for Skin and Soft Tissue Infections
Table I. Demographic data and diagnoses at admission for evaluable patients
Treatment group cefpodoxime 200mg (n = 142)
cefpodoxime 400mg (n = 29)
Mean age (years) [range]
44.7 [13-87]
44.7 [13-77]
Sex (M/F)
85/57
21/8
Race White Black Hispanic Other
104 33 4
17 10 2 0
75.1 [45-141]
79.3 [45-145]
39 2 4 5 14 6 8 57 1 6
6 0
Mean weight (kg) [range] Diagnosis Abscess Carbuncle Furuncle Folliculitis Cellulitis Pyoderma Paronychia Wound infection Infected ulcer Other
4 0 0 11 3 3
2. Results 2.1 Patient Population 13 investigators enrolled 251 patients in the study: 204 into the 200mg treatment group and 47 into the 400mg treatment group. 171 patients, 142 in the 200mg group and 29 in the 400mg group, were evaluable for efficacy. The most frequent reason for nonevaluability was failure to isolate a pathogen from the admission culture. Key demographic data and diagnoses for evaluable patients are presented in table I. All patients in the 200mg group had infections classified by the investigator as mild or moderate, and all patients in the 400mg group had infections classified as severe.
2.2 In Vitro Susceptibility In vitro susceptibility testing was performed on 274 of 279 pathogens isolated from evaluable and none valuable patients at study admission. Of these,
53
248 (90.5%) were susceptible, 17 (6.2%) were moderately susceptible, and 9 (3.3%) were resistant. The most commonly isolated pathogens were S. aureus, Staphylococcus epidermidis, S. pyogenes, and Escherichia coli. Two isolates of methicillin-susceptible S. epidermidis were resistant to cefpodoxime, as were single isolates of methicillin-resistant S. epidermidis and S. aureus, methicillin-susceptible S. aureus, Enterococcus faecalis, group D Streptococcus species, Enterobacter cloacae, and Klebsiella
pneumoniae. 2.3 Efficacy Microbiological eradication rates by pathogen and treatment group for evaluable patients at the end of therapy are summarised in table II. 161 of 165 (97.6%) pathogens in the 200mg group were eradicated, as were 38 of 38 in the 400mg group. The overall pathogen eradication rate for both groups was 199 of 203 (98.0%). The only persisting pathogen was S. aureus, and only in the 200mg group where the eradication rate regardless of {JTable II. Microbiological eradication rates for evaluable patients at the end of therapy
Pathogen
No. isolates eradicated/total cefpodoxime 200mg (n = 142)
cefpodoxime 400mg (n = 29)
Staphylococcus aureus BL S. aureus non-BL S. aureus NOS S. epidermidis Other Staphylococcus spp. Streptococcus pyogenes Other Streptococcus spp. Escherichia coli Proteus mirabilis Other Enterobacteriaceae
51/54
15/15
13/13 5/6 27/27 5/5
0/0 1/1 3/3 0.0
18/18 13/13 20/20 3/3 6/6
6/6 4/4 3/3 2/2 4/4
Totals
161/165 (97.6%) 38/38 (100%)
Abbreviations: BL = Jj-Iactamase producing; non-BL = non-Jjlactamase producing; NOS = not otherwise specified.
Drugs 42 (Supp/. 3) 1991
54
Table III. Clinical outcomes for evaluable patients at the end of therapy
Treatment group
Cefpodoxime 200mg Cefpodoxime 400mg
No. of patients/total (%) cured
improved
failed
132/142 (93.0) 22/29 (75.9)
10/142 (7.0)
0/142 (0.0)
7/29 (24.1)
0/28 (0.0)
lactamase status was still excellent, 69 of73 (94.5%), and did not differ to a statistically significant extent from that in the 400mg group. Eradication rates for both Streptococcus species and Enterobacteriaceae were 100% in bOlh treatment groups. Of the 142 evaluable patients in the 200mg group, 138 (97.2%) had all pathogens eradicated, 2 (1.4%) had at least I but not all pathogens in a polymicrobial infection eradicated, and 2 (1.4%) had persistence of pathogens. All patients in the 400mg group had all pathogens eradicated. Clinical outcomes for evaluable patients at the end of therapy are summarised in table III. All patients responded clinically, the clinical cure rate being higher in the 200mg group, most probably reflecting the greater severity of the initial infections in the 400mg group. No recurrences in either dose group were reported at the follow-up visit. Microbiological and clinical outcomes in the nonevaluable patients were similar to those in the evaluable group. Among those nonevaluable patients with a pathogen isolated at admission and who returned for end-of-therapy assessment, the responsible pathogen(s) were eradicated from all of 28 in the 200mg group and 13 of 14 (92.9%) in the 400mg group; 38 of 38 and 18 of 19 (94.7%) pathogens were eradicated in the 2 groups, respectively. For nonevaluable patients with an end-oftherapy clinical assessment, in the 200mg group 36 of 50 (72.0~/o) were cured, 12 (24.0%) were improved, and 2 (4.0%) failed therapy, and in the 400mggroup 9 of 14 (64.3%) were cured, 3 (21.4%) were improved, and 2 (14.3%) failed therapy.
2.4 Safety Cefpodoxime proxetil was well tolerated. 34 (16.7%) patients in the cefpodoxime 200mg group and 5 (10.6%) in the 400mg group reported I or more adverse event, either drug related or not drug related, over the course of the study. Most of these events, 58 of 61 (95.1 %) in the 200mg group and 6 of 6 in the 400mg group, were classified as mild or moderate in intensity. Drug-related adverse events (adverse reactions) occurred in 18 (8.8%) patients in the 200mg group, and in 2 (4.3%) in the 400mg group. Most adverse reactions affected the gastrointestinal tract, with diarrhoea being the most common (12 of251, 4.8%) complaint (table IV). Complaints related to alterations in vaginal flora were also relatively frequent. There was no apparent increase in the incidence of adverse events or reactions with the larger dose. Five (2.5%) patients in the 200mg group discontinued cefpodoxime proxetil because of conTable IV. Number of patients reporting cefpodoxime-related adverse reactions
Adverse reaction
Number of patients cefpodoxime 200mg (n = 204)
Gastrointestinal Diarrhoea Loose stools Nausea Abdominal pain Heartburn
11 2
General Vaginitis
4
Dermatological Rash
o
Neurological Headache
2
cefpodoxime 400mg (n = 47)
1
o o o o o
o
Respiratory Wheezing
o
Body as a whole Malaise
o
55
Cefpodoxime for Skin and Soft Tissue Infections
comitant adverse events: 2 because of diarrhoea and I each because of contact dermatitis (thought to be unrelated to cefpodoxime), wheezing and nausea. One patient (2.1 %) in the 400mg group discontinued cefpodoxime because of a rash. Thus, the overall rate of drug discontinuation as a result of adverse reactions (possibly drug-related events) was 5 of 251 (2.0%). Screening laboratory studies revealed statistically significant drops in mean peripheral WBC in the 200mg group, and decreases in immature polymorphonuclear cells in both treatment groups, both changes consistent with resolution of infection. Five patients in the 200mg group and 4 in the 400mg group developed eosinophilia after completion of therapy. One patient in each group developed a positive Coombs' test post-therapy, unaccompanied by a drop in haemoglobin or other indications of haemolysis. Elevations in alkaline phosphatase, AST and ALT were seen infrequently in patients; increases were not clinically significant and it was unclear whether these were related to the study drug.
3. Discussion Infections of the skin and soft tissues are commonly encountered in clinical practice. Cellulitis, wound infections and abscesses are most often due to S. aureus and S. pyogenes in outpatients, but may also be due to Gram-negative organisms such as E. coli. The role of S. epidermidis in the pathogenesis of skin infections has only recently been appreciated. This study demonstrates that cefpodoxime proxetil is highly effective in the treatment of outpatient infections of the skin and skin structures. A dosage regimen of 200mg twice daily for mild to moderate infections and 400mg twice daily for severe infections resulted in clinical cure or improvement in all evaluable patients and eradication of most of the responsible pathogens (167 of 171, 97.7%). The most commonly encountered pathogens were, as expected, S. aureus. S. epidermidis. S. pyogenes. and E. coli. Although the MIC90 of cefpodoxime for S. aureus is close to plasma con-
centrations achieved after a 400mg dose, eradication rates for this organism were excellent in both the 200mg and 400mg groups. Cefpodoxime proxetil was generally well tolerated. 39 of the 251 (15.5%) patients experienced at least 1 adverse event and, of these, 20 (8.0%) experienced a drug-related adverse event (an adverse reaction). Most adverse reactions were mild and involved the gastrointestinal tract, diarrhoea being the most frequent (4.8%). Approximately 2% of patients discontinued cefpodoxime proxetil therapy because of adverse reactions, usually diarrhoea or hypersensitivity, which are typical of cephalosporins. Clinically significant laboratory abnormalities developing during therapy were rare, and the relationship to cefpodoxime was unclear. Two patients developed positive Coombs' tests. However, the development of positive Coombs' tests during cephalosporin therapy is usually of no clinical significance (Molthan et al. 1967). In conclusion, cefpodoxime proxetil appears to be a useful agent in the therapy of skin and soft tissue infections in the outpatient setting.
Acknowledgement This study was supported by a grant from the Upjohn Company. Principal investigators (and centres) for this study were: Harry Collins. MD (Edison NJ): Robert D. Chiulli. MD (Clinton, MA): Stanley G. Crossland. MD (Arlington, VA): L. Edward Ellinwood. Ph D. MD (Grand Junction, CO): Calvin H. Frasier. MD/Kim K. Shirin. Ph D (Glendale, CAl: Bernard S. Gaffe (Seattle, WA): K. Dale Hooker. Pharm.D (Kansas City, MO): Thomas M. Hooton. MD (Seattle, WA): Paul Lucky. MD (Cincinnati, OH): Larry Millikan. MD (New Orleans, LA): Anthony Puopolo. MD (Milford, MA): Gregory Semerdjian. MD (San Diego, CAl: Keith Swenson. MD (Portland, OR).
References Borin MT, Hughes GS, Spillers CR, Patel RK. Pharmacokinetics of cefpodoxime in plasma and skin blister fluid following oral dosing of cefpodoxime proxetil. Antimicrobial Agents and Chemotherapy 34: 1094-1099. 1990 Jones RN. Barry AL. Antimicrobial activity and disk diffusion testing of U-76,253A (R-3746), the active metabolite of the new cephalosporin ester, U-76,252 (CS-807). Antimicrobial Agents and Chemotherapy 32: 443-449, 1988 Komai T, Kawai K, Tsubaki H, Tokui T, Kinoshita T, et al.
56
Absorption. distribution. metabolism. and excretion of CS-807. a new oral cephem antibiotic. in experimental animals. Chemotherapy (Tokyo) 36: 129-240. 1988 Molthan L. Reidenberg MM. Eichman MF. Positive Coombs' tests due to cephalothin. New England Journal of Medicine 277: 123.1967 National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial disk susceptibility tests. 4th ed .. NCCLS. Villanova Pennsylvania. 1990 O'Neill P. Nye K. Dounce G. Andrews J. Wise R. Pharmacoki-
Drugs 42 (Suppl. 3) 1991
netics and inflammatory fluid penetration of cefpodoxime proxetil in volunteers. Antimicrobial Agents and Chemotherapy 34: 232-234, 1990.
Correspondence and reprints: Nancy E. Wilks. The Upjohn Company, 9155-298-232,301 Henrietta Street. Kalamazoo. MI4900l, USA.
Cefpodoxime Proxetil in the Treatment of Skin and Soft Tissue Infections Kenneth J. Tack,l Nancy E. Wilks,l Gregory Semerdjian,2 Calvin H. Frazier, 3 Kim Shirin,3 Anthony Puopolo,4 Stanley G. Crossland,s Bernard S. Goffe 6 and Larry Millikan 7 Parke Davis, Ann Arbor, Michigan, I San Diego, California,2 Glendale, California,3 Milford, Massachusetts,4 Arlington, Virginia,5 Seattle, Washington,6 Department of Dermatology, New Orleans, Louisiana,7 USA
Summary
Patients with skin and soft tissue infections were enrolled in a study comparing 2 dosage regimens of orally administered cefpodoxime proxetil; 204 patients with mild to moderate infections received cefpodoxime proxetil 200mg twice daily and 47 patients with severe infections received 400mg twice daily. Both dosage regimens were given for 7 to 14 days. 132 of 142 (93.0%) evaluable patients in the 200mg group and 22 of 29 (75.9%) in the 400mg group were clinically cured post-therapy, the remainder in both groups being classified as improved. The pathogen eradication rate at the end of therapy in the 200mg group was 161 of 165 (97.6%), and 38 of 38 (100%) in the 400mg group. Adverse reactions (drug-related) were reported by 20 (8.0%) patients overall, and there was no apparent relationship between the dosage group and the incidence of adverse reactions. The most commonly reported reactions involved the gastrointestinal tract (diarrhoea) or female genital tract (vaginitis). Cefpodoxime proxetil appears to be a useful and safe agent in the therapy of skin and soft tissue infections.
Cefpodoxime proxetil is an orally administered third generation cephalosporin that is broken down by intestinal esterases to the active moiety cefpodoxime (Komai et at. 1988). In vitro susceptibility testing has shown that cefpodoxime is highly active against many species of common bacterial pathogens such as Streptococcus pyogenes and Staphylococcus aureus, as well as many species of Enterobacteriaceae (Jones & Barry 1988). Single oral doses of 200mg achieved a mean peak serum concentration of 2.2 mg/L, and the drug had a half-life of 2.7 hours (Borin et at. 1990). After a 400mg dose, a mean peak concentration of 4.2 mg/L was achieved in healthy subjects (Borin et at. 1990). Tissue penetration, as assessed by a skin blister
technique, was excellent, with penetration from plasma estimated to be 67 to 101% (Borin et at. 1990) or more (O'Neill et at. (990). As cefpodoxime is active in vitro against commonly encountered skin pathogens, and its relatively long half-life permits twice-daily administration, the current study was performed to evaluate its usefulness in skin and skin structure infections.
1. Patients and Methods Written informed consent was obtained from all study patients after the potential risks and benefits of the study had been explained. The protocol and informed consent document were approved by the
52
Drugs 42 (Suppl. J) 1991
Institutional Review Board of each participating institution. Many study sites were outpatient clinic settings.
were planned: (I) on days 7 to 10 of therapy (2) at the end of therapy, up to 6 days after completion of drug, and (3) a long term follow-up, 2 to 3 weeks after completion of therapy.
1.1 Eligibility 1.3 Assessment of Response Patients were recruited at 13 sites throughout the United States. Males and nonpregnant/nonlacTherapeutic outcome was assessed at completating females aged ~ 12 years with skin and soft of therapy. Clinical response was graded as tion tissue infections, such as wound infections, follicure (complete resolution of signs and symptoms culitis, cellulitis, infected ulcers or burns, carbunof infection), improvement (partial resolution), or cles, or infected dermatoses, of < 7 days' duration failure (little or no resolution of signs and sympwere eligible for the study. Patients with a history toms of infection). Microbiological outcome was of allergy to cephalosporins or severe reaction to defined as eradication or persistence of the reother J3-lactams were excluded, as were women of sponsible pathogen(s). Recurrence was defined as childbearing potential not on adequate contracepreappearance of symptoms and signs of the original tion and patients with osteomyelitis, diabetic foot infection between the end-of-therapy visit and the infections, or serious underlying illness. long term follow-up visit. After confirming the diagnosis of skin and/or soft tissue infections and obtaining informed conPatients were considered evaluable for efficacy sent, specimens from the infection sites were obanalysis if (I) a pathogen susceptible to cefpodoxtained for culture and susceptibility testing. Susime was isolated at study admission, (2) the patient ceptibility testing was performed using NCCL~ was compliant with therapy (i.e. took at least 80% approved methodology (National Committee for\ of assigned study medi~ation), (3) returned for the Clinical Laboratory Standards 1990). A IOI-'g \ end-of-therapy evaluatIOn, and (4) took no other cefpodoxime disk was used for disk diffusion sussystemic antimicrobials over the treatment period. ceptibility testing, or minimum inhibitory concenPatients who discontinued the study drug because trations (MICs) were determined using agar plates. of poor clinical response after 48 hours of cefpoThe following breakpoints were used: susceptible, " doxime therapy, but before taking 80% of the inMIC':::; 2 I-'g/ml or disk zone ~ 2lmm; moderately tended course of drug, were considered to be evsusceptible, MIC = 4 I-'g/ml or disk zone 18 to aluable for the efficacy analysis and were classified 20mm; resistant MIC ~ 8 I-'g/ml or disk zone':::; as clinical failures. 17mm (Jones & Barry 1988). All patients who received the study drug were considered evaluable for the safety analysis. Patients were questioned at each visit for possible adverse 1.2 Dosage Regimen events and all such events were recorded. The investigator was required to determine the relationPatients were administered cefpodoxime proxship of each event to the study drug (probably reetil orally, twice daily, and were assigned to I of 2 lated, possibly related, or not related to study drug). treatment regimens depending on the severity of Events considered possibly or probably related to the infection; patients with infections of mild to the study drug were designated drug-related admoderate severity were administered cefpodoxime proxetil equivalent to 200mg cefpodoxime, and verse events (adverse reactions). A battery of patients with severe infections were administered screening laboratory assays was obtained from each cefpodoxime proxetil equivalent to 400mg cefpopatient at admission to the study and repeated at doxime. The duration of therapy was 7 to 14 days the end-of-therapy visit to investigate changes posin both treatment groups. Three follow-up visits sibly indicative of drug toxicity.
Cefpodoxime for Skin and Soft Tissue Infections
Table I. Demographic data and diagnoses at admission for evaluable patients
Treatment group cefpodoxime 200mg (n = 142)
cefpodoxime 400mg (n = 29)
Mean age (years) [range]
44.7 [13-87]
44.7 [13-77]
Sex (M/F)
85/57
21/8
Race White Black Hispanic Other
104 33 4
17 10 2 0
75.1 [45-141]
79.3 [45-145]
39 2 4 5 14 6 8 57 1 6
6 0
Mean weight (kg) [range] Diagnosis Abscess Carbuncle Furuncle Folliculitis Cellulitis Pyoderma Paronychia Wound infection Infected ulcer Other
4 0 0 11 3 3
2. Results 2.1 Patient Population 13 investigators enrolled 251 patients in the study: 204 into the 200mg treatment group and 47 into the 400mg treatment group. 171 patients, 142 in the 200mg group and 29 in the 400mg group, were evaluable for efficacy. The most frequent reason for nonevaluability was failure to isolate a pathogen from the admission culture. Key demographic data and diagnoses for evaluable patients are presented in table I. All patients in the 200mg group had infections classified by the investigator as mild or moderate, and all patients in the 400mg group had infections classified as severe.
2.2 In Vitro Susceptibility In vitro susceptibility testing was performed on 274 of 279 pathogens isolated from evaluable and none valuable patients at study admission. Of these,
53
248 (90.5%) were susceptible, 17 (6.2%) were moderately susceptible, and 9 (3.3%) were resistant. The most commonly isolated pathogens were S. aureus, Staphylococcus epidermidis, S. pyogenes, and Escherichia coli. Two isolates of methicillin-susceptible S. epidermidis were resistant to cefpodoxime, as were single isolates of methicillin-resistant S. epidermidis and S. aureus, methicillin-susceptible S. aureus, Enterococcus faecalis, group D Streptococcus species, Enterobacter cloacae, and Klebsiella
pneumoniae. 2.3 Efficacy Microbiological eradication rates by pathogen and treatment group for evaluable patients at the end of therapy are summarised in table II. 161 of 165 (97.6%) pathogens in the 200mg group were eradicated, as were 38 of 38 in the 400mg group. The overall pathogen eradication rate for both groups was 199 of 203 (98.0%). The only persisting pathogen was S. aureus, and only in the 200mg group where the eradication rate regardless of {JTable II. Microbiological eradication rates for evaluable patients at the end of therapy
Pathogen
No. isolates eradicated/total cefpodoxime 200mg (n = 142)
cefpodoxime 400mg (n = 29)
Staphylococcus aureus BL S. aureus non-BL S. aureus NOS S. epidermidis Other Staphylococcus spp. Streptococcus pyogenes Other Streptococcus spp. Escherichia coli Proteus mirabilis Other Enterobacteriaceae
51/54
15/15
13/13 5/6 27/27 5/5
0/0 1/1 3/3 0.0
18/18 13/13 20/20 3/3 6/6
6/6 4/4 3/3 2/2 4/4
Totals
161/165 (97.6%) 38/38 (100%)
Abbreviations: BL = Jj-Iactamase producing; non-BL = non-Jjlactamase producing; NOS = not otherwise specified.
Drugs 42 (Supp/. 3) 1991
54
Table III. Clinical outcomes for evaluable patients at the end of therapy
Treatment group
Cefpodoxime 200mg Cefpodoxime 400mg
No. of patients/total (%) cured
improved
failed
132/142 (93.0) 22/29 (75.9)
10/142 (7.0)
0/142 (0.0)
7/29 (24.1)
0/28 (0.0)
lactamase status was still excellent, 69 of73 (94.5%), and did not differ to a statistically significant extent from that in the 400mg group. Eradication rates for both Streptococcus species and Enterobacteriaceae were 100% in bOlh treatment groups. Of the 142 evaluable patients in the 200mg group, 138 (97.2%) had all pathogens eradicated, 2 (1.4%) had at least I but not all pathogens in a polymicrobial infection eradicated, and 2 (1.4%) had persistence of pathogens. All patients in the 400mg group had all pathogens eradicated. Clinical outcomes for evaluable patients at the end of therapy are summarised in table III. All patients responded clinically, the clinical cure rate being higher in the 200mg group, most probably reflecting the greater severity of the initial infections in the 400mg group. No recurrences in either dose group were reported at the follow-up visit. Microbiological and clinical outcomes in the nonevaluable patients were similar to those in the evaluable group. Among those nonevaluable patients with a pathogen isolated at admission and who returned for end-of-therapy assessment, the responsible pathogen(s) were eradicated from all of 28 in the 200mg group and 13 of 14 (92.9%) in the 400mg group; 38 of 38 and 18 of 19 (94.7%) pathogens were eradicated in the 2 groups, respectively. For nonevaluable patients with an end-oftherapy clinical assessment, in the 200mg group 36 of 50 (72.0~/o) were cured, 12 (24.0%) were improved, and 2 (4.0%) failed therapy, and in the 400mggroup 9 of 14 (64.3%) were cured, 3 (21.4%) were improved, and 2 (14.3%) failed therapy.
2.4 Safety Cefpodoxime proxetil was well tolerated. 34 (16.7%) patients in the cefpodoxime 200mg group and 5 (10.6%) in the 400mg group reported I or more adverse event, either drug related or not drug related, over the course of the study. Most of these events, 58 of 61 (95.1 %) in the 200mg group and 6 of 6 in the 400mg group, were classified as mild or moderate in intensity. Drug-related adverse events (adverse reactions) occurred in 18 (8.8%) patients in the 200mg group, and in 2 (4.3%) in the 400mg group. Most adverse reactions affected the gastrointestinal tract, with diarrhoea being the most common (12 of251, 4.8%) complaint (table IV). Complaints related to alterations in vaginal flora were also relatively frequent. There was no apparent increase in the incidence of adverse events or reactions with the larger dose. Five (2.5%) patients in the 200mg group discontinued cefpodoxime proxetil because of conTable IV. Number of patients reporting cefpodoxime-related adverse reactions
Adverse reaction
Number of patients cefpodoxime 200mg (n = 204)
Gastrointestinal Diarrhoea Loose stools Nausea Abdominal pain Heartburn
11 2
General Vaginitis
4
Dermatological Rash
o
Neurological Headache
2
cefpodoxime 400mg (n = 47)
1
o o o o o
o
Respiratory Wheezing
o
Body as a whole Malaise
o
55
Cefpodoxime for Skin and Soft Tissue Infections
comitant adverse events: 2 because of diarrhoea and I each because of contact dermatitis (thought to be unrelated to cefpodoxime), wheezing and nausea. One patient (2.1 %) in the 400mg group discontinued cefpodoxime because of a rash. Thus, the overall rate of drug discontinuation as a result of adverse reactions (possibly drug-related events) was 5 of 251 (2.0%). Screening laboratory studies revealed statistically significant drops in mean peripheral WBC in the 200mg group, and decreases in immature polymorphonuclear cells in both treatment groups, both changes consistent with resolution of infection. Five patients in the 200mg group and 4 in the 400mg group developed eosinophilia after completion of therapy. One patient in each group developed a positive Coombs' test post-therapy, unaccompanied by a drop in haemoglobin or other indications of haemolysis. Elevations in alkaline phosphatase, AST and ALT were seen infrequently in patients; increases were not clinically significant and it was unclear whether these were related to the study drug.
3. Discussion Infections of the skin and soft tissues are commonly encountered in clinical practice. Cellulitis, wound infections and abscesses are most often due to S. aureus and S. pyogenes in outpatients, but may also be due to Gram-negative organisms such as E. coli. The role of S. epidermidis in the pathogenesis of skin infections has only recently been appreciated. This study demonstrates that cefpodoxime proxetil is highly effective in the treatment of outpatient infections of the skin and skin structures. A dosage regimen of 200mg twice daily for mild to moderate infections and 400mg twice daily for severe infections resulted in clinical cure or improvement in all evaluable patients and eradication of most of the responsible pathogens (167 of 171, 97.7%). The most commonly encountered pathogens were, as expected, S. aureus. S. epidermidis. S. pyogenes. and E. coli. Although the MIC90 of cefpodoxime for S. aureus is close to plasma con-
centrations achieved after a 400mg dose, eradication rates for this organism were excellent in both the 200mg and 400mg groups. Cefpodoxime proxetil was generally well tolerated. 39 of the 251 (15.5%) patients experienced at least 1 adverse event and, of these, 20 (8.0%) experienced a drug-related adverse event (an adverse reaction). Most adverse reactions were mild and involved the gastrointestinal tract, diarrhoea being the most frequent (4.8%). Approximately 2% of patients discontinued cefpodoxime proxetil therapy because of adverse reactions, usually diarrhoea or hypersensitivity, which are typical of cephalosporins. Clinically significant laboratory abnormalities developing during therapy were rare, and the relationship to cefpodoxime was unclear. Two patients developed positive Coombs' tests. However, the development of positive Coombs' tests during cephalosporin therapy is usually of no clinical significance (Molthan et al. 1967). In conclusion, cefpodoxime proxetil appears to be a useful agent in the therapy of skin and soft tissue infections in the outpatient setting.
Acknowledgement This study was supported by a grant from the Upjohn Company. Principal investigators (and centres) for this study were: Harry Collins. MD (Edison NJ): Robert D. Chiulli. MD (Clinton, MA): Stanley G. Crossland. MD (Arlington, VA): L. Edward Ellinwood. Ph D. MD (Grand Junction, CO): Calvin H. Frasier. MD/Kim K. Shirin. Ph D (Glendale, CAl: Bernard S. Gaffe (Seattle, WA): K. Dale Hooker. Pharm.D (Kansas City, MO): Thomas M. Hooton. MD (Seattle, WA): Paul Lucky. MD (Cincinnati, OH): Larry Millikan. MD (New Orleans, LA): Anthony Puopolo. MD (Milford, MA): Gregory Semerdjian. MD (San Diego, CAl: Keith Swenson. MD (Portland, OR).
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Correspondence and reprints: Nancy E. Wilks. The Upjohn Company, 9155-298-232,301 Henrietta Street. Kalamazoo. MI4900l, USA.
