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Clinical Trials of Cefprozil for Treatment of Skin and Skin-Structure Infections: Review Thomas M. Nolen
From the Department of Family Medicine, University of Alabama School of Medicine, Tuscaloosa, Alabama
While serious skin and skin-structure infections often require parenteral antibiotic therapy, most mild-to-moderate infections can be treated adequately with oral agents. Two issues of central concern in such treatment are (1) selection of the most appropriate antibiotic and (2) choice of a dosing regimen most likely to assure patient compliance. While the antistaphylococcal penicillins are effective therapy for many gram-positive cutaneous infections, both the oral cephalosporins and erythromycin are also used widely, particularly in cases of penicillin allergy [1, 2]. Furthermore, oral second-generation cephalosporins such as cefaclor have gained wider usage in the last 10 years owing to their excellent in vitro activity against both gram-positive and gramnegative organisms, although they may not be specifically indicated for skin infections caused by gram-negative organisms. Unfortunately, there are limitations to these familiar therapeutic options. Mounting resistance of Staphylococcus aureus to both penicillin and erythromycin has curtailed the effectiveness of these drugs in many cases [2, 3]. While the development of the antistaphylococcal penicillins has helped to address this problem, these agents have only a narrow spectrum of activity and are generally reserved for serious infections [2]. Moreover, the short half-life of both the oral penicillins and erythromycin necessitates frequent dosing intervals. Frequent dosing may contribute to or cause patient noncompliance. Even though the second-generation cephalosporins generally offer longer half-lives, cefaclor is usually administered three times a day. Reprints or correspondence: Dr. Thomas M. Nolen, Columbiana Associates, 200 Mildred Street, P.O. Box 1006, Columbiana, Alabama 35051. Clinical Infectious Diseases 1992;14(Suppl 2):S255-63
© 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1406-0052$02.00
Cefprozil is an oral cephalosporin with an in vitro spectrum of antimicrobial activity that includes S. aureus and Streptococcus pyogenes, the pathogens most frequently associated with skin and soft-tissue infections [1, 4-9]. Its spectrum of antimicrobial activity is comparable with that of cefaclor [10]. Nonetheless, cefprozil has greater in vitro activity on a microgram basis against S. aureus than cefaclor and cefixime have [10]. It is also active in vitro against other gram-positive and gram-negative pathogens, such as Proteus mirabilis, Propionibacterium acnes, Escherichia coli, Klebsiella organisms, and Clostridium perfringens [1, 5, 8, 11, 12].
Finally, the half-life of cefprozil is considerably longer than that of cefaclor (-1.3 hours vs. 0.6-0.9 hour, respectively) [12, 13]. The prolonged activity of cefprozil and its excellent tissue penetration permit twice-daily and even once-daily dosing [14]; doses of cefaclor and erythromycin are administered three and four times daily, respectively [15-17]. Given these facts, it would be important to know if cefprozil has any clinical advantages over cefaclor or erythromycin in the treatment of mild-to-moderate infections of the skin and skin structure, specifically if twice-daily or oncedaily dosing with cefprozil is as effective and safe as standard regimens of either cefaclor or erythromycin. Three recently completed multicenter clinical trials examined just these issues; the results of these studies, which are published substantially elsewhere, are summarized below [15-17]. Overview of Study Designs
The above-mentioned studies [15-17] were multicenter, open-label, randomized trials comparing the safety and efficacy of two dosing regimens of cefprozil with those of one standard dosing regimen of either cefaclor or erythromycin ethylsuccinate (EES) in patients with mild-to-moderate cuta-
Downloaded from http://cid.oxfordjournals.org/ at New York University on May 7, 2015
Limitations of currently used antimicrobial agents for the treatment of skin and skin-structure infections (e.g., increased resistance to penicillin and erythromycin and inconvenient dosing schedules) have led to an adjustment in the kinds of antimicrobial agents prescribed for these diseases. Three recently completed clinical studies have demonstrated some therapeutic advantages of cefprozil, a new broad-spectrum oral cephalosporin, over cefaclor and erythromycin in the treatment of skin and skin-structure infections. Specifically, cefprozil offers clinical efficacy equivalent to those of cefaclor and erythromycin both at lower total doses and on a less frequent dosing schedule (once or twice daily vs. three to four times daily). The advantage of once-daily or twice-daily dosing with cefprozil may contribute to patient convenience and compliance.
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Nolen
Table 1. Overview of designs of cefprozil clinical trials. Study (no. of patients) A (N = 448) B* (N = 598) C*(N= 221)
Randomization ratio No. of centers involved
Cefprozil: cefaclor
19 18 8
Dosing frequency (mg) Cefprozil: erythromycin Cefprozil Cefaclor Erythromycin
2:1 1:1 1:1
250 b.i.d. 500 q.d. 500 q.d.
250 t.i.d. 250 t.i.d. 400 q.i.d.
No. of minimum doses Dosage form Po Po Po
Cefprozil Cefaclor Erythromycin 10 5 ND
15 15
Duration of treatment (d)
ND
5-10 5-10 10
Age requirements (y) .,18
NOTE. ND = not determined; not a parameter for evaluability in this study.
* Pediatric dosages for cefprozil and cefaclor were 20 mg/[kg • d] q.d. and 20 mg/[kg • d] in three equally divided doses, respectively. *Pediatric patients who were randomized to the cefprozil group and who weighed 5 ND
18 (CFZ) and 27 (Cfac) 9 (CFZ) and 27 (Cfac) ND
2-14 4-18 4-8/14-18
NOTE. CFZ = cefprozil; Cfac = cefaclor; GAS = group A streptococci; ND = not determined—not a parameter for evaluability in this study..
Downloaded from http://cid.oxfordjournals.org/ at New York University on May 7, 2015
neous infections. Study A compared cefprozil (250 mg twice daily) with cefaclor (250 mg three times daily) [15]; study B compared cefprozil (500 mg once daily or 20 mg/[kg • d]) with cefaclor (250 mg three times daily or 20 mg/[kg • d] in three equally divided doses) [16]; and study C compared cefprozil (500 mg once daily or 20 mg/[kg • d]) with EES (400 mg four times daily or 30 mg/[kg • d] in four equally divided doses) [17]. All three drugs were given in oral form for a period of 5-10 days. A total of 1,267 patients were enrolled in the three studies, of whom 856 were evaluable for efficacy. Tables I and 2 outline the three study designs. In general, the evaluable groups in each study were comparable in terms of age, sex, race (table 3), weight, severity and chronicity of infection, and underlying illness. The exceptions in study A were that the patients in the cefprozil group were significantly heavier, had a higher percentage of acute infections, and had a higher prevalence of history of diabetes mellitus (table 4). In study B, the patients receiving cefprozil had a higher prevalence of a history of diabetes mellitus. Patients enrolled in the trials had to demonstrate one or more clinical signs or symptoms (e.g., tenderness, erythema, edema, purulent drainage, fever, etc.) consistent with a mildto-moderate cutaneous infection for which treatment with an oral cephalosporin (studies A and B) or oral erythromycin (study C) was appropriate. Exclusion criteria included pregnancy; lactation; history of a serious reaction to cephalosporins, penicillins, or erythromycin (study C only); presence of
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Cefprozil for Skin and Skin-Structure Infections
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Table 3. Characteristics of evaluable patients in clinical trials of cefprozil. No. of evaluable patients/
No. (%) of males/
Mean age
No. (%) of white/black/
total no. enrolled
no. (%) of females
in y (range)
other race patients
11 l (79)/25 (18)/4 (3)
Study, group A Cefprozil
140/301
86 (61)/54 (39)
43.1 (18-81)
Cefaclor
73/147
43 (59)/30 (41)
47.2 (13-85)
Cefprozil
212/300
122 (58)/90 (42)
28.1 (2-90)
185 (87)/22 (10)/5 (3)
Cefaclor
210/298
130 (62)/80 (38)
27.9 (2-99)
177 (84)/27 (13)/6 (3)
59 (81)/14 (19)/0
B
C Cefprozil
87/108*
64 (59)/44 (41)
34.0 (1-88)
Erythromycin
78/113*
67 (59)/46 (41)
35.7 (2-87)
95 (88)/10 (9)/3 (3) 101 (89)/8 (7)/4 (4)
* Evaluable for clinical efficacy.
Overview of Study Results
Subjects in the three studies exhibited a wide variety of skin and skin-structure infections; the most common infections were cellulitis (127), impetigo (115), superficial infection (99), pyoderma (98), superficial abscess (97), subcutaneous infection (81), wound infection (33), and folliculitis (28). Culture-identified pathogens included S. aureus (471), group A streptococci (129), Staphylococcus epidermidis (108), Klebsiella pneumoniae (13), E. coli (11), P. mirabilis (11), coagulase-negative staphylococci (10), and Pasteurella multocida (1).
The response of patients to therapy was assessed both clinically and bacteriologically. A patient's clinical outcome was considered satisfactory if there was resolution or abatement of the signs and symptoms of infection, with no new signs or symptoms being present. A patient's bacteriologic outcome was considered satisfactory if there was eradication of the causative organism or there was no culturable material present at the original site of infection. Failure to achieve eradication or the need to change antibiotic therapy constituted an unsatisfactory response. Bacteriologic efficacy for each pathogen isolated in the pretreatment cultures was determined
post-treatment. Overall effectiveness was judged on the basis of clinical plus patient bacteriologic efficacy. A brief summary of the results of each study follows (see also table 5). Study A. The results of this study showed that cefprozil (250 mg twice daily) provided greater clinical, bacteriologic, and overall efficacy than cefaclor (250 mg three times daily) did [15]. Rates of pathogen bacteriologic eradication were higher for cefprozil than for cefaclor (88% vs. 76%, respectively). In addition, when controlled for weight, the number of patients for whom successful bacteriologic eradication was achieved with cefprozil was significantly higher than that achieved with cefaclor (86% vs. 74%, respectively; P = .040), as were satisfactory clinical response rates (95% vs. 78%, respectively; P = .001) and overall efficacy rates (84% vs. 67%, respectively; P = .006). Both cefprozil and cefaclor were well tolerated, with the two treatment groups showing no difference in the incidence of drug-related or unknown relationship adverse events (P = .434) (tables 5 and 6). Study B. Findings in this study showed that patients fared as well with cefprozil (500 mg once daily) as they did with cefaclor (250 mg three times daily) [16]. For cefprozil and cefaclor, efficacy rates were similar for satisfactory clinical response (93% vs. 92%, respectively; P = .782), pathogen bacteriologic eradication (92% vs. 90%, respectively), patient bacteriologic eradication (91% vs. 89%, respectively; P =
Table 4. Demographic variables showing significant differences in Study A. No. (%) of patients with Weight* (kg)
indicated infection*
Treatment group Mean
SD
Range
Acute
Cefprozil
81.27
19.85
Cefaclor
77.14
18.00
40.8-128.4 45.4-123.4
(no. of evaluable patients)
(N = 140) (N = 73)
Chronic
diabetes mellitus*
135 (96)
5 (4)
24 (17)
63 (86)
10(14)
7(10)
NOTE. Significance determined by alpha level
Clinical Trials of Cefprozil for Treatment of Skin and Skin-Structure Infections: Review Thomas M. Nolen
From the Department of Family Medicine, University of Alabama School of Medicine, Tuscaloosa, Alabama
While serious skin and skin-structure infections often require parenteral antibiotic therapy, most mild-to-moderate infections can be treated adequately with oral agents. Two issues of central concern in such treatment are (1) selection of the most appropriate antibiotic and (2) choice of a dosing regimen most likely to assure patient compliance. While the antistaphylococcal penicillins are effective therapy for many gram-positive cutaneous infections, both the oral cephalosporins and erythromycin are also used widely, particularly in cases of penicillin allergy [1, 2]. Furthermore, oral second-generation cephalosporins such as cefaclor have gained wider usage in the last 10 years owing to their excellent in vitro activity against both gram-positive and gramnegative organisms, although they may not be specifically indicated for skin infections caused by gram-negative organisms. Unfortunately, there are limitations to these familiar therapeutic options. Mounting resistance of Staphylococcus aureus to both penicillin and erythromycin has curtailed the effectiveness of these drugs in many cases [2, 3]. While the development of the antistaphylococcal penicillins has helped to address this problem, these agents have only a narrow spectrum of activity and are generally reserved for serious infections [2]. Moreover, the short half-life of both the oral penicillins and erythromycin necessitates frequent dosing intervals. Frequent dosing may contribute to or cause patient noncompliance. Even though the second-generation cephalosporins generally offer longer half-lives, cefaclor is usually administered three times a day. Reprints or correspondence: Dr. Thomas M. Nolen, Columbiana Associates, 200 Mildred Street, P.O. Box 1006, Columbiana, Alabama 35051. Clinical Infectious Diseases 1992;14(Suppl 2):S255-63
© 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1406-0052$02.00
Cefprozil is an oral cephalosporin with an in vitro spectrum of antimicrobial activity that includes S. aureus and Streptococcus pyogenes, the pathogens most frequently associated with skin and soft-tissue infections [1, 4-9]. Its spectrum of antimicrobial activity is comparable with that of cefaclor [10]. Nonetheless, cefprozil has greater in vitro activity on a microgram basis against S. aureus than cefaclor and cefixime have [10]. It is also active in vitro against other gram-positive and gram-negative pathogens, such as Proteus mirabilis, Propionibacterium acnes, Escherichia coli, Klebsiella organisms, and Clostridium perfringens [1, 5, 8, 11, 12].
Finally, the half-life of cefprozil is considerably longer than that of cefaclor (-1.3 hours vs. 0.6-0.9 hour, respectively) [12, 13]. The prolonged activity of cefprozil and its excellent tissue penetration permit twice-daily and even once-daily dosing [14]; doses of cefaclor and erythromycin are administered three and four times daily, respectively [15-17]. Given these facts, it would be important to know if cefprozil has any clinical advantages over cefaclor or erythromycin in the treatment of mild-to-moderate infections of the skin and skin structure, specifically if twice-daily or oncedaily dosing with cefprozil is as effective and safe as standard regimens of either cefaclor or erythromycin. Three recently completed multicenter clinical trials examined just these issues; the results of these studies, which are published substantially elsewhere, are summarized below [15-17]. Overview of Study Designs
The above-mentioned studies [15-17] were multicenter, open-label, randomized trials comparing the safety and efficacy of two dosing regimens of cefprozil with those of one standard dosing regimen of either cefaclor or erythromycin ethylsuccinate (EES) in patients with mild-to-moderate cuta-
Downloaded from http://cid.oxfordjournals.org/ at New York University on May 7, 2015
Limitations of currently used antimicrobial agents for the treatment of skin and skin-structure infections (e.g., increased resistance to penicillin and erythromycin and inconvenient dosing schedules) have led to an adjustment in the kinds of antimicrobial agents prescribed for these diseases. Three recently completed clinical studies have demonstrated some therapeutic advantages of cefprozil, a new broad-spectrum oral cephalosporin, over cefaclor and erythromycin in the treatment of skin and skin-structure infections. Specifically, cefprozil offers clinical efficacy equivalent to those of cefaclor and erythromycin both at lower total doses and on a less frequent dosing schedule (once or twice daily vs. three to four times daily). The advantage of once-daily or twice-daily dosing with cefprozil may contribute to patient convenience and compliance.
S256
CID 1992;14 (Suppl 2)
Nolen
Table 1. Overview of designs of cefprozil clinical trials. Study (no. of patients) A (N = 448) B* (N = 598) C*(N= 221)
Randomization ratio No. of centers involved
Cefprozil: cefaclor
19 18 8
Dosing frequency (mg) Cefprozil: erythromycin Cefprozil Cefaclor Erythromycin
2:1 1:1 1:1
250 b.i.d. 500 q.d. 500 q.d.
250 t.i.d. 250 t.i.d. 400 q.i.d.
No. of minimum doses Dosage form Po Po Po
Cefprozil Cefaclor Erythromycin 10 5 ND
15 15
Duration of treatment (d)
ND
5-10 5-10 10
Age requirements (y) .,18
NOTE. ND = not determined; not a parameter for evaluability in this study.
* Pediatric dosages for cefprozil and cefaclor were 20 mg/[kg • d] q.d. and 20 mg/[kg • d] in three equally divided doses, respectively. *Pediatric patients who were randomized to the cefprozil group and who weighed 5 ND
18 (CFZ) and 27 (Cfac) 9 (CFZ) and 27 (Cfac) ND
2-14 4-18 4-8/14-18
NOTE. CFZ = cefprozil; Cfac = cefaclor; GAS = group A streptococci; ND = not determined—not a parameter for evaluability in this study..
Downloaded from http://cid.oxfordjournals.org/ at New York University on May 7, 2015
neous infections. Study A compared cefprozil (250 mg twice daily) with cefaclor (250 mg three times daily) [15]; study B compared cefprozil (500 mg once daily or 20 mg/[kg • d]) with cefaclor (250 mg three times daily or 20 mg/[kg • d] in three equally divided doses) [16]; and study C compared cefprozil (500 mg once daily or 20 mg/[kg • d]) with EES (400 mg four times daily or 30 mg/[kg • d] in four equally divided doses) [17]. All three drugs were given in oral form for a period of 5-10 days. A total of 1,267 patients were enrolled in the three studies, of whom 856 were evaluable for efficacy. Tables I and 2 outline the three study designs. In general, the evaluable groups in each study were comparable in terms of age, sex, race (table 3), weight, severity and chronicity of infection, and underlying illness. The exceptions in study A were that the patients in the cefprozil group were significantly heavier, had a higher percentage of acute infections, and had a higher prevalence of history of diabetes mellitus (table 4). In study B, the patients receiving cefprozil had a higher prevalence of a history of diabetes mellitus. Patients enrolled in the trials had to demonstrate one or more clinical signs or symptoms (e.g., tenderness, erythema, edema, purulent drainage, fever, etc.) consistent with a mildto-moderate cutaneous infection for which treatment with an oral cephalosporin (studies A and B) or oral erythromycin (study C) was appropriate. Exclusion criteria included pregnancy; lactation; history of a serious reaction to cephalosporins, penicillins, or erythromycin (study C only); presence of
CID 1992;14 (Suppl 2)
Cefprozil for Skin and Skin-Structure Infections
S257
Table 3. Characteristics of evaluable patients in clinical trials of cefprozil. No. of evaluable patients/
No. (%) of males/
Mean age
No. (%) of white/black/
total no. enrolled
no. (%) of females
in y (range)
other race patients
11 l (79)/25 (18)/4 (3)
Study, group A Cefprozil
140/301
86 (61)/54 (39)
43.1 (18-81)
Cefaclor
73/147
43 (59)/30 (41)
47.2 (13-85)
Cefprozil
212/300
122 (58)/90 (42)
28.1 (2-90)
185 (87)/22 (10)/5 (3)
Cefaclor
210/298
130 (62)/80 (38)
27.9 (2-99)
177 (84)/27 (13)/6 (3)
59 (81)/14 (19)/0
B
C Cefprozil
87/108*
64 (59)/44 (41)
34.0 (1-88)
Erythromycin
78/113*
67 (59)/46 (41)
35.7 (2-87)
95 (88)/10 (9)/3 (3) 101 (89)/8 (7)/4 (4)
* Evaluable for clinical efficacy.
Overview of Study Results
Subjects in the three studies exhibited a wide variety of skin and skin-structure infections; the most common infections were cellulitis (127), impetigo (115), superficial infection (99), pyoderma (98), superficial abscess (97), subcutaneous infection (81), wound infection (33), and folliculitis (28). Culture-identified pathogens included S. aureus (471), group A streptococci (129), Staphylococcus epidermidis (108), Klebsiella pneumoniae (13), E. coli (11), P. mirabilis (11), coagulase-negative staphylococci (10), and Pasteurella multocida (1).
The response of patients to therapy was assessed both clinically and bacteriologically. A patient's clinical outcome was considered satisfactory if there was resolution or abatement of the signs and symptoms of infection, with no new signs or symptoms being present. A patient's bacteriologic outcome was considered satisfactory if there was eradication of the causative organism or there was no culturable material present at the original site of infection. Failure to achieve eradication or the need to change antibiotic therapy constituted an unsatisfactory response. Bacteriologic efficacy for each pathogen isolated in the pretreatment cultures was determined
post-treatment. Overall effectiveness was judged on the basis of clinical plus patient bacteriologic efficacy. A brief summary of the results of each study follows (see also table 5). Study A. The results of this study showed that cefprozil (250 mg twice daily) provided greater clinical, bacteriologic, and overall efficacy than cefaclor (250 mg three times daily) did [15]. Rates of pathogen bacteriologic eradication were higher for cefprozil than for cefaclor (88% vs. 76%, respectively). In addition, when controlled for weight, the number of patients for whom successful bacteriologic eradication was achieved with cefprozil was significantly higher than that achieved with cefaclor (86% vs. 74%, respectively; P = .040), as were satisfactory clinical response rates (95% vs. 78%, respectively; P = .001) and overall efficacy rates (84% vs. 67%, respectively; P = .006). Both cefprozil and cefaclor were well tolerated, with the two treatment groups showing no difference in the incidence of drug-related or unknown relationship adverse events (P = .434) (tables 5 and 6). Study B. Findings in this study showed that patients fared as well with cefprozil (500 mg once daily) as they did with cefaclor (250 mg three times daily) [16]. For cefprozil and cefaclor, efficacy rates were similar for satisfactory clinical response (93% vs. 92%, respectively; P = .782), pathogen bacteriologic eradication (92% vs. 90%, respectively), patient bacteriologic eradication (91% vs. 89%, respectively; P =
Table 4. Demographic variables showing significant differences in Study A. No. (%) of patients with Weight* (kg)
indicated infection*
Treatment group Mean
SD
Range
Acute
Cefprozil
81.27
19.85
Cefaclor
77.14
18.00
40.8-128.4 45.4-123.4
(no. of evaluable patients)
(N = 140) (N = 73)
Chronic
diabetes mellitus*
135 (96)
5 (4)
24 (17)
63 (86)
10(14)
7(10)
NOTE. Significance determined by alpha level
