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Review of the Experience with Cefprozil for the Treatment of Lower Respiratory Tract Infections Lawrence L. Pelletier, Jr.
From the Medical Service, Wichita Veterans Administration Medical Center, and the Department of Internal Medicine, University of Kansas School of Medicine, Wichita, Kansas
Cefprozil is a new oral broad-spectrum cephalosporin with activity against common respiratory pathogens, including Streptococcus pneumoniae [1-3], Haemophilus influenzae [4, 5], Staphylococcus aureus [6-7], and Moraxella catarrhalis [8]. Pharmacokinetic studies have shown that cefprozil is well absorbed after oral administration; mean peak serum levels of 9.6-11.2 ktg/mL are reached after a 500-mg dose has been administered [9-10]. Cefprozil has a half-life of 1.3 hours and excellent tissue penetration, which permit twicedaily dosing [9, 10]; moreover, its absorption in the capsule form studied is not adversely affected by food intake [11]. Studies of administration of single and multiple doses have shown that twice-daily dosing with cefprozil is well tolerated and produces serum levels comparable to those obtained with administration of cefaclor three times a day [12, 13]. Favorable in vitro activity against respiratory pathogens and suitable pharmacokinetics prompted three clinical studies of the efficacy and safety of cefprozil in the treatment of mild-to-moderate lower respiratory tract infections (LRTIs), which mainly included acute bronchitis and exacerbations of chronic bronchitis. This review summarizes the clinical data from these studies, which have been published substantially elsewhere [14-16].
Reprints or correspondence: Dr. Lawrence L. Pelletier, Jr., Medical Service ( I I I), Wichita Veterans Administration Medical Center, 5500 East Kellogg Street, Wichita, Kansas 67218. Clinical Infectious Diseases 1992;14(Suppl 2):S238-43 This article is in the public domain.
Overview of Study Designs
All three studies were open-label, multiinvestigator trials designed for comparing the safety and efficacy of cefprozil with that of cefaclor, cefuroxime axetil, or amoxicillin/ clavulanate potassium. In each instance enrolled patients were given 500 mg of oral cefprozil twice daily for 10 days or one of the following for 10 days: 500 mg of cefaclor three times a day (Study A) [14], 500 mg of oral cefuroxime axetil twice daily (Study B) [1S], or 500 mg/ 125 mg of oral amoxicillin/clavulanate three times a day (Study C) [16]. Patients were randomly assigned to receive one of these drugs in each study. Subjects included inpatients and outpatients (adults, >18 years of age) with signs and symptoms of LRTI. Exclusion criteria included pregnancy or lactation; a history of a serious reaction to a cephalosporin or penicillin; administration of a long-acting penicillin within the previous 2 weeks; presence of a severe infection that might necessitate parenteral therapy; presence of an underlying disease that might interfere with the absorption, metabolism, or excretion of either study drug; prior enrollment in the study; the presence of complicating diseases that would make interpretation of the therapeutic response difficult; and the presence of antibodies to human immunodeficiency virus type 1 (Studies B and C only). A complete medical history was obtained, and physical examination, chest roentgenogram, gram stain and culture of sputum, clinical evaluation, and laboratory tests were performed within 48 hours before treatment was initiated. The
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A regimen of cefprozil (500 mg twice daily), a new oral cephalosporin with a broad in vitro spectrum of antimicrobial activity, was compared to standard regimens of cefaclor (500 mg three times daily), cefuroxime axetil (500 mg twice daily), or amoxicillin/clavulanate (500 mg/125 mg three times daily) for the treatment of lower respiratory tract infections (mainly bronchitis and acute exacerbations of chronic bronchitis) in adults in three open-label, randomized trials. In the first trial, in which bacterial pathogens were isolated in initial cultures for only one-third of the patients, 90% of the pathogens were susceptible to cefprozil. A satisfactory clinical response was noted for 84% of the evaluable patients who received cefprozil versus 79% of those who received cefaclor for treatment of lower respiratory tract infections; rates of bacteriologic efficacy were 82% and 78%, respectively. In the second study rates of satisfactory clinical response were 96% with cefprozil and 83% with cefuroxime axetil (P < .03) for treatment of bronchitis; the respective bacteriologic response rates were 100% and 92%. In the third trial, clinical efficacy was 91% for cefprozil and 87% for amoxicillin/clavulanate for treatment of bronchitis; bacteriologic efficacy was 95% and 96 0/o, respectively. Tolerability and safety profiles were comparable, except that there was a higher rate of diarrhea among patients who received amoxicillin/clavulanate (P = .03).
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Overview of Study Results A variety of pathogens were isolated in all three studies— H. influenzae, S. pneumoniae, M. catarrhalis, S. aureus, Haemophilus parainfluenzae, and others. Study A. In this comparison between cefprozil and cefa-
clor, the most common diagnosis was bronchitis (250 pa-
Table 1. Efficacy of cefprozil versus that of cefaclor on the basis of severity of infection in 302 evaluable patients enrolled in Study A. No. of patients with satisfactory response/no. of patients receiving indicated drug (%) Satisfactory response/ severity of infection Clinical Mild Moderate Severe Bacteriologic Mild Moderate Severe Overall effectiveness Mild Moderate Severe
Cefprozil
Cefaclor
(n = 186)
(n = 116)
50/55 (91) 96/115 (83) 11/16 (69)
24/28 (86) 67/86 (78) 1/2 (50)
49/55 (89) 91/115 (79) 12/16 (75)
18/28 (64)* 71/86 (83) 1/2 (50)
45/55 (82) 86/115 (75) 10/16 (63)
18/28 (64)t 62/86 (72) 1/2 (50)
NOTE. The cefprozil group includes 160 patients with bronchitis; 24 patients with lobar, lobular, or bronchopneumonia; and two with "other" respiratory infections. The cefaclor group includes 90 patients with bronchitis; 24 with lobar, lobular, or bronchopneumonia; one patient with "other" respiratory infection, and one with bronchiectasis.
*P= .016. t P = .104.
tients), followed by bronchopneumonia and lobar or lobular pneumonia (48), and other (4) [14]. Most infections were acute (274) versus chronic (28). The majority of the infections were moderate (201); only a minority were mild (83) or severe (18). Demographically, the two study groups were well matched; the patients ranged in age from 18-99 years (mean, —56 years). The only significant difference between them was a higher percentage of moderate infections among the cefaclor users (74% vs. 62%, P = .054). Bacteriologic testing showed similar susceptibilities of common respiratory pathogens identified in pretreatment cultures, 90% of which proved susceptible to cefprozil and 87% of which proved susceptible to cefaclor. Only about onethird of the 951 enrolled subjects (302) were evaluable for the clinical and bacteriologic efficacy of the two drugs (32% of the patients who received cefprozil and 31% of those who received cefaclor). The main reason that many of these patients were not evaluated was that a pathogen was not isolated from the pretreatment culture. Additional patients were excluded from analyses of efficacy for other reasons (e.g., delayed posttreatment visit, resistance of the pathogen, noncompletion of therapy regimen, improper dosage, and other violations of the study protocol). Among those patients in both treatment groups who qualified for evaluation, the clinical efficacy of the two drugs proved similar (cefprozil, 84%; cefaclor, 79%) even when the analysis was controlled for severity of infection (table 1).
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laboratory studies were repeated after 3-7 days of therapy, at which point the need for an additional sputum culture or clinical evaluation was determined by the investigator. One to 18 days after the conclusion of treatment, a complete history was obtained and physical examination, sputum culture, laboratory tests, and clinical evaluation were carried out. In the study comparing cefprozil with cefaclor, standard methods of bacterial susceptibility testing were used [17]. A total of 1,345 patients were enrolled in the three studies; 566 of these patients were considered evaluable (Study A included 302 patients; Study B, 120; and Study C, 144). For Study A, patients were considered evaluable if the following criteria were met: a respiratory pathogen that was susceptible to both cefprozil and cefaclor was isolated from the pretreatment sputum culture; a chest roentgenogram was taken before treatment and during or after treatment in cases where pneumonia was present; the patient had received >5 consecutive days of therapy with the study drug; and microbiological and clinical evaluations were performed between the last day of therapy and posttreatment day 18. These same criteria were used in Studies B and C; however, in these studies the isolation of a bacterial respiratory pathogen from the pretreatment culture was not required. Instead, patients were evaluated for a clinical response alone if no pathogen had been found initially but gram stain of their sputum showed 25 leukocytes per low-power field; they were evaluated for both a clinical and a bacteriologic response if a pathogen had also been isolated from the pretreatment culture. In addition, patients who had a pretreatment pathogen that was susceptible to the assigned study drug were considered clinically evaluable. The criteria for assessing clinical and bacteriologic responses were similar in each study: clinical responses were deemed satisfactory if all signs and symptoms of an LRTI were resolved or had abated and if no new ones associated with the original infection were observed at the final followup visit. Clinical responses were deemed unsatisfactory if signs and symptoms persisted or worsened after treatment or new signs and symptoms associated with the original infection were noted at the final follow-up visit. Two bacteriologic responses were defined: eradicated or satisfactory, if the original pathogen(s) were no longer present in the posttreatment sputum culture or if sputum was unavailable for culture; and persisted or unsatisfactory, if the original pathogen(s) were found in the sputum culture after therapy had been completed.
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Table 2. Bacteriologic response of evaluable patients to cefprozil
versus cefaclor in Study A.
No. of pathogens for patients who received cefprozil/no. of pathogens for patients who received cefaclor Pathogen
Persisted
Eradicated
Total
20/15 6/7 1/2 0/2 3/0 9/4
57/32 48/19 12/11 13/8 16/11 34/27
77/47 54/26 13/13 13/10 19/11 43/31
180/108
219/138
Haemophilus influenzae Streptococcus pneumoniae Staphylococcus aureus Haemophilus parainfluenzae Moraxella catarrhalis
Less common pathogens
39/30
Total
influenzae isolates in evaluable cefaclor recipients. However, analysis of subgroups showed that cefprozil was superior to cefaclor in eradicating pathogens in patients with mild LRTIs (P = .016). Finally, both cefprozil and cefaclor were well tolerated and had similar safety profiles. Ninety adverse clinical events considered to be related to or to be of unknown relation to the study drug were reported by 57 patients who received cefprozil (10%), and 57 such events were reported by 44 patients who received cefaclor (12%) (table 3); in contrast, laboratory tests revealed no adverse effects in either group. The eight deaths that occurred during the study (five in the cefprozil group, three in the cefaclor group) were due to underlying disease in eight cases, and in 2 cases the infection contributed to the deaths. Study B. This comparison between cefprozil and cefuroxime axetil involved 170 patients (120 were considered evaluable). Owing to the low percentage of pathogens cultured before treatment was instituted, the study protocol was amended so that all qualifying patients were evaluated for clinical response on an intent-to-treat basis. Whereas 57 cefprozil users (51 with bronchitis) proved to be clinically evaluable, only 16 (14 with bronchitis) were bacteriologically evaluable. Among recipients of cefuroxime axetil, the respective numbers were 63 (57 with bronchitis) and 28 (24 with bronchitis). Altogether, only 28% of the 170 patients in Study B were evaluable for bacteriologic efficacy. Since the majority of patients in this study had bronchitis, only results for these patients are reviewed here. Demographically, the two study groups were well matched and ranged in age from 18-82 years (mean, —45 years). The results of Study B showed that the use of cefprozil
Table 3. Most common adverse clinical events (of probable or definite relation to study drugs) in
three comparative cefprozil trials in patients with all diagnoses.
No. of patients affected (%)
Adverse effect Diarrhea Nausea Upset stomach Rash or urticaria Vaginal symptoms Vomiting Fungal infection Headache Abdominal cramps Constipation
Cefprozil/cefaclor* 577/374) (n 16 (2.8)/14 (3.7) 15 (2.6)/9 (2.4) 6(1.0)/4 (1.1) 7 (1.2)/5 (1.3) 4 (0.7)/3 (0.8) 3 (0.5)/2 (0.5) 3 (0.5)/0 2 (0.3)/2 (0.5) 3 (0.5)/4 (1.1) 3 (0.5)/1 (0.3)
Cefprozil/cefuroxime axetil* (n = 79/84)
Cefprozil/amoxicillin/ clavulanatet (n 109/110)
4 (5)/7 (8) 3 (4)/4 (5)
8 (7)/20 (18) 6 (6)/5 (5)
2 (3)/2 (2) 0/1 (I)
3 (3)/4 (4) 7 (6)/4 (4) 0/2 (2) 2 (2)/3 (3)
2 (3)/1 (I)
3 ( 3 )/ 3 ( 3 )
* Seventy-nine of 82 patients enrolled received cefprozil, and 84/88 received cefuroxime axetil. One hundred-nine of 110 patients enrolled received cefprozil, and 1 10/1 14 received amoxicillin/clavulanate. P = .03. Of probable or unknown relation to study drugs.
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Among subjects lacking a history of lung disease, the rate of satisfactory clinical response was higher with cefprozil than with cefaclor (97% vs. 85%; P = .052). In an analysis of a subgroup of patients with bronchitis, there was no significant difference in clinical (cefprozil, 84%; cefaclor, 79%), bacteriologic (cefprozil, 82%; cefaclor, 74%), or overall response rates (cefprozil, 75%; cefaclor, 66%) for patients with a history of smoking [18]. For patients with bronchitis and a history of bronchopulmonary disease, there were also no significant differences in clinical (cefprozil, 77%; cefaclor, 74%) or bacteriologic (cefprozil, 75%; cefaclor, 68%) response rates between the two drugs [18]. Bacteriologic efficacy rates were also similar: 82% for cefprozil and 78% for cefaclor (table 2). Persistence was noted for 26% of the H. influenzae isolates (the most common pathogen) in evaluable cefprozil recipients and for 32% of the H.
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Table 4. Clinical and bacteriologic efficacy of cefprozil versus
that of cefuroxime axetil in evaluable patients in Study B with bronchitis. No. of patients with indicated response/no. of patients receiving drug (%)* Cefprozil
Cefuroxime axetil
49/51 (96) 2/51 (4)
47/57 (83)t 10/57 (18)
14/14 (100) 0
22/24 (92) 2/24 (8)
Response Clinical Satisfactory Unsatisfactory Bacteriologic Satisfactory Unsatisfactory
resulted in superior clinical and comparable bacteriologic responses to those achieved with the use of cefuroxime axetil in the treatment of bronchitis. Specifically, clinical efficacy was 96% for the recipients of cefprozil and 83% for those treated with cefuroxime axetil (P = .032); the bacteriologic responses were 100% and 92%, respectively (table 4). For many patients for whom pretherapy cultures were positive, eradication of the organism could not be documented since no sputum was produced for culture. Of the total patient group, two patients in the cefuroxime axetil group had cultures that remained positive: one remained positive for Citrobacter species and another remained positive for Klebsiella pneumoniae (table 5). Finally, the rate of adverse effects in both the cefprozil and cefuroxime axetil groups was similar (table 3). Complaints consisted mainly of diarrhea, nausea, vaginal symptoms, and abdominal pain. No deaths occurred during this study. Study C. Of the 224 patients enrolled in this trial, 110
were randomized to receive cefprozil and 114 to receive amoxicillin/clavulanate. Demographically, the study groups were similar and ranged in age from 18-85 years (mean, —43 years). As in Study B, this protocol was amended so that all qualifying patients were evaluated for a clinical response alone on an intent-to-treat basis and for a bacteriologic response as well if the pretreatment sputum culture yielded a pathogen. Because few initial cultures were positive, only 25% of the enrollees were assessed for the bacteriologic efficacy of the drugs. Altogether, 65 patients (56 with bronchitis) randomized to receive cefprozil were clinically evaluable and 22 patients (19 with bronchitis) were bacteriologically evaluable. Among the patients randomized to receive amoxicillin/clavulanate, the respective numbers were 79 (69 with bronchitis) and 30 (28 with bronchitis). As in Study B, the majority of patients had bronchitis, and therefore only results for these patients are reviewed here. The two treatment groups were demographically equivalent. This study showed that the use of either cefprozil or amoxicillin/clavulanate resulted in similar clinical and bacteriologic efficacies for patients with bronchitis. Clinical efficacy was 91% among recipients of cefprozil and 87% among patients treated with amoxicillin/clavulanate; bacteriologic efficacy was 95% and 96%, respectively (table 6). As in Study B, many patients did not produce enough sputum for culture; therefore, documentation of persistence and eradication of bacteria was difficult. In the total patient group there were three cases of H. influenzae infection that persisted— two in the cefprozil group and one in the amoxicillin/ clavulanate group—and one case of M. catarrhalis infection that persisted in the cefprozil group (table 7). The use of amoxicillin/clavulanate resulted in a statistically higher incidence of diarrhea. Twenty patients in the amoxicillin/clavulanate group (18%) and eight in the cefprozil group (7%) complained of this adverse effect (P = .03;
Table 5. Bacteriologic response of evaluable patients with all diagnoses to cefprozil vs. cefuroxime
in Study B.
No. of patients who received cefprozil/no. who received cefuroxime axetil Infecting pathogen Haemophilus influenzae Streptococcus pneumoniae Staphylococcus amens Haemophilus parainfluenzae Mora.rella catarrhalis Klebsiella pneumoniae Citrobacter
Total
species
Eradicated
Persisted
No sputum specimen obtained*
Total
1/1 1/ 0 1/0 0/1 0/0 0/0 0/0
0/0 0/0 0/0 0/0 0/0 0/1 0/I
1/8 6/4 1/4 1/0 0/0 1/3 0/0
2/9 7/4 2/4 1/I 0/0 1/4 0/1
3/2
0/2
10/19
13/23
* Patients who were positive for the organism at pretreatment but who were not able to provide a follow-up sputum specimen.
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* Since the majority of patients had bronchitis, only results for these patients are included. P = .032.
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Table 6. Clinical and bacteriologic efficacy of cefprozil versus that of amoxicillin/clavulanate in evaluable patients with bronchitis in Study C. No. of patients with indicated response/ no. of patients receiving drug (%)* Cefprozil
Amoxicillin/clavulanate
51/56 (91) 5/56 (9)
60/69 (87) 9/69 (13)
18/19 (95) 1/19 (5)
27/28 (96) 1/28 (4)
Response Clinical Satisfactory Unsatisfactory Bacteriologic Satisfactory Unsatisfactory
table 3). No other differences in adverse reactions were noted.
Discussion These three studies have shown that when cefprozil is administered twice daily, it is well tolerated and equally efficacious as cefaclor, cefuroxime axetil, and amoxicillin/ clavulanate in patients with mild-to-moderate LRTIs, such as bronchitis or acute exacerbations of chronic bronchitis. Study A showed that cefprozil is as effective as cefaclor in producing a satisfactory clinical response in patients with LRTIs (84% vs. 79%, respectively; table I ). Furthermore, its tolerability and safety profiles are similar to those of cefaclor. According to the findings of this trial, the majority (90%) of respiratory pathogens encountered are susceptible to cefprozil. In Study B, cefprozil was found to have superior clinical and comparable bacteriologic efficacy compared with that of cefuroxime axetil. In Study C, cefprozil was found to have
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clinical and bacteriologic efficacy comparable to that of amoxicillin/clavulanate. In addition, its tolerability and safety profiles proved similar to those of the other agents, except that it caused significantly fewer cases of diarrhea than did amoxicillin/clavulanate. As in Study A, H. influenzae and other respiratory pathogens persisted in a small proportion of bacteriologically evaluable patients. One limitation of the three studies reviewed here was that it was impossible to determine if clinical treatment failures due to persistence of the initial pathogen or persistence of bacteria in patients who responded clinically was caused by fl-lactamase production or some other mechanism of antimicrobial resistance. In addition, whether persistent organisms were clinically significant and caused subsequent clinical relapses after the initial follow-up phase ended was not determined, as these studies were designed only to assess patients' initial response to therapy. A third limitation was the small number of patients enrolled who had pneumonia. Therefore no conclusions can be drawn at this time about the value of cefprozil in the treatment of LRTIs other than bronchitis. The results of previous studies of cefaclor as therapy for LRTI suggest an earlier recurrence of chronic bronchitis as compared with the use of doxycycline [19]. In spite of the persistence of bacteria in some patients in the studies reported here, cefprozil was effective in the majority of Those treated, resulting in a satisfactory clinical response in 84%— 96% of all patients who were evaluated. A fourth limitation was that in each of the trials only a relatively small proportion of subjects with signs and symptoms of LRTI and purulent sputum were bacteriologically evaluable because relatively few pathogens were isolated from the pretreatment sputum culture (32% of subjects in Study A, 25% in Studies B and C). This limitation was first observed in Study A and was addressed in the subsequent trials by evaluating patients' clinical response to therapy when cultures were negative. When such patients' responses
Table 7. Bacteriologic response of evaluable patients with all diagnoses to cefprozil versus amoxicillin/clavulanate in Study C. No. of patients who received cefprozil/no. of patients who received amoxicillin/clavulanate
Pathogen Huemophilus influenzue Streptococcus pnewnoniue Staphylococcus carrells Haenzophilus parainfluen:ue Mora.vella cwarrhalis
Total
Eradicated
Persisted
No sputum obtained*
Total
0/0 0/1 0/0 0/1 0/0
2/1 0/0 0/0 0/0 1/0
8/9 7/3 0/0 0/1 0/0
10/10 7/4 0/0 0/1 0/1
0/2
3/1
15/13
17/16
* Patients who were positive for the organism at pretreatment but who were not able to provide a follow-up sputum specimen.
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* Since the majority of patients had bronchitis, only results for these patients are included.
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References I. Mazzulli T, Simor AE, Jaeger R, Fuller S, Low DE. Comparative in vitro activities of several new fluoroquinolones and beta-lactam antimicrobial agents against community isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 1990;34:467-9. 2. Chin NX, Neu HC. Comparative antibacterial activity of a new oral cephalosporin, BMY-28100. Antimicrob Agents Chemother 1987; 31:480-3. 3. Leitner F, Pursiano TA, Buck RE, et al. BMY-28100, a new oral cephalosporin. Antimicrob Agents Chemother 1987;31:238-43. 4. Kayser FH: Comparative antibacterial activity of the new oral cephalosporin BMY-28100. Eur J Clin Microbiol 1987;6:309-12. 5. Steele J, Edwards B, Rissing J. In vitro activity of BMY-28100, a new oral cephalosporin. Eur J Clin Microbiol 1987;6:111-3. 6. Hiraoka M, Masuyoshi S, Tomatsu K, Inoue M, Mitsuhashi S. In vitro
activity and beta-lactamase stability of the oral cephalosporin BMY28100. Eur J Clin Microbiol 1987;6:559-63. 7. Eliopoulos GM, Reiszner E, Wennersten C, Moellering RC Jr. In vitro activity of BMY-28100, a new oral cephalosporin. Antimicrob Agents Chemother 1987;31:653-6. 8. Aldridge, KE, Schiro DD, Sanders CV. Comparative in vitro activity of the new oral cephalosporin BMY-28100. Eur J Clin Microbiol 1987;6:170-2. 9. Barbhaiya RH, Gleason CR, Shyu WC, Wilber RB, Martin RR, Pittman KA. Phase I study of single-dose BMY-28100, a new oral cephalosporin. Antimicrob Agents Chemother 1990;34:202-5. 10. Nye K, O'Neill P, Andrews JM, Wise R. Pharmacokinetics and tissue penetration of cefprozil. J Antimicrob Chemother 1990;25:831-5. 11. Barbhaiya RH, Shukla UA, Gleason CR, Shyu WC, Pittman KA. Comparison of the effects of food on the pharmacokinetics of cefprozil and cefaclor. Antimicrob Agents Chemother 1990;34:1210-3. 12. Barbhaiya RH, Shukla UA, Gleason CR, Shyu WC, Wilber RB, Pittman KA. Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration. Antimicrob Agents Chemother 1990;34: 1204-9. 13. Barbhaiya RH, Shukla UA, Gleason CR, et al. Phase I study of multiple-dose cefprozil and comparison with cefaclor. Antimicrob Agents Chemother 1990;34:1198-203. 14. Wilber RB, Hamilton H, Leroy A, et al. Cefprozil vs. cefaclor in the treatment of lower respiratory tract infections. Infect Med 1992; 9(suppl C):44-55. 15. Bonnet JP, Ginsberg D, Nolen T, et al. Cefprozil vs. cefuroxime axetil in mild to moderate lower respiratory tract infections: a focus on bronchitis. Infect Med 1992;9(suppl E):48-56. 16. Barbarash RA, Solomon E, Thieneman AC, et al. Cefprozil vs. amoxicillin-clavulanate potassium in mild to moderate lower respiratory tract infections: a focus on bronchitis. Infect Med 1992;9(suppl E):40-7. 17. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial disk susceptibility tests. 4th ed. Approved standard M2-A4. Villanova, Pennsylvania: National Committee for Clinical Laboratory Standards, 1990. 18. Wilber RB, Hamilton H, Leroy A, et al. Cefprozil vs. cefaclor in the treatment of lower respiratory tract infections: a focus on bronchitis. Infect Med 1992;9(Suppl E):33-9. 19. Chodosh S, Tuck J, Pizzuto D. Comparative trials of doxycycline versus amoxicillin, cephalexin, and enoxacin in bacterial infections in chronic bronchitis and asthma. Scand J Infect Dis Suppl 1988;53:22-8.
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were analyzed, it was found that the rate of clinical response to cefprozil among those with bronchitis was equal to or better than that seen in the worldwide comparison with cefaclor. The increase in the rate of clinical response to cefprozil from 84% in Study A to 91% in Study C (the comparison with amoxicillin/clavulanate) and 96% in Study B (the comparison with cefuroxime axetil) may have been due to a younger patient population and higher proportion of patients with acute bronchitis without underlying lung disease in the latter two trials. Another possibility is that patients for whom a defined bacterial pathogen was lacking on pretreatment culture may be more responsive to antimicrobial therapy or more likely to experience spontaneous improvement. In summary, these three clinical trials show that cefprozil, given twice daily, provides effective treatment of patients who have bronchitis or acute exacerbations of chronic bronchitis. Therapy with this well-tolerated, broad-spectrum oral cephalosporin results in clinical and bacteriologic efficacy equal to that observed with cefaclor and amoxicillin/ clavulanate; its clinical efficacy is superior to that of cefuroxime axetil. The value of cefprozil in treating other LRTIs such as pneumonia has yet to be established.
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Review of the Experience with Cefprozil for the Treatment of Lower Respiratory Tract Infections Lawrence L. Pelletier, Jr.
From the Medical Service, Wichita Veterans Administration Medical Center, and the Department of Internal Medicine, University of Kansas School of Medicine, Wichita, Kansas
Cefprozil is a new oral broad-spectrum cephalosporin with activity against common respiratory pathogens, including Streptococcus pneumoniae [1-3], Haemophilus influenzae [4, 5], Staphylococcus aureus [6-7], and Moraxella catarrhalis [8]. Pharmacokinetic studies have shown that cefprozil is well absorbed after oral administration; mean peak serum levels of 9.6-11.2 ktg/mL are reached after a 500-mg dose has been administered [9-10]. Cefprozil has a half-life of 1.3 hours and excellent tissue penetration, which permit twicedaily dosing [9, 10]; moreover, its absorption in the capsule form studied is not adversely affected by food intake [11]. Studies of administration of single and multiple doses have shown that twice-daily dosing with cefprozil is well tolerated and produces serum levels comparable to those obtained with administration of cefaclor three times a day [12, 13]. Favorable in vitro activity against respiratory pathogens and suitable pharmacokinetics prompted three clinical studies of the efficacy and safety of cefprozil in the treatment of mild-to-moderate lower respiratory tract infections (LRTIs), which mainly included acute bronchitis and exacerbations of chronic bronchitis. This review summarizes the clinical data from these studies, which have been published substantially elsewhere [14-16].
Reprints or correspondence: Dr. Lawrence L. Pelletier, Jr., Medical Service ( I I I), Wichita Veterans Administration Medical Center, 5500 East Kellogg Street, Wichita, Kansas 67218. Clinical Infectious Diseases 1992;14(Suppl 2):S238-43 This article is in the public domain.
Overview of Study Designs
All three studies were open-label, multiinvestigator trials designed for comparing the safety and efficacy of cefprozil with that of cefaclor, cefuroxime axetil, or amoxicillin/ clavulanate potassium. In each instance enrolled patients were given 500 mg of oral cefprozil twice daily for 10 days or one of the following for 10 days: 500 mg of cefaclor three times a day (Study A) [14], 500 mg of oral cefuroxime axetil twice daily (Study B) [1S], or 500 mg/ 125 mg of oral amoxicillin/clavulanate three times a day (Study C) [16]. Patients were randomly assigned to receive one of these drugs in each study. Subjects included inpatients and outpatients (adults, >18 years of age) with signs and symptoms of LRTI. Exclusion criteria included pregnancy or lactation; a history of a serious reaction to a cephalosporin or penicillin; administration of a long-acting penicillin within the previous 2 weeks; presence of a severe infection that might necessitate parenteral therapy; presence of an underlying disease that might interfere with the absorption, metabolism, or excretion of either study drug; prior enrollment in the study; the presence of complicating diseases that would make interpretation of the therapeutic response difficult; and the presence of antibodies to human immunodeficiency virus type 1 (Studies B and C only). A complete medical history was obtained, and physical examination, chest roentgenogram, gram stain and culture of sputum, clinical evaluation, and laboratory tests were performed within 48 hours before treatment was initiated. The
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A regimen of cefprozil (500 mg twice daily), a new oral cephalosporin with a broad in vitro spectrum of antimicrobial activity, was compared to standard regimens of cefaclor (500 mg three times daily), cefuroxime axetil (500 mg twice daily), or amoxicillin/clavulanate (500 mg/125 mg three times daily) for the treatment of lower respiratory tract infections (mainly bronchitis and acute exacerbations of chronic bronchitis) in adults in three open-label, randomized trials. In the first trial, in which bacterial pathogens were isolated in initial cultures for only one-third of the patients, 90% of the pathogens were susceptible to cefprozil. A satisfactory clinical response was noted for 84% of the evaluable patients who received cefprozil versus 79% of those who received cefaclor for treatment of lower respiratory tract infections; rates of bacteriologic efficacy were 82% and 78%, respectively. In the second study rates of satisfactory clinical response were 96% with cefprozil and 83% with cefuroxime axetil (P < .03) for treatment of bronchitis; the respective bacteriologic response rates were 100% and 92%. In the third trial, clinical efficacy was 91% for cefprozil and 87% for amoxicillin/clavulanate for treatment of bronchitis; bacteriologic efficacy was 95% and 96 0/o, respectively. Tolerability and safety profiles were comparable, except that there was a higher rate of diarrhea among patients who received amoxicillin/clavulanate (P = .03).
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Overview of Study Results A variety of pathogens were isolated in all three studies— H. influenzae, S. pneumoniae, M. catarrhalis, S. aureus, Haemophilus parainfluenzae, and others. Study A. In this comparison between cefprozil and cefa-
clor, the most common diagnosis was bronchitis (250 pa-
Table 1. Efficacy of cefprozil versus that of cefaclor on the basis of severity of infection in 302 evaluable patients enrolled in Study A. No. of patients with satisfactory response/no. of patients receiving indicated drug (%) Satisfactory response/ severity of infection Clinical Mild Moderate Severe Bacteriologic Mild Moderate Severe Overall effectiveness Mild Moderate Severe
Cefprozil
Cefaclor
(n = 186)
(n = 116)
50/55 (91) 96/115 (83) 11/16 (69)
24/28 (86) 67/86 (78) 1/2 (50)
49/55 (89) 91/115 (79) 12/16 (75)
18/28 (64)* 71/86 (83) 1/2 (50)
45/55 (82) 86/115 (75) 10/16 (63)
18/28 (64)t 62/86 (72) 1/2 (50)
NOTE. The cefprozil group includes 160 patients with bronchitis; 24 patients with lobar, lobular, or bronchopneumonia; and two with "other" respiratory infections. The cefaclor group includes 90 patients with bronchitis; 24 with lobar, lobular, or bronchopneumonia; one patient with "other" respiratory infection, and one with bronchiectasis.
*P= .016. t P = .104.
tients), followed by bronchopneumonia and lobar or lobular pneumonia (48), and other (4) [14]. Most infections were acute (274) versus chronic (28). The majority of the infections were moderate (201); only a minority were mild (83) or severe (18). Demographically, the two study groups were well matched; the patients ranged in age from 18-99 years (mean, —56 years). The only significant difference between them was a higher percentage of moderate infections among the cefaclor users (74% vs. 62%, P = .054). Bacteriologic testing showed similar susceptibilities of common respiratory pathogens identified in pretreatment cultures, 90% of which proved susceptible to cefprozil and 87% of which proved susceptible to cefaclor. Only about onethird of the 951 enrolled subjects (302) were evaluable for the clinical and bacteriologic efficacy of the two drugs (32% of the patients who received cefprozil and 31% of those who received cefaclor). The main reason that many of these patients were not evaluated was that a pathogen was not isolated from the pretreatment culture. Additional patients were excluded from analyses of efficacy for other reasons (e.g., delayed posttreatment visit, resistance of the pathogen, noncompletion of therapy regimen, improper dosage, and other violations of the study protocol). Among those patients in both treatment groups who qualified for evaluation, the clinical efficacy of the two drugs proved similar (cefprozil, 84%; cefaclor, 79%) even when the analysis was controlled for severity of infection (table 1).
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laboratory studies were repeated after 3-7 days of therapy, at which point the need for an additional sputum culture or clinical evaluation was determined by the investigator. One to 18 days after the conclusion of treatment, a complete history was obtained and physical examination, sputum culture, laboratory tests, and clinical evaluation were carried out. In the study comparing cefprozil with cefaclor, standard methods of bacterial susceptibility testing were used [17]. A total of 1,345 patients were enrolled in the three studies; 566 of these patients were considered evaluable (Study A included 302 patients; Study B, 120; and Study C, 144). For Study A, patients were considered evaluable if the following criteria were met: a respiratory pathogen that was susceptible to both cefprozil and cefaclor was isolated from the pretreatment sputum culture; a chest roentgenogram was taken before treatment and during or after treatment in cases where pneumonia was present; the patient had received >5 consecutive days of therapy with the study drug; and microbiological and clinical evaluations were performed between the last day of therapy and posttreatment day 18. These same criteria were used in Studies B and C; however, in these studies the isolation of a bacterial respiratory pathogen from the pretreatment culture was not required. Instead, patients were evaluated for a clinical response alone if no pathogen had been found initially but gram stain of their sputum showed 25 leukocytes per low-power field; they were evaluated for both a clinical and a bacteriologic response if a pathogen had also been isolated from the pretreatment culture. In addition, patients who had a pretreatment pathogen that was susceptible to the assigned study drug were considered clinically evaluable. The criteria for assessing clinical and bacteriologic responses were similar in each study: clinical responses were deemed satisfactory if all signs and symptoms of an LRTI were resolved or had abated and if no new ones associated with the original infection were observed at the final followup visit. Clinical responses were deemed unsatisfactory if signs and symptoms persisted or worsened after treatment or new signs and symptoms associated with the original infection were noted at the final follow-up visit. Two bacteriologic responses were defined: eradicated or satisfactory, if the original pathogen(s) were no longer present in the posttreatment sputum culture or if sputum was unavailable for culture; and persisted or unsatisfactory, if the original pathogen(s) were found in the sputum culture after therapy had been completed.
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Table 2. Bacteriologic response of evaluable patients to cefprozil
versus cefaclor in Study A.
No. of pathogens for patients who received cefprozil/no. of pathogens for patients who received cefaclor Pathogen
Persisted
Eradicated
Total
20/15 6/7 1/2 0/2 3/0 9/4
57/32 48/19 12/11 13/8 16/11 34/27
77/47 54/26 13/13 13/10 19/11 43/31
180/108
219/138
Haemophilus influenzae Streptococcus pneumoniae Staphylococcus aureus Haemophilus parainfluenzae Moraxella catarrhalis
Less common pathogens
39/30
Total
influenzae isolates in evaluable cefaclor recipients. However, analysis of subgroups showed that cefprozil was superior to cefaclor in eradicating pathogens in patients with mild LRTIs (P = .016). Finally, both cefprozil and cefaclor were well tolerated and had similar safety profiles. Ninety adverse clinical events considered to be related to or to be of unknown relation to the study drug were reported by 57 patients who received cefprozil (10%), and 57 such events were reported by 44 patients who received cefaclor (12%) (table 3); in contrast, laboratory tests revealed no adverse effects in either group. The eight deaths that occurred during the study (five in the cefprozil group, three in the cefaclor group) were due to underlying disease in eight cases, and in 2 cases the infection contributed to the deaths. Study B. This comparison between cefprozil and cefuroxime axetil involved 170 patients (120 were considered evaluable). Owing to the low percentage of pathogens cultured before treatment was instituted, the study protocol was amended so that all qualifying patients were evaluated for clinical response on an intent-to-treat basis. Whereas 57 cefprozil users (51 with bronchitis) proved to be clinically evaluable, only 16 (14 with bronchitis) were bacteriologically evaluable. Among recipients of cefuroxime axetil, the respective numbers were 63 (57 with bronchitis) and 28 (24 with bronchitis). Altogether, only 28% of the 170 patients in Study B were evaluable for bacteriologic efficacy. Since the majority of patients in this study had bronchitis, only results for these patients are reviewed here. Demographically, the two study groups were well matched and ranged in age from 18-82 years (mean, —45 years). The results of Study B showed that the use of cefprozil
Table 3. Most common adverse clinical events (of probable or definite relation to study drugs) in
three comparative cefprozil trials in patients with all diagnoses.
No. of patients affected (%)
Adverse effect Diarrhea Nausea Upset stomach Rash or urticaria Vaginal symptoms Vomiting Fungal infection Headache Abdominal cramps Constipation
Cefprozil/cefaclor* 577/374) (n 16 (2.8)/14 (3.7) 15 (2.6)/9 (2.4) 6(1.0)/4 (1.1) 7 (1.2)/5 (1.3) 4 (0.7)/3 (0.8) 3 (0.5)/2 (0.5) 3 (0.5)/0 2 (0.3)/2 (0.5) 3 (0.5)/4 (1.1) 3 (0.5)/1 (0.3)
Cefprozil/cefuroxime axetil* (n = 79/84)
Cefprozil/amoxicillin/ clavulanatet (n 109/110)
4 (5)/7 (8) 3 (4)/4 (5)
8 (7)/20 (18) 6 (6)/5 (5)
2 (3)/2 (2) 0/1 (I)
3 (3)/4 (4) 7 (6)/4 (4) 0/2 (2) 2 (2)/3 (3)
2 (3)/1 (I)
3 ( 3 )/ 3 ( 3 )
* Seventy-nine of 82 patients enrolled received cefprozil, and 84/88 received cefuroxime axetil. One hundred-nine of 110 patients enrolled received cefprozil, and 1 10/1 14 received amoxicillin/clavulanate. P = .03. Of probable or unknown relation to study drugs.
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Among subjects lacking a history of lung disease, the rate of satisfactory clinical response was higher with cefprozil than with cefaclor (97% vs. 85%; P = .052). In an analysis of a subgroup of patients with bronchitis, there was no significant difference in clinical (cefprozil, 84%; cefaclor, 79%), bacteriologic (cefprozil, 82%; cefaclor, 74%), or overall response rates (cefprozil, 75%; cefaclor, 66%) for patients with a history of smoking [18]. For patients with bronchitis and a history of bronchopulmonary disease, there were also no significant differences in clinical (cefprozil, 77%; cefaclor, 74%) or bacteriologic (cefprozil, 75%; cefaclor, 68%) response rates between the two drugs [18]. Bacteriologic efficacy rates were also similar: 82% for cefprozil and 78% for cefaclor (table 2). Persistence was noted for 26% of the H. influenzae isolates (the most common pathogen) in evaluable cefprozil recipients and for 32% of the H.
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Table 4. Clinical and bacteriologic efficacy of cefprozil versus
that of cefuroxime axetil in evaluable patients in Study B with bronchitis. No. of patients with indicated response/no. of patients receiving drug (%)* Cefprozil
Cefuroxime axetil
49/51 (96) 2/51 (4)
47/57 (83)t 10/57 (18)
14/14 (100) 0
22/24 (92) 2/24 (8)
Response Clinical Satisfactory Unsatisfactory Bacteriologic Satisfactory Unsatisfactory
resulted in superior clinical and comparable bacteriologic responses to those achieved with the use of cefuroxime axetil in the treatment of bronchitis. Specifically, clinical efficacy was 96% for the recipients of cefprozil and 83% for those treated with cefuroxime axetil (P = .032); the bacteriologic responses were 100% and 92%, respectively (table 4). For many patients for whom pretherapy cultures were positive, eradication of the organism could not be documented since no sputum was produced for culture. Of the total patient group, two patients in the cefuroxime axetil group had cultures that remained positive: one remained positive for Citrobacter species and another remained positive for Klebsiella pneumoniae (table 5). Finally, the rate of adverse effects in both the cefprozil and cefuroxime axetil groups was similar (table 3). Complaints consisted mainly of diarrhea, nausea, vaginal symptoms, and abdominal pain. No deaths occurred during this study. Study C. Of the 224 patients enrolled in this trial, 110
were randomized to receive cefprozil and 114 to receive amoxicillin/clavulanate. Demographically, the study groups were similar and ranged in age from 18-85 years (mean, —43 years). As in Study B, this protocol was amended so that all qualifying patients were evaluated for a clinical response alone on an intent-to-treat basis and for a bacteriologic response as well if the pretreatment sputum culture yielded a pathogen. Because few initial cultures were positive, only 25% of the enrollees were assessed for the bacteriologic efficacy of the drugs. Altogether, 65 patients (56 with bronchitis) randomized to receive cefprozil were clinically evaluable and 22 patients (19 with bronchitis) were bacteriologically evaluable. Among the patients randomized to receive amoxicillin/clavulanate, the respective numbers were 79 (69 with bronchitis) and 30 (28 with bronchitis). As in Study B, the majority of patients had bronchitis, and therefore only results for these patients are reviewed here. The two treatment groups were demographically equivalent. This study showed that the use of either cefprozil or amoxicillin/clavulanate resulted in similar clinical and bacteriologic efficacies for patients with bronchitis. Clinical efficacy was 91% among recipients of cefprozil and 87% among patients treated with amoxicillin/clavulanate; bacteriologic efficacy was 95% and 96%, respectively (table 6). As in Study B, many patients did not produce enough sputum for culture; therefore, documentation of persistence and eradication of bacteria was difficult. In the total patient group there were three cases of H. influenzae infection that persisted— two in the cefprozil group and one in the amoxicillin/ clavulanate group—and one case of M. catarrhalis infection that persisted in the cefprozil group (table 7). The use of amoxicillin/clavulanate resulted in a statistically higher incidence of diarrhea. Twenty patients in the amoxicillin/clavulanate group (18%) and eight in the cefprozil group (7%) complained of this adverse effect (P = .03;
Table 5. Bacteriologic response of evaluable patients with all diagnoses to cefprozil vs. cefuroxime
in Study B.
No. of patients who received cefprozil/no. who received cefuroxime axetil Infecting pathogen Haemophilus influenzae Streptococcus pneumoniae Staphylococcus amens Haemophilus parainfluenzae Mora.rella catarrhalis Klebsiella pneumoniae Citrobacter
Total
species
Eradicated
Persisted
No sputum specimen obtained*
Total
1/1 1/ 0 1/0 0/1 0/0 0/0 0/0
0/0 0/0 0/0 0/0 0/0 0/1 0/I
1/8 6/4 1/4 1/0 0/0 1/3 0/0
2/9 7/4 2/4 1/I 0/0 1/4 0/1
3/2
0/2
10/19
13/23
* Patients who were positive for the organism at pretreatment but who were not able to provide a follow-up sputum specimen.
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* Since the majority of patients had bronchitis, only results for these patients are included. P = .032.
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Table 6. Clinical and bacteriologic efficacy of cefprozil versus that of amoxicillin/clavulanate in evaluable patients with bronchitis in Study C. No. of patients with indicated response/ no. of patients receiving drug (%)* Cefprozil
Amoxicillin/clavulanate
51/56 (91) 5/56 (9)
60/69 (87) 9/69 (13)
18/19 (95) 1/19 (5)
27/28 (96) 1/28 (4)
Response Clinical Satisfactory Unsatisfactory Bacteriologic Satisfactory Unsatisfactory
table 3). No other differences in adverse reactions were noted.
Discussion These three studies have shown that when cefprozil is administered twice daily, it is well tolerated and equally efficacious as cefaclor, cefuroxime axetil, and amoxicillin/ clavulanate in patients with mild-to-moderate LRTIs, such as bronchitis or acute exacerbations of chronic bronchitis. Study A showed that cefprozil is as effective as cefaclor in producing a satisfactory clinical response in patients with LRTIs (84% vs. 79%, respectively; table I ). Furthermore, its tolerability and safety profiles are similar to those of cefaclor. According to the findings of this trial, the majority (90%) of respiratory pathogens encountered are susceptible to cefprozil. In Study B, cefprozil was found to have superior clinical and comparable bacteriologic efficacy compared with that of cefuroxime axetil. In Study C, cefprozil was found to have
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clinical and bacteriologic efficacy comparable to that of amoxicillin/clavulanate. In addition, its tolerability and safety profiles proved similar to those of the other agents, except that it caused significantly fewer cases of diarrhea than did amoxicillin/clavulanate. As in Study A, H. influenzae and other respiratory pathogens persisted in a small proportion of bacteriologically evaluable patients. One limitation of the three studies reviewed here was that it was impossible to determine if clinical treatment failures due to persistence of the initial pathogen or persistence of bacteria in patients who responded clinically was caused by fl-lactamase production or some other mechanism of antimicrobial resistance. In addition, whether persistent organisms were clinically significant and caused subsequent clinical relapses after the initial follow-up phase ended was not determined, as these studies were designed only to assess patients' initial response to therapy. A third limitation was the small number of patients enrolled who had pneumonia. Therefore no conclusions can be drawn at this time about the value of cefprozil in the treatment of LRTIs other than bronchitis. The results of previous studies of cefaclor as therapy for LRTI suggest an earlier recurrence of chronic bronchitis as compared with the use of doxycycline [19]. In spite of the persistence of bacteria in some patients in the studies reported here, cefprozil was effective in the majority of Those treated, resulting in a satisfactory clinical response in 84%— 96% of all patients who were evaluated. A fourth limitation was that in each of the trials only a relatively small proportion of subjects with signs and symptoms of LRTI and purulent sputum were bacteriologically evaluable because relatively few pathogens were isolated from the pretreatment sputum culture (32% of subjects in Study A, 25% in Studies B and C). This limitation was first observed in Study A and was addressed in the subsequent trials by evaluating patients' clinical response to therapy when cultures were negative. When such patients' responses
Table 7. Bacteriologic response of evaluable patients with all diagnoses to cefprozil versus amoxicillin/clavulanate in Study C. No. of patients who received cefprozil/no. of patients who received amoxicillin/clavulanate
Pathogen Huemophilus influenzue Streptococcus pnewnoniue Staphylococcus carrells Haenzophilus parainfluen:ue Mora.vella cwarrhalis
Total
Eradicated
Persisted
No sputum obtained*
Total
0/0 0/1 0/0 0/1 0/0
2/1 0/0 0/0 0/0 1/0
8/9 7/3 0/0 0/1 0/0
10/10 7/4 0/0 0/1 0/1
0/2
3/1
15/13
17/16
* Patients who were positive for the organism at pretreatment but who were not able to provide a follow-up sputum specimen.
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* Since the majority of patients had bronchitis, only results for these patients are included.
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References I. Mazzulli T, Simor AE, Jaeger R, Fuller S, Low DE. Comparative in vitro activities of several new fluoroquinolones and beta-lactam antimicrobial agents against community isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 1990;34:467-9. 2. Chin NX, Neu HC. Comparative antibacterial activity of a new oral cephalosporin, BMY-28100. Antimicrob Agents Chemother 1987; 31:480-3. 3. Leitner F, Pursiano TA, Buck RE, et al. BMY-28100, a new oral cephalosporin. Antimicrob Agents Chemother 1987;31:238-43. 4. Kayser FH: Comparative antibacterial activity of the new oral cephalosporin BMY-28100. Eur J Clin Microbiol 1987;6:309-12. 5. Steele J, Edwards B, Rissing J. In vitro activity of BMY-28100, a new oral cephalosporin. Eur J Clin Microbiol 1987;6:111-3. 6. Hiraoka M, Masuyoshi S, Tomatsu K, Inoue M, Mitsuhashi S. In vitro
activity and beta-lactamase stability of the oral cephalosporin BMY28100. Eur J Clin Microbiol 1987;6:559-63. 7. Eliopoulos GM, Reiszner E, Wennersten C, Moellering RC Jr. In vitro activity of BMY-28100, a new oral cephalosporin. Antimicrob Agents Chemother 1987;31:653-6. 8. Aldridge, KE, Schiro DD, Sanders CV. Comparative in vitro activity of the new oral cephalosporin BMY-28100. Eur J Clin Microbiol 1987;6:170-2. 9. Barbhaiya RH, Gleason CR, Shyu WC, Wilber RB, Martin RR, Pittman KA. Phase I study of single-dose BMY-28100, a new oral cephalosporin. Antimicrob Agents Chemother 1990;34:202-5. 10. Nye K, O'Neill P, Andrews JM, Wise R. Pharmacokinetics and tissue penetration of cefprozil. J Antimicrob Chemother 1990;25:831-5. 11. Barbhaiya RH, Shukla UA, Gleason CR, Shyu WC, Pittman KA. Comparison of the effects of food on the pharmacokinetics of cefprozil and cefaclor. Antimicrob Agents Chemother 1990;34:1210-3. 12. Barbhaiya RH, Shukla UA, Gleason CR, Shyu WC, Wilber RB, Pittman KA. Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration. Antimicrob Agents Chemother 1990;34: 1204-9. 13. Barbhaiya RH, Shukla UA, Gleason CR, et al. Phase I study of multiple-dose cefprozil and comparison with cefaclor. Antimicrob Agents Chemother 1990;34:1198-203. 14. Wilber RB, Hamilton H, Leroy A, et al. Cefprozil vs. cefaclor in the treatment of lower respiratory tract infections. Infect Med 1992; 9(suppl C):44-55. 15. Bonnet JP, Ginsberg D, Nolen T, et al. Cefprozil vs. cefuroxime axetil in mild to moderate lower respiratory tract infections: a focus on bronchitis. Infect Med 1992;9(suppl E):48-56. 16. Barbarash RA, Solomon E, Thieneman AC, et al. Cefprozil vs. amoxicillin-clavulanate potassium in mild to moderate lower respiratory tract infections: a focus on bronchitis. Infect Med 1992;9(suppl E):40-7. 17. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial disk susceptibility tests. 4th ed. Approved standard M2-A4. Villanova, Pennsylvania: National Committee for Clinical Laboratory Standards, 1990. 18. Wilber RB, Hamilton H, Leroy A, et al. Cefprozil vs. cefaclor in the treatment of lower respiratory tract infections: a focus on bronchitis. Infect Med 1992;9(Suppl E):33-9. 19. Chodosh S, Tuck J, Pizzuto D. Comparative trials of doxycycline versus amoxicillin, cephalexin, and enoxacin in bacterial infections in chronic bronchitis and asthma. Scand J Infect Dis Suppl 1988;53:22-8.
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were analyzed, it was found that the rate of clinical response to cefprozil among those with bronchitis was equal to or better than that seen in the worldwide comparison with cefaclor. The increase in the rate of clinical response to cefprozil from 84% in Study A to 91% in Study C (the comparison with amoxicillin/clavulanate) and 96% in Study B (the comparison with cefuroxime axetil) may have been due to a younger patient population and higher proportion of patients with acute bronchitis without underlying lung disease in the latter two trials. Another possibility is that patients for whom a defined bacterial pathogen was lacking on pretreatment culture may be more responsive to antimicrobial therapy or more likely to experience spontaneous improvement. In summary, these three clinical trials show that cefprozil, given twice daily, provides effective treatment of patients who have bronchitis or acute exacerbations of chronic bronchitis. Therapy with this well-tolerated, broad-spectrum oral cephalosporin results in clinical and bacteriologic efficacy equal to that observed with cefaclor and amoxicillin/ clavulanate; its clinical efficacy is superior to that of cefuroxime axetil. The value of cefprozil in treating other LRTIs such as pneumonia has yet to be established.
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