Drugs 42 (Suppl. 3): 41-50. 1991 0012-6667/91/0300-0041/$5.00/0 © Adis International Limited. All rights reserved. DRSUP3233
Review of Clinical Experience in the United States with Cefpodoxime Proxetil in Adults with Uncomplicated Urinary Tract Infections Clair E. Cox,l Jane F. Graveline2 and JoAnna M. Luongo 2 I University of Tennessee. Memphis. Tennessee. USA 2 Sankyo USA Corporation. New York. New York. USA
Summary
Two controlled United States trials compared the safety and efficacy of cefpodoxime proxetil (100mg twice daily) with either cefaclor (250mg 3 times daily) or amoxicillin (250mg 3 times daily) in patients with uncomplicated urinary tract infections. Treatment duration was 7 days. 307 of 762 patients treated with cefpodoxime proxetil, 99 of 190 treated with cefaclor, and 57 of 185 treated with amoxicillin were evaluable for efficacy. 311, 99 and 59 pathogens were isolated from cefpodoxime proxetil, cefaclor and amoxicillin patients, respectively, the most common pathogens being Escherichia coli. Klebsiella spp., Proteus mirabilis. and Staphylococcus saprophyticus. Bacteriological cure rates were 80% (247/307),82% (81/99) and 70% (40/57) for cefpodoxime proxetil, cefaclor and amoxicillin, respectively. Respective clinical cure rates were 79% (242/307), 79% (78/99) and 72% (41/57). Cefpodoxime proxetil was well tolerated, and there was no significant difference between the groups in the overall incidence of adverse experiences. Thus, cefpodoxime proxetil is efficacious and safe in the treatment of patients with uncomplicated urinary tract infections and compares favourably with cefaclor and amoxicillin.
Cefpodoxime proxetil is the orally administered prod rug of cefpodoxime (fig. I), a broad spectrum third generation cephalosporin antibiotic possessing in vitro and in vivo bactericidal activity com-
CH3
I
"'N\(S'jl o~~~~:~')' N-.!LCCONHn~J II
NOCH3
H
H
S
Fig. 1. Chemical structure of cefpodoxime proxetil.
parable or superior to that of currently available oral and parenteral iJ-Iactam antibiotics. Results of in vitro susceptibility testing conducted against more than 9000 clinical isolates obtained from patients in the United States and Japan reveal that cefpodoxime has low minimum inhibitory concentrations (MICs) against Gram-negative and Grampositive aerobic organisms, including staphylococci, streptococci, Haemophilus spp., Moraxella (Branhamella) catarrhalis, Neisseria spp. and Enterobacteriaceae (Jones & Barry 1988). As with many other cephalosporins, cefpodoxime does not demonstrate significant activity against Pseudomonas spp., Enterococcus spp., methicillin-resistant staphylococci or Bacteroides tragi/is (Jones & Barry 1988).
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Drugs 42 (Suppl. 3) 1991
Table I. Results of a cefpodoxime proxetil dose-ranging study in patients with urinary tract infections (after Iravani et al. 1990) Cefpodoxime proxetil dosage a 200mg daily
Bacteriological cure rate Clinical cure rate a b
(n = 39)
400mg daily (n = 43)
(n = 38)
35/39 (90%) 38/39 (97%)
41/43 (95%) 35/41 b (85%)
34/38 (89%) 35/38 (92%)
600mg daily
Dosage given as cefpodoxime equivalent. Two patients did not have clinical assessments.
Results of preclinical studies conducted in the United States and Japan have not revealed significant toxicity, and the efficacy of cefpodoxime proxetil has been shown to be equal or superior to that of comparative antibiotics, including cefalexin, cefaclor and ampicillin (data on file, Sankyo Co. Ltd., Tokyo). Extensive clinical experience with cefpodoxime proxetil in Japan has demonstrated its efficacy and safety in the treatment of patients with various types of infections, including urinary tract infections (Kumazawa 1991). Several clinical studies in the United States have assessed the efficacy and safety of cefpodoxime proxetil in the treatment of urinary tract infections. On the basis of results of a randomised, multicentre dose-ranging study (table I), a 200mg daily dosage of cefpodoxime proxetil was selected for phase III clinical trials in patients with urinary tract infections. This paper examines the results of 2 separate and previously unpublished multicentre prospective double-blind parallel group randomised comparative phase III clinical trials evaluating the efficacy and safety of cefpodoxime proxetil in the treatment of patients with uncomplicated urinary tract infections at investigational sites throughout the United States. Except for the comparative antibiotic (cefaclor or amoxicillin), the trial design was identical for the 2 studies and the methods for both are described here.
1. Materials and Methods 1.1 Patients Male or female patients aged 12 years or older with bacteriuria [~ 1 bacterium/high power field [HPF] (lOOX)], pyuria [~ 10 WBC/HPF (lOOX)]
and at least 1 sign or symptom typical of urinary tract infections (e.g. urgency, frequency, dysuria, back pain, costovertebral angle tenderness, nocturia, fever, chills or haematuria) were eligible for enrolment. In the 48 hours before administration of the first dose of study medication (baseline visit), a physical examination was conducted and a medical history obtained. Excluded were patients who were asymptomatic, who had complicated urinary tract infections, or a history of allergy or hypersensitivity to cephalosporins, cephamycins, or penicillins. Also excluded were patients with significant hepatic or renal dysfunction, those with underlying medical conditions, which in the opinion of the investigator would interfere with the assessment of response to study medications, those with impaired immunological function, and those with a history of antibiotic-associated colitis. Patients who had received antimicrobial agents or phenazopyridine during the 48 hours (or a depot injection in the 2 weeks), or an investigational drug during the 30 days, before enrolling in the trials were excluded, as were those requiring concomitant nonstudy antibiotic therapy. Patients previously treated with cefpodoxime proxetil in other trials were also excluded. All patients participating in the trials provided written informed consent. 1.2 Study Design Eligible patients with a diagnosis of uncomplicated urinary tract infections were randomised to receive either cefpodoxime proxetil 100mg twice daily or the comparative agent, cefaclor (250mg 3
Review of Cefpodoxime Proxetil in Uncomplicated UTI
43
times daily) or amoxicillin (250mg 3 times daily) for a period of7 days. A 2 : I randomisation schedule was utilised to include twice as many patients in the cefpodoxime proxetil group as in the comparative group. At baseline, urine was collected for culture and susceptibility testing; patients were allowed to continue in the trial if at least I pathogen susceptible or moderately susceptible to both cefpodoxime and the comparative agent was isolated in a quantity of ~ 105 colony forming units (CFU) per/ml of urine. Patients were scheduled for a total of 4 protocol visits: I) the baseline or pretreatment visit in the 48 hours before the first dose of study drug; 2) the day 3 to 4 visit during treatment; 3) the 'end of treatment' visit (within 48 hours of the last dose of study medication); and 4) the post-treatment visit (5 to 9 days after the last dose of study medication). A long term follow-up visit 4 to 6 weeks after the last dose of study drug was scheduled for patients considered clinically and bacteriologically cured at the post-treatment visit.
The investigator assessed each patient's clinical response to treatment with the study drug at the (day 5 to 9) post-treatment visit. This assessment was based on the progression or amelioration of the patient's signs and symptoms of urinary tract infection monitored during the treatment period. The following categories of clinical response were used: 1) clinical cure, defined as elimination of signs and symptoms of urinary tract infections; 2) clinical improvement, defined as clinically significant alleviation of the signs and symptoms of urinary tract infections; 3) cure/recurrence, defined as elimination of signs and symptoms of urinary tract infections during therapy but recurrence 5 to 9 days posttreatment; and 4) clinical failure, defined as a lack of clinically significant alleviation of signs and symptoms of urinary tract infections. At each study visit, the investigator assessed the patient for clinical adverse experiences (observed by the investigator or volunteered by the patient). If present, these were recorded in terms of signs/ symptoms, intensity (mild, moderate or severe), and relationship to study drug (none, remote, possible or probable). Before and at the end of therapy, laboratory testing was performed, including haematology, blood chemistry, and urinalysis. Laboratory adverse experiences were defined as those judged by the investigator to be clinically important changes from baseline in laboratory test values, whether or not considered to be drug related. All adverse experiences, clinical or laboratory, were to be studied, when possible, in a manner deemed medically appropriate by the investigator.
1.3 Evaluations The bacteriological response to treatment was based solely on results of urine cultures obtained on day 3 to 4 during therapy and 5 to 9 days after therapy. For each evaluable patient one of the following bacteriological responses was assigned by the investigator: I) bacteriological cure, defined as eradication of the evaluable pretreatment pathogen(s) in urine specimens « 10 3 CFU/ml); 2) bacteriological cure/superinfection, defined as eradication of the evaluable pretreatment pathogen(s) but emergence of a different organism or a different strain of the pretreatment pathogen(s) in quantities ~ 105 CFU/ml; or 3) bacteriological failure, defined as persistence of at least I evaluable pretreatment pathogen in urine specimens. Additionally, each evaluable baseline pathogen was assessed as follows: I) eradication, defined as absence or reduction to insignificant numbers « 10 3 CFU/ml) in urine specimens; or 2) persistence, defined as presence of significant numbers (~ 10 3 CFU/ml) in urine specimens.
2. Results 2.1 Comparison with Cefaclor
2.1.1 Patients A total of 568 patients with uncomplicated urinary tract infections were enrolled at 27 investigational sites. 378 patients were randomised to the cefpodoxime proxetil treatment group and 190 to the cefaclor group. Of the 568 patients enrolled, 287 were evaluable for efficacy (188 receiving cefpodoxime proxetil and 99 receiving cefaclor).
44
Drugs 42 (Suppl. 3) 1991
The primary reasons for nonevaluation included negative baseline culture (n = 144), a resistant pathogen (n = 40), an off-schedule culture (n = 24), or protocol violation (n = 17). With the exception of age, the 2 evaluable treatment groups were similar with regard to demographic and pretreatment genitourinary characteristics (table II). The median duration of study drug therapy for both groups was 8 days.
2.1.2 Pretreatment Pathogens 290 pretreatment pathogens were isolated from the 287 evaluable patients (3 patients in the cefpodoxime proxetil group each had 2 pathogens; no patients in the cefaclor group had multiple pathogens). The frequency of isolation and range of these organisms were similar for the 2 treatment groups. The most frequently isolated pathogens included Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Staphylococcus saprophyticus, accounting for 172 of the 191 (90%) and 95 of the 99 (96%) pretreatment isolates from patients in the cefpodoxime proxetil and cefaclor groups, respectively.
Table II. Demographic and genitourinary characteristics of evaluable patients with uncomplicated urinary tract infections (UTI) treated with cefpodoxime proxetil or cefaclor in a multicentre double-blind randomised comparison Characteristic
Mean age (years)a [± SOl Sex Male Female Race White Black Other Mean duration of UTI (days) [± SO] a
Cefpodoxime proxetil (n = 188) 38.4 ± 18.25
Cefaclor (n = 99)
33 ± 15.34
9(5%) 179 (95%)
1(1%) 98 (99%)
144 (77%) 40 (21%) 4 (2%) 4.5 ± 6.77
80 (81%) 16 (16%) 3(3%) 4.9 ± 5.73
Difference in mean age between cefpodoxime proxetil and cefaclor patients statistically significant (p = 0.012).
2.1.3 Efficacy Clinical signs and symptoms of urinary tract infections recorded at each study visit were similar in severity and frequency for both treatment groups, with the exception of the 'end of treatment' visit. At this visit. a significantly higher percentage of cefaclor-treated patients (36%) reported at least I sign or symptom, compared with those in the group receiving cefpodoxime proxetil (22%) [p = 0.012). Clinical cure rates at days 5 to 9 post-treatment, summarised in table III, were similar for both treatment groups. In addition, clinical improvement was observed in 12 (6%) cefpodoxime proxetil-treated and 10 (10%) cefaclor-treated patients, yielding overall clinical efficacy rates of 88 and 89%, respectively. There was no statistically significant difference in the overall bacteriological cure rate between the 2 treatment groups: 80% (151 of 188) and 82% (81 of 99) in the cefpodoxime proxetil and cefaclor groups, respectively (table III). Only 14 patients (8 cefpodoxime proxetil, 4%; 6 cefaclor, 6%) had a superinfection with eradication of the pretreatment pathogen. 34 (18%) patients treated with cefpodoxime proxetil and 16 (16%) treated with cefaclor were judged to be bacteriological failures. However, 22 of the 34 patients treated with cefpodoxime proxetil and 12 of the 16 treated with cefaclor who failed therapy bacteriologically were clinically cured or improved. The bacteriological eradication rates are presented in table III. There were no statistically significant differences between treatment with cefpodoxime proxetil and cefaclor. There were similar eradication rates for the predominant pathogen, E. coli, in both treatment groups. Cefpodoxime proxetil was successful in eradicating all isolates of K. pneumoniae, and cefaclor eradicated all isolates of S. saprophytic us. Five evaluable patients (3 cefpodoxime proxetil, 2 cefaclor) who were withdrawn from the study because of inadequate therapeutic effect, were assessed as clinical failures and did not receive an overall bacteriological evaluation.
Review of Cefpodoxime Proxetil in Uncomplicated UTI
45
Table III. Clinical and bacteriological efficacy results from a multicentre double-blind randomised comparison of cefpodoxime proxetil and cefaclor in uncomplicated urinary tract infections Parameter
Cefpodoxime proxetil (%) [n = 188]
Cefacior (%) [n = 99]
Bacteriological cure
151/188 (80)
81/99 (82)
Clinical cure
154/188 (82)
78/99 (79)
Overall bacteriological eradication Escherichia coli
153/191 (80) 114/147 (78)
81/99 (82)
8/8 (100) 6/8 (75)
4/7 (57) 6/7 (86)
8/9 (89) 17/19 (89)
6/6 (100) 4/4 (100)
Klebsiella pneumoniae Proteus mirabilis Staphylococcus saprophyticus Othera
a
61/75 (81)
Other organisms include Citrobacter spp., Enterobacter aerogenes, Group D Enterococcus, Streptococcus spp. and Staphylococcus spp.
A total of 206 patients (132 treated with cefpodoxime proxetil and 74 treated with cefaclor) who had achieved both bacteriological and clinical cure at the day 5 to 9 post-treatment visit returned at 4 to 6 weeks for long term follow-up, Results were similar for the 2 groups; 80% (105 of 132) of patients treated with cefpodoxime proxetil and 82% (61 of 74) treated with cefaclor showed no pathogen growth or signs and symptoms of urinary tract infections.
2.1.4 Safety All 568 patients were included in the analysis of safety. Cefpodoxime proxetil and cefaclor were generally well tolerated, with no difference between groups in the overall incidence of adverse experiences [38% (144 of 378) for cefpodoxime proxetil; 35% (66 of 190) for cefaclor]. There was also no difference in the frequency of early withdrawal from the trial because of adverse experiences [2% (9 of 378) for cefpodoxime proxetil and 2% (4 of 190) for cefaclor]. There were no adverse experiences reported in this trial that were not typical of those observed during treatment with other {3-lactam antibiotics. Events judged by the investigator to be moderate or severe in intensity and possibly or probably drug related are of particular importance clinically. Nine percent (34 of 378) of patients ex-
posed to cefpodoxime proxetil and 10% (19 of 190) exposed to cefaclor reported at least 1 moderate or severe drug-related adverse experience. This difference was not statistically significant. Only I severe adverse experience was reported, i.e. diarrhoea in a patient administered cefpodoxime proxetil. The most commonly reported events were associated with the gastrointestinal (6% cefpodoxime proxetil; 0% cefaclor) and genital tracts (2% cefpodoxime proxetil; 7% cefaclor). All other moderate or severe drug-related adverse experiences occurred with a frequency of.:s; I % and included neurological events, dermatological events, allergy, and unspecified pain. Moderate or severe adverse experiences considered by the investigator to be drug related resulted in withdrawal of 7 (1.9%) patients treated with cefpodoxime proxetil (diarrhoea, nausea, flushing, rash or itching) and 1 (0.5%) treated with cefaclor (itching of the hands). Six (1.6%) patients in the cefpodoxime proxetil group and 2 (1.1%) in the cefaclor group exhibited changes from baseline that were considered to be clinically important in laboratory test values. Tests for which such changes were observed included haemoglobin, haematocrit, WBC count (decrease below normal limits), liver transaminases, lactic dehydrogenase, direct Coombs' test, and urinalysis. These changes were infrequent and typical of those encountered in association with treatment with {3-lactam antibiotics.
46
Drugs 42 (Suppl. 3) 1991
Table IV. Demographic and genitourinary characteristiCs of evaluable patients with uncomplicated urinary tract infections (UTI) treated with cefpodoxime proxetil or amoxicillin in a multicentre double-blind randomised comparison
Characteristic
Mean age (years) [± SD] Sex Male Female Race White Black Other Mean duration of UTI (days) [± SD]
Cefpodoxime proxetil (n = 119)
Amoxicillin (n = 57)
40.4 ± 19.8
37 ± 18.8
9 (8%) 110 (92%)
1 (2%) 56 (98%)
106 (89%) 10(8%) 3 (3%) 4.2 ± 3.6
48 (84%) 6 (11%) 3 (5%) 4.5 ± 5.4
2.2 Comparison with Amoxicillin
2.2.1 Patients A total of 569 patients with uncomplicated urinary tract infections were enrolled in a second comparative trial evaluating the efficacy and safety of cefpodoxime proxetil and amoxicillin. 384 patients were randomised to the cefpodoxime proxetil group and 185 to the amoxicillin group. 176 patients were evaluable for efficacy (119 in the cefpodoxime proxetil group and 57 in the amoxicillin group). Patients were nonevaluable if they showed a negative baseline culture (n = 201), a resistant pathogen (n = 101), an off-schedule culture (n = 29), or a protocol violation (n = 30). The 2 evaluable treatment groups were similar in terms of demographic and genitourinary characteristics at baseline (table IV). Median duration of study drug therapy for each group was 8 days. 2.2.2 Pretreatment Pathogens 179 pretreatment pathogens were isolated from the 176 evaluable patients (I patient in the cefpodoxime proxetil group and 2 in the amoxicillin group each had 2 pathogens). The most commonly isolated organism was E. coli, including 106 isolates from patients in the cefpodoxime proxetil group and 48 from those in the amoxicillin group.
Other organisms isolated (from 3 or more patients) included P. mirabilis and S. saprophyticus.
2.2.3 Efficacy Clinical cure rates at days 5 to 9 post-treatment were similar for the 2 treatment groups (table V). Additionally, 20 patients treated with cefpodoxime proxetil and 7 with amoxicillin were judged to be clinically improved, yielding an overall clinical efficacy rate of 91 % (108 of 119) and 84% (48 of 57), respectively. Clinical signs and symptoms of urinary tract infections for patients in both treatment groups were similar in severity and frequency throughout the study period. The overall bacteriological cure rates, presented in table V, were similar for the 2 treatment groups: 81 % (96 of 119) and 70% (40 of 57) in the cefpodoxime proxetil and amoxicillin groups, respectively. This difference was not statistically significant. Only 7 patients (5 cefpodoxime proxetil, 4%; 2 amoxicillin, 4%) had a response of bacteriological cure with superinfection. 21 (18%) patients treated with cefpodoxime proxetil and 15 (26%) with amoxicillin were judged to be bacteriological failures; 16 of the 21 cefpoTable V. Clinical and bacteriological efficacy results from a multicentre double-blind randomised comparison of cefpodoxime proxetil and amoxicillin in uncomplicated urinary tract
infections Parameters
Cefpodoxime proxetil (%) [n = 119]
Amoxicillin (%) [n = 57]
Bacteriological cure Clinical cure Overall bacteriological eradication Escherichia coli Klebsiella spp. Proteus mirabilis Staphylococcus saprophyticus Othera
96/119 (81) 88/119 (74) 97/120 (81)
40/57 (70) 41/57 (72) 41/59 (69)
86/106 (81) 1/1 (100) 6/8 (75) 0/1
33/48 (69) 0/0 3/4 (75) 3/3 (100)
4/4 (100)
2/4 (50)
a
Other organisms include aerobic Gram-negative coccobacillus, Group D Enterococcus, Group B Streptococcus, Lac· tobacillus spp. and S. aureus.
Review of Cefpodoxime Proxetil in Uncomplicated UTI
doxime proxetil-treated patients and 9 of the IS treated with amoxicillin who were judged to be bacteriological failures were clinically cured or improved. The bacteriological eradication rates are presented in table V. Although the overall eradication rate was higher in the cefpodoxime proxetil group than in the amoxicillin group, this difference did not achieve statistical significance. Cefpodoxime proxetil eradicated a greater percentage of E. coli isolates than did amoxicillin, and was comparable to amoxicillin in eradicating P. mirabilis. Four evaluable patients (2 cefpodoxime proxetil, 2 amoxicillin) who discontinued the study because of inadequate therapeutic effect were assessed as clinical failures and did not receive an overall bacteriological evaluation. 88 cefpodoxime proxetil-treated and 37 amoxicillin-treated patients who achieved both bacteriological and clinical cure 5 to 9 days post-treatment returned for long term follow-up 4 to 6 weeks after the end of therapy. The results observed at this visit were similar for the 2 treatment groups. 66 (75%) and 24 (65%) patients treated with cefpodoxime proxetil and amoxicillin, respectively, had no signs or symptoms of urinary tract infections and no pathogen growth. 2.2.4 Safety All 569 patients exposed to study medication were included in the analysis of efficacy. As was consistent with the results of the previous study, cefpodoxime proxetil and amoxicillin were generally well tolerated, with no statistically significant difference between the groups in terms of the overall incidence of adverse experiences [23% (90 of 384) for cefpodoxime proxetil; 21% (38 of 185) for amoxicillin]. Three (1%) patients treated with cefpodoxime proxetil and 3 (2%) with amoxicillin were withdrawn as a result of adverse experiences. Reasons for discontinuation of cefpodoxime proxetil included diarrhoea, abdominal pain, nausea, and an allergic reaction, all of moderate severity. Rash (mild), itching (moderate) and back pain (severe) resulted in discontinuation of amoxicillin. Six percent of patients in each group reported
47
at least I adverse event considered to be moderate or severe in intensity and possibly or probably drug related (23 of 384 cefpodoxime proxetil; 12 of 185 amoxicillin). Of these 35 patients, only 5 had severe events [4 cefpodoxime (2 headache, I diarrhoea, I vaginitis); I amoxicillin (headache)]. Most of these events were associated with the gastrointestinal (2% for each group) and genital tracts (2% cefpodoxime proxetil; 3% amoxicillin). The incidence of each of the other adverse experiences was :s; I % and included the following systems or categories: metabolic/nutritional, neurological, special senses, respiratory, dermatological, allergy, and miscellaneous. Three (1 %) patients in the cefpodoxime proxetil group and I (1%) in the amoxicillin group were withdrawn from the trial because of moderate drug-related adverse experiences. 12 (3%) patients treated with cefpodoxime proxetil and 4 (2%) with amoxicillin exhibited clinically important changes in laboratory test values. In the cefpodoxime proxetil group, these tests included haemoglobin, haematocrit, polymorphonuclear leucocytes (below normal limits), BUN, alkaline phosphatase, lactic dehydrogenase, and liver transaminases. In the amoxicillin group, clinically important changes were observed for eosinophils, uric acid, and alkaline phosphatase. Such changes are typically, although infrequently, encountered in association with treatment with i3-lactam antibiotics. In some of these patients, abnormalities were present at baseline.
3. Summary of Combined Results and Discussion Because the 2 trials were identical in design, their combined results are summarised in order to put into perspective the position of cefpodoxime proxetil in the medical management of patients with uncomplicated urinary tract infections. Overall, 1137 patients participated in the 2 controlled comparative trials. A total of 762 patients were ranto treatment with cefpodoxime proxetil and 375 to comparative treatment groups (cefaclor, 190; amoxicillin, 185). 307 patients receiving cefpodoxime proxetil and 156 receiving comparative agents
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Drugs 42 (Supp/. J) 1991
Table VI. Combined efficacy results and bacteriological eradication rates for predominant pathogens in 2 multicentre double-blind randomised comparisons of cefpodoxime proxetil in adults with uncomplicated urinary tract infections Parameters
Bacteriological cure Clinical cure Bacteriological eradication Escherichia coli Klebsiella spp. Proteus mirabilis Staphylococcus saprophyticus Other
Cefpodoxime proxetil 100mg bid (%) [n : 307)
Cefaclor 250mg tid (%) [n: 99)
(%) [n: 57)
Amoxicillin 250mg tid
247/307 (80) 242/307 (79)
81/99 (82) 78/99 (79)
40/57 (70) 41/57 (72)
200/253 (79) 10/10 (100) 12/16 (75) 8/10 (80) 20/22 (91)
61/75 (81) 5/8 (63) 6/7 (86) 6/6 (100) 3/3 (100)
33/48 (69) 0/0 3/4 (75) 3/3 (100) 2/4 (50)
Abbreviations: bid = twice daily; tid: 3 times daily.
(cefaclor, 99; amoxicillin, 57) were eligible for the efficacy analyses. The bacteriological and clinical cure rates provide evidence that cefpodoxime proxetil compares favourably with cefaclor and amoxicillin in the treatment of patients with uncomplicated urinary tract infections. The clinical and bacteriological cure rates of cefpodoxime proxetil were similar to those of cefaclor and tended to be higher than those of amoxicillin (table VI). Overall, the bacteriological cure rate in the 307 evaluable patients treated with cefpodoxime proxetil was 80% (247 of 307) [table VI]. For evaluable patients receiving the comparative agents, bacteriological cure rates were 82% (81 of 99) and 70% (40 of 57) for the cefaclor and amoxicillin groups, respectively. Most patients who were both clinically and bacteriologically cured at the day 5 to 9 post-treatment visit, and who returned for long term follow-up 4 to 6 weeks after the end of therapy, showed no signs or symptoms, nor pathogen growth (78% for cefpodoxime pro xetil; 82% for cefaclor; 65% for amoxicillin). The most frequently isolated pathogens and their respective eradication rates are summarised, by treatment group, in table VI. Cefpodoxime proxetil compared well with cefaclor and amoxicillin: the eradication rate for E. coli, the predominant pathogen, was comparable to that with cefaclor and higher than that with amoxicillin, and cefpodoxime proxetil was successful in eradicating all iso-
lates of Klebsiella spp. and gave good results against the Gram-positive pathogen, S. saprophyticus. The overall incidence of adverse experiences was 31 % (234 of 762) for cefpodoxime proxetil, 35% (66 of 190) for cefaclor and 21% (38 of 185) for amoxicillin (table VII); this includes all events, regardless of severity or relationship to drug. Only I patient, in the cefpodoxime proxetil group, experienced an adverse event (hypersensitivity reaction) that was considered both serious and drug related, and which led to withdrawal from the study. The most frequently reported adverse events, judged to be moderate or severe in intensity and possibly or probably drug related, were associated with the gastrointestinal (e.g. diarrhoea and nausea) and genital tracts (table VII). Gastrointestinal adverse experiences are typically observed with the administration of broad spectrum cephalosporins, and in the present studies the incidence tended to be higher for cefpodoxime proxetil than for the comparative agents. Nonetheless, there was no difference between the groups in the overall frequency of withdrawal from the trial as a result of adverse events (2% for all groups; table VIII) and no patient in these studies developed pseudomembranous colitis. Vaginal candidiasis, a typical adverse event associated with broad spectrum antibiotic use, was the most frequently reported genital tract problem. The incidence of this event was generally similar
49
Re view of Cefpodox ime Proxetil in Uncomplicated UTI
Table VII. Incidence of adverse events reported in 2 multicentre double-blind randomised comparisons of cefpodoxime proxetil in adults with uncomplicated urinary tract infections Adverse event
Overall a Drug related Moderate Severe Moderate/severe by system b Gastrointestinal Diarrhoea Nausea Genital tract Candidiasis/vaginitis
Cefpodoxirne proxetil 100mg bid (n = 762)
(n = 190)
Amoxicillin 250mg tid (n = 185)
234 (31 %)
66 (35%)
38 (21 %)
52 (7%)
19 (10%) 0
11 (6%) 1 « 1%)
5 « 1%) 29 (4%)C
Cefaclor 250mg tid
0 0 0
19 (3%) 9 (1%) 14 (2%)d
13(7%)
4 (2%) 1 « 1%) 2 (1%) 6(3%)
a Regardless of severity or relationship to drug. b Only events reported at an incidence of > 1% are listed. cOnly 2 patients had severe events . d Only 1 patient had a severe event. Abbreviations: bid = twice daily; tid = 3 times daily.
Table VIII. Patients withdrawn from study ·because of adverse events in 2 multicentre double-blind randomised comparisons of cefpodoxime proxetil in adults with uncomplicated urinary tract infections Adverse event
No. of patients cefpodoxime proxetil (n = 762)
Hypersensitivity Rash, pruritus Gastrointestinal Diarrhoea Nausea Vomiting Miscellaneous a Total a
3
cefaclor (n = 190)
amoxicillin (n = 185)
2
2
4(2%)
3(2%)
5 3
12 (2%)
Increased fever (cefpodoxime proxetil), ruptured appendix (cefaclor), and back pain (amoxicillin).
to that reported for other cephalosporins, but was highest in cefaclor-treated patients; no patients were withdrawn from the trial because of vaginal candidiasis and most were treated with topical antifungal drug therapy.
4. Conclusions The safety and efficacy of cefpodoxime proxetil in the treatment of patients with uncomplicated urinary tract infections have been established in
Drugs 42 (Suppl. 3) 1991
50
clinical trials conducted in Japan (Kumazawa 1991). This review, which reports the results of 2 controlled US clinical trials evaluating cefpodoxime proxetil at a dosage of IOOmg twice daily for 7 days, confirms those results. The bacteriological and clinical efficacy of cefpodoxime proxetil compared favourably with that of 2 established antibacterials, cefaclor and amoxicilIin. The type, severity, and incidence of adverse events observed in patients treated with cefpodoxime proxetil were typical of those associated with iJ-lactam antibacterial therapy. Furthermore, cefpodoxime proxetil offers a more convenient twice-daily dosage regimen compared with the 3 daily doses required for
cefaclor and amoxicillin. Thus, cefpodoxime proxetil has been shown to be a clinically useful therapeutic agent and is an effective alternative in the treatment of patients with uncomplicated urinary tract infections.
References Jones R. Barry A. Antimicrobial activity and disk diffusion susceptibility testing of U-76.523A (R-3746), the active metabolite of the new cephalosporin ester. U-76,252 (CS-807). Antimicrobial Agents and Chemotherapy 32: 443-449. 1988 Kumazawa J. Summary of clinical experience with cefpodoxime proxetil in adults in Japan. Drugs 42 (Suppl. 3): 1-5. 1991 Correspondence and reprints: Dr c.£. Cox. 956 Court Avenue Hl16. University of Tennessee. Memphis. TN 38163. USA.
Review of Clinical Experience in the United States with Cefpodoxime Proxetil in Adults with Uncomplicated Urinary Tract Infections Clair E. Cox,l Jane F. Graveline2 and JoAnna M. Luongo 2 I University of Tennessee. Memphis. Tennessee. USA 2 Sankyo USA Corporation. New York. New York. USA
Summary
Two controlled United States trials compared the safety and efficacy of cefpodoxime proxetil (100mg twice daily) with either cefaclor (250mg 3 times daily) or amoxicillin (250mg 3 times daily) in patients with uncomplicated urinary tract infections. Treatment duration was 7 days. 307 of 762 patients treated with cefpodoxime proxetil, 99 of 190 treated with cefaclor, and 57 of 185 treated with amoxicillin were evaluable for efficacy. 311, 99 and 59 pathogens were isolated from cefpodoxime proxetil, cefaclor and amoxicillin patients, respectively, the most common pathogens being Escherichia coli. Klebsiella spp., Proteus mirabilis. and Staphylococcus saprophyticus. Bacteriological cure rates were 80% (247/307),82% (81/99) and 70% (40/57) for cefpodoxime proxetil, cefaclor and amoxicillin, respectively. Respective clinical cure rates were 79% (242/307), 79% (78/99) and 72% (41/57). Cefpodoxime proxetil was well tolerated, and there was no significant difference between the groups in the overall incidence of adverse experiences. Thus, cefpodoxime proxetil is efficacious and safe in the treatment of patients with uncomplicated urinary tract infections and compares favourably with cefaclor and amoxicillin.
Cefpodoxime proxetil is the orally administered prod rug of cefpodoxime (fig. I), a broad spectrum third generation cephalosporin antibiotic possessing in vitro and in vivo bactericidal activity com-
CH3
I
"'N\(S'jl o~~~~:~')' N-.!LCCONHn~J II
NOCH3
H
H
S
Fig. 1. Chemical structure of cefpodoxime proxetil.
parable or superior to that of currently available oral and parenteral iJ-Iactam antibiotics. Results of in vitro susceptibility testing conducted against more than 9000 clinical isolates obtained from patients in the United States and Japan reveal that cefpodoxime has low minimum inhibitory concentrations (MICs) against Gram-negative and Grampositive aerobic organisms, including staphylococci, streptococci, Haemophilus spp., Moraxella (Branhamella) catarrhalis, Neisseria spp. and Enterobacteriaceae (Jones & Barry 1988). As with many other cephalosporins, cefpodoxime does not demonstrate significant activity against Pseudomonas spp., Enterococcus spp., methicillin-resistant staphylococci or Bacteroides tragi/is (Jones & Barry 1988).
42
Drugs 42 (Suppl. 3) 1991
Table I. Results of a cefpodoxime proxetil dose-ranging study in patients with urinary tract infections (after Iravani et al. 1990) Cefpodoxime proxetil dosage a 200mg daily
Bacteriological cure rate Clinical cure rate a b
(n = 39)
400mg daily (n = 43)
(n = 38)
35/39 (90%) 38/39 (97%)
41/43 (95%) 35/41 b (85%)
34/38 (89%) 35/38 (92%)
600mg daily
Dosage given as cefpodoxime equivalent. Two patients did not have clinical assessments.
Results of preclinical studies conducted in the United States and Japan have not revealed significant toxicity, and the efficacy of cefpodoxime proxetil has been shown to be equal or superior to that of comparative antibiotics, including cefalexin, cefaclor and ampicillin (data on file, Sankyo Co. Ltd., Tokyo). Extensive clinical experience with cefpodoxime proxetil in Japan has demonstrated its efficacy and safety in the treatment of patients with various types of infections, including urinary tract infections (Kumazawa 1991). Several clinical studies in the United States have assessed the efficacy and safety of cefpodoxime proxetil in the treatment of urinary tract infections. On the basis of results of a randomised, multicentre dose-ranging study (table I), a 200mg daily dosage of cefpodoxime proxetil was selected for phase III clinical trials in patients with urinary tract infections. This paper examines the results of 2 separate and previously unpublished multicentre prospective double-blind parallel group randomised comparative phase III clinical trials evaluating the efficacy and safety of cefpodoxime proxetil in the treatment of patients with uncomplicated urinary tract infections at investigational sites throughout the United States. Except for the comparative antibiotic (cefaclor or amoxicillin), the trial design was identical for the 2 studies and the methods for both are described here.
1. Materials and Methods 1.1 Patients Male or female patients aged 12 years or older with bacteriuria [~ 1 bacterium/high power field [HPF] (lOOX)], pyuria [~ 10 WBC/HPF (lOOX)]
and at least 1 sign or symptom typical of urinary tract infections (e.g. urgency, frequency, dysuria, back pain, costovertebral angle tenderness, nocturia, fever, chills or haematuria) were eligible for enrolment. In the 48 hours before administration of the first dose of study medication (baseline visit), a physical examination was conducted and a medical history obtained. Excluded were patients who were asymptomatic, who had complicated urinary tract infections, or a history of allergy or hypersensitivity to cephalosporins, cephamycins, or penicillins. Also excluded were patients with significant hepatic or renal dysfunction, those with underlying medical conditions, which in the opinion of the investigator would interfere with the assessment of response to study medications, those with impaired immunological function, and those with a history of antibiotic-associated colitis. Patients who had received antimicrobial agents or phenazopyridine during the 48 hours (or a depot injection in the 2 weeks), or an investigational drug during the 30 days, before enrolling in the trials were excluded, as were those requiring concomitant nonstudy antibiotic therapy. Patients previously treated with cefpodoxime proxetil in other trials were also excluded. All patients participating in the trials provided written informed consent. 1.2 Study Design Eligible patients with a diagnosis of uncomplicated urinary tract infections were randomised to receive either cefpodoxime proxetil 100mg twice daily or the comparative agent, cefaclor (250mg 3
Review of Cefpodoxime Proxetil in Uncomplicated UTI
43
times daily) or amoxicillin (250mg 3 times daily) for a period of7 days. A 2 : I randomisation schedule was utilised to include twice as many patients in the cefpodoxime proxetil group as in the comparative group. At baseline, urine was collected for culture and susceptibility testing; patients were allowed to continue in the trial if at least I pathogen susceptible or moderately susceptible to both cefpodoxime and the comparative agent was isolated in a quantity of ~ 105 colony forming units (CFU) per/ml of urine. Patients were scheduled for a total of 4 protocol visits: I) the baseline or pretreatment visit in the 48 hours before the first dose of study drug; 2) the day 3 to 4 visit during treatment; 3) the 'end of treatment' visit (within 48 hours of the last dose of study medication); and 4) the post-treatment visit (5 to 9 days after the last dose of study medication). A long term follow-up visit 4 to 6 weeks after the last dose of study drug was scheduled for patients considered clinically and bacteriologically cured at the post-treatment visit.
The investigator assessed each patient's clinical response to treatment with the study drug at the (day 5 to 9) post-treatment visit. This assessment was based on the progression or amelioration of the patient's signs and symptoms of urinary tract infection monitored during the treatment period. The following categories of clinical response were used: 1) clinical cure, defined as elimination of signs and symptoms of urinary tract infections; 2) clinical improvement, defined as clinically significant alleviation of the signs and symptoms of urinary tract infections; 3) cure/recurrence, defined as elimination of signs and symptoms of urinary tract infections during therapy but recurrence 5 to 9 days posttreatment; and 4) clinical failure, defined as a lack of clinically significant alleviation of signs and symptoms of urinary tract infections. At each study visit, the investigator assessed the patient for clinical adverse experiences (observed by the investigator or volunteered by the patient). If present, these were recorded in terms of signs/ symptoms, intensity (mild, moderate or severe), and relationship to study drug (none, remote, possible or probable). Before and at the end of therapy, laboratory testing was performed, including haematology, blood chemistry, and urinalysis. Laboratory adverse experiences were defined as those judged by the investigator to be clinically important changes from baseline in laboratory test values, whether or not considered to be drug related. All adverse experiences, clinical or laboratory, were to be studied, when possible, in a manner deemed medically appropriate by the investigator.
1.3 Evaluations The bacteriological response to treatment was based solely on results of urine cultures obtained on day 3 to 4 during therapy and 5 to 9 days after therapy. For each evaluable patient one of the following bacteriological responses was assigned by the investigator: I) bacteriological cure, defined as eradication of the evaluable pretreatment pathogen(s) in urine specimens « 10 3 CFU/ml); 2) bacteriological cure/superinfection, defined as eradication of the evaluable pretreatment pathogen(s) but emergence of a different organism or a different strain of the pretreatment pathogen(s) in quantities ~ 105 CFU/ml; or 3) bacteriological failure, defined as persistence of at least I evaluable pretreatment pathogen in urine specimens. Additionally, each evaluable baseline pathogen was assessed as follows: I) eradication, defined as absence or reduction to insignificant numbers « 10 3 CFU/ml) in urine specimens; or 2) persistence, defined as presence of significant numbers (~ 10 3 CFU/ml) in urine specimens.
2. Results 2.1 Comparison with Cefaclor
2.1.1 Patients A total of 568 patients with uncomplicated urinary tract infections were enrolled at 27 investigational sites. 378 patients were randomised to the cefpodoxime proxetil treatment group and 190 to the cefaclor group. Of the 568 patients enrolled, 287 were evaluable for efficacy (188 receiving cefpodoxime proxetil and 99 receiving cefaclor).
44
Drugs 42 (Suppl. 3) 1991
The primary reasons for nonevaluation included negative baseline culture (n = 144), a resistant pathogen (n = 40), an off-schedule culture (n = 24), or protocol violation (n = 17). With the exception of age, the 2 evaluable treatment groups were similar with regard to demographic and pretreatment genitourinary characteristics (table II). The median duration of study drug therapy for both groups was 8 days.
2.1.2 Pretreatment Pathogens 290 pretreatment pathogens were isolated from the 287 evaluable patients (3 patients in the cefpodoxime proxetil group each had 2 pathogens; no patients in the cefaclor group had multiple pathogens). The frequency of isolation and range of these organisms were similar for the 2 treatment groups. The most frequently isolated pathogens included Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Staphylococcus saprophyticus, accounting for 172 of the 191 (90%) and 95 of the 99 (96%) pretreatment isolates from patients in the cefpodoxime proxetil and cefaclor groups, respectively.
Table II. Demographic and genitourinary characteristics of evaluable patients with uncomplicated urinary tract infections (UTI) treated with cefpodoxime proxetil or cefaclor in a multicentre double-blind randomised comparison Characteristic
Mean age (years)a [± SOl Sex Male Female Race White Black Other Mean duration of UTI (days) [± SO] a
Cefpodoxime proxetil (n = 188) 38.4 ± 18.25
Cefaclor (n = 99)
33 ± 15.34
9(5%) 179 (95%)
1(1%) 98 (99%)
144 (77%) 40 (21%) 4 (2%) 4.5 ± 6.77
80 (81%) 16 (16%) 3(3%) 4.9 ± 5.73
Difference in mean age between cefpodoxime proxetil and cefaclor patients statistically significant (p = 0.012).
2.1.3 Efficacy Clinical signs and symptoms of urinary tract infections recorded at each study visit were similar in severity and frequency for both treatment groups, with the exception of the 'end of treatment' visit. At this visit. a significantly higher percentage of cefaclor-treated patients (36%) reported at least I sign or symptom, compared with those in the group receiving cefpodoxime proxetil (22%) [p = 0.012). Clinical cure rates at days 5 to 9 post-treatment, summarised in table III, were similar for both treatment groups. In addition, clinical improvement was observed in 12 (6%) cefpodoxime proxetil-treated and 10 (10%) cefaclor-treated patients, yielding overall clinical efficacy rates of 88 and 89%, respectively. There was no statistically significant difference in the overall bacteriological cure rate between the 2 treatment groups: 80% (151 of 188) and 82% (81 of 99) in the cefpodoxime proxetil and cefaclor groups, respectively (table III). Only 14 patients (8 cefpodoxime proxetil, 4%; 6 cefaclor, 6%) had a superinfection with eradication of the pretreatment pathogen. 34 (18%) patients treated with cefpodoxime proxetil and 16 (16%) treated with cefaclor were judged to be bacteriological failures. However, 22 of the 34 patients treated with cefpodoxime proxetil and 12 of the 16 treated with cefaclor who failed therapy bacteriologically were clinically cured or improved. The bacteriological eradication rates are presented in table III. There were no statistically significant differences between treatment with cefpodoxime proxetil and cefaclor. There were similar eradication rates for the predominant pathogen, E. coli, in both treatment groups. Cefpodoxime proxetil was successful in eradicating all isolates of K. pneumoniae, and cefaclor eradicated all isolates of S. saprophytic us. Five evaluable patients (3 cefpodoxime proxetil, 2 cefaclor) who were withdrawn from the study because of inadequate therapeutic effect, were assessed as clinical failures and did not receive an overall bacteriological evaluation.
Review of Cefpodoxime Proxetil in Uncomplicated UTI
45
Table III. Clinical and bacteriological efficacy results from a multicentre double-blind randomised comparison of cefpodoxime proxetil and cefaclor in uncomplicated urinary tract infections Parameter
Cefpodoxime proxetil (%) [n = 188]
Cefacior (%) [n = 99]
Bacteriological cure
151/188 (80)
81/99 (82)
Clinical cure
154/188 (82)
78/99 (79)
Overall bacteriological eradication Escherichia coli
153/191 (80) 114/147 (78)
81/99 (82)
8/8 (100) 6/8 (75)
4/7 (57) 6/7 (86)
8/9 (89) 17/19 (89)
6/6 (100) 4/4 (100)
Klebsiella pneumoniae Proteus mirabilis Staphylococcus saprophyticus Othera
a
61/75 (81)
Other organisms include Citrobacter spp., Enterobacter aerogenes, Group D Enterococcus, Streptococcus spp. and Staphylococcus spp.
A total of 206 patients (132 treated with cefpodoxime proxetil and 74 treated with cefaclor) who had achieved both bacteriological and clinical cure at the day 5 to 9 post-treatment visit returned at 4 to 6 weeks for long term follow-up, Results were similar for the 2 groups; 80% (105 of 132) of patients treated with cefpodoxime proxetil and 82% (61 of 74) treated with cefaclor showed no pathogen growth or signs and symptoms of urinary tract infections.
2.1.4 Safety All 568 patients were included in the analysis of safety. Cefpodoxime proxetil and cefaclor were generally well tolerated, with no difference between groups in the overall incidence of adverse experiences [38% (144 of 378) for cefpodoxime proxetil; 35% (66 of 190) for cefaclor]. There was also no difference in the frequency of early withdrawal from the trial because of adverse experiences [2% (9 of 378) for cefpodoxime proxetil and 2% (4 of 190) for cefaclor]. There were no adverse experiences reported in this trial that were not typical of those observed during treatment with other {3-lactam antibiotics. Events judged by the investigator to be moderate or severe in intensity and possibly or probably drug related are of particular importance clinically. Nine percent (34 of 378) of patients ex-
posed to cefpodoxime proxetil and 10% (19 of 190) exposed to cefaclor reported at least 1 moderate or severe drug-related adverse experience. This difference was not statistically significant. Only I severe adverse experience was reported, i.e. diarrhoea in a patient administered cefpodoxime proxetil. The most commonly reported events were associated with the gastrointestinal (6% cefpodoxime proxetil; 0% cefaclor) and genital tracts (2% cefpodoxime proxetil; 7% cefaclor). All other moderate or severe drug-related adverse experiences occurred with a frequency of.:s; I % and included neurological events, dermatological events, allergy, and unspecified pain. Moderate or severe adverse experiences considered by the investigator to be drug related resulted in withdrawal of 7 (1.9%) patients treated with cefpodoxime proxetil (diarrhoea, nausea, flushing, rash or itching) and 1 (0.5%) treated with cefaclor (itching of the hands). Six (1.6%) patients in the cefpodoxime proxetil group and 2 (1.1%) in the cefaclor group exhibited changes from baseline that were considered to be clinically important in laboratory test values. Tests for which such changes were observed included haemoglobin, haematocrit, WBC count (decrease below normal limits), liver transaminases, lactic dehydrogenase, direct Coombs' test, and urinalysis. These changes were infrequent and typical of those encountered in association with treatment with {3-lactam antibiotics.
46
Drugs 42 (Suppl. 3) 1991
Table IV. Demographic and genitourinary characteristiCs of evaluable patients with uncomplicated urinary tract infections (UTI) treated with cefpodoxime proxetil or amoxicillin in a multicentre double-blind randomised comparison
Characteristic
Mean age (years) [± SD] Sex Male Female Race White Black Other Mean duration of UTI (days) [± SD]
Cefpodoxime proxetil (n = 119)
Amoxicillin (n = 57)
40.4 ± 19.8
37 ± 18.8
9 (8%) 110 (92%)
1 (2%) 56 (98%)
106 (89%) 10(8%) 3 (3%) 4.2 ± 3.6
48 (84%) 6 (11%) 3 (5%) 4.5 ± 5.4
2.2 Comparison with Amoxicillin
2.2.1 Patients A total of 569 patients with uncomplicated urinary tract infections were enrolled in a second comparative trial evaluating the efficacy and safety of cefpodoxime proxetil and amoxicillin. 384 patients were randomised to the cefpodoxime proxetil group and 185 to the amoxicillin group. 176 patients were evaluable for efficacy (119 in the cefpodoxime proxetil group and 57 in the amoxicillin group). Patients were nonevaluable if they showed a negative baseline culture (n = 201), a resistant pathogen (n = 101), an off-schedule culture (n = 29), or a protocol violation (n = 30). The 2 evaluable treatment groups were similar in terms of demographic and genitourinary characteristics at baseline (table IV). Median duration of study drug therapy for each group was 8 days. 2.2.2 Pretreatment Pathogens 179 pretreatment pathogens were isolated from the 176 evaluable patients (I patient in the cefpodoxime proxetil group and 2 in the amoxicillin group each had 2 pathogens). The most commonly isolated organism was E. coli, including 106 isolates from patients in the cefpodoxime proxetil group and 48 from those in the amoxicillin group.
Other organisms isolated (from 3 or more patients) included P. mirabilis and S. saprophyticus.
2.2.3 Efficacy Clinical cure rates at days 5 to 9 post-treatment were similar for the 2 treatment groups (table V). Additionally, 20 patients treated with cefpodoxime proxetil and 7 with amoxicillin were judged to be clinically improved, yielding an overall clinical efficacy rate of 91 % (108 of 119) and 84% (48 of 57), respectively. Clinical signs and symptoms of urinary tract infections for patients in both treatment groups were similar in severity and frequency throughout the study period. The overall bacteriological cure rates, presented in table V, were similar for the 2 treatment groups: 81 % (96 of 119) and 70% (40 of 57) in the cefpodoxime proxetil and amoxicillin groups, respectively. This difference was not statistically significant. Only 7 patients (5 cefpodoxime proxetil, 4%; 2 amoxicillin, 4%) had a response of bacteriological cure with superinfection. 21 (18%) patients treated with cefpodoxime proxetil and 15 (26%) with amoxicillin were judged to be bacteriological failures; 16 of the 21 cefpoTable V. Clinical and bacteriological efficacy results from a multicentre double-blind randomised comparison of cefpodoxime proxetil and amoxicillin in uncomplicated urinary tract
infections Parameters
Cefpodoxime proxetil (%) [n = 119]
Amoxicillin (%) [n = 57]
Bacteriological cure Clinical cure Overall bacteriological eradication Escherichia coli Klebsiella spp. Proteus mirabilis Staphylococcus saprophyticus Othera
96/119 (81) 88/119 (74) 97/120 (81)
40/57 (70) 41/57 (72) 41/59 (69)
86/106 (81) 1/1 (100) 6/8 (75) 0/1
33/48 (69) 0/0 3/4 (75) 3/3 (100)
4/4 (100)
2/4 (50)
a
Other organisms include aerobic Gram-negative coccobacillus, Group D Enterococcus, Group B Streptococcus, Lac· tobacillus spp. and S. aureus.
Review of Cefpodoxime Proxetil in Uncomplicated UTI
doxime proxetil-treated patients and 9 of the IS treated with amoxicillin who were judged to be bacteriological failures were clinically cured or improved. The bacteriological eradication rates are presented in table V. Although the overall eradication rate was higher in the cefpodoxime proxetil group than in the amoxicillin group, this difference did not achieve statistical significance. Cefpodoxime proxetil eradicated a greater percentage of E. coli isolates than did amoxicillin, and was comparable to amoxicillin in eradicating P. mirabilis. Four evaluable patients (2 cefpodoxime proxetil, 2 amoxicillin) who discontinued the study because of inadequate therapeutic effect were assessed as clinical failures and did not receive an overall bacteriological evaluation. 88 cefpodoxime proxetil-treated and 37 amoxicillin-treated patients who achieved both bacteriological and clinical cure 5 to 9 days post-treatment returned for long term follow-up 4 to 6 weeks after the end of therapy. The results observed at this visit were similar for the 2 treatment groups. 66 (75%) and 24 (65%) patients treated with cefpodoxime proxetil and amoxicillin, respectively, had no signs or symptoms of urinary tract infections and no pathogen growth. 2.2.4 Safety All 569 patients exposed to study medication were included in the analysis of efficacy. As was consistent with the results of the previous study, cefpodoxime proxetil and amoxicillin were generally well tolerated, with no statistically significant difference between the groups in terms of the overall incidence of adverse experiences [23% (90 of 384) for cefpodoxime proxetil; 21% (38 of 185) for amoxicillin]. Three (1%) patients treated with cefpodoxime proxetil and 3 (2%) with amoxicillin were withdrawn as a result of adverse experiences. Reasons for discontinuation of cefpodoxime proxetil included diarrhoea, abdominal pain, nausea, and an allergic reaction, all of moderate severity. Rash (mild), itching (moderate) and back pain (severe) resulted in discontinuation of amoxicillin. Six percent of patients in each group reported
47
at least I adverse event considered to be moderate or severe in intensity and possibly or probably drug related (23 of 384 cefpodoxime proxetil; 12 of 185 amoxicillin). Of these 35 patients, only 5 had severe events [4 cefpodoxime (2 headache, I diarrhoea, I vaginitis); I amoxicillin (headache)]. Most of these events were associated with the gastrointestinal (2% for each group) and genital tracts (2% cefpodoxime proxetil; 3% amoxicillin). The incidence of each of the other adverse experiences was :s; I % and included the following systems or categories: metabolic/nutritional, neurological, special senses, respiratory, dermatological, allergy, and miscellaneous. Three (1 %) patients in the cefpodoxime proxetil group and I (1%) in the amoxicillin group were withdrawn from the trial because of moderate drug-related adverse experiences. 12 (3%) patients treated with cefpodoxime proxetil and 4 (2%) with amoxicillin exhibited clinically important changes in laboratory test values. In the cefpodoxime proxetil group, these tests included haemoglobin, haematocrit, polymorphonuclear leucocytes (below normal limits), BUN, alkaline phosphatase, lactic dehydrogenase, and liver transaminases. In the amoxicillin group, clinically important changes were observed for eosinophils, uric acid, and alkaline phosphatase. Such changes are typically, although infrequently, encountered in association with treatment with i3-lactam antibiotics. In some of these patients, abnormalities were present at baseline.
3. Summary of Combined Results and Discussion Because the 2 trials were identical in design, their combined results are summarised in order to put into perspective the position of cefpodoxime proxetil in the medical management of patients with uncomplicated urinary tract infections. Overall, 1137 patients participated in the 2 controlled comparative trials. A total of 762 patients were ranto treatment with cefpodoxime proxetil and 375 to comparative treatment groups (cefaclor, 190; amoxicillin, 185). 307 patients receiving cefpodoxime proxetil and 156 receiving comparative agents
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Drugs 42 (Supp/. J) 1991
Table VI. Combined efficacy results and bacteriological eradication rates for predominant pathogens in 2 multicentre double-blind randomised comparisons of cefpodoxime proxetil in adults with uncomplicated urinary tract infections Parameters
Bacteriological cure Clinical cure Bacteriological eradication Escherichia coli Klebsiella spp. Proteus mirabilis Staphylococcus saprophyticus Other
Cefpodoxime proxetil 100mg bid (%) [n : 307)
Cefaclor 250mg tid (%) [n: 99)
(%) [n: 57)
Amoxicillin 250mg tid
247/307 (80) 242/307 (79)
81/99 (82) 78/99 (79)
40/57 (70) 41/57 (72)
200/253 (79) 10/10 (100) 12/16 (75) 8/10 (80) 20/22 (91)
61/75 (81) 5/8 (63) 6/7 (86) 6/6 (100) 3/3 (100)
33/48 (69) 0/0 3/4 (75) 3/3 (100) 2/4 (50)
Abbreviations: bid = twice daily; tid: 3 times daily.
(cefaclor, 99; amoxicillin, 57) were eligible for the efficacy analyses. The bacteriological and clinical cure rates provide evidence that cefpodoxime proxetil compares favourably with cefaclor and amoxicillin in the treatment of patients with uncomplicated urinary tract infections. The clinical and bacteriological cure rates of cefpodoxime proxetil were similar to those of cefaclor and tended to be higher than those of amoxicillin (table VI). Overall, the bacteriological cure rate in the 307 evaluable patients treated with cefpodoxime proxetil was 80% (247 of 307) [table VI]. For evaluable patients receiving the comparative agents, bacteriological cure rates were 82% (81 of 99) and 70% (40 of 57) for the cefaclor and amoxicillin groups, respectively. Most patients who were both clinically and bacteriologically cured at the day 5 to 9 post-treatment visit, and who returned for long term follow-up 4 to 6 weeks after the end of therapy, showed no signs or symptoms, nor pathogen growth (78% for cefpodoxime pro xetil; 82% for cefaclor; 65% for amoxicillin). The most frequently isolated pathogens and their respective eradication rates are summarised, by treatment group, in table VI. Cefpodoxime proxetil compared well with cefaclor and amoxicillin: the eradication rate for E. coli, the predominant pathogen, was comparable to that with cefaclor and higher than that with amoxicillin, and cefpodoxime proxetil was successful in eradicating all iso-
lates of Klebsiella spp. and gave good results against the Gram-positive pathogen, S. saprophyticus. The overall incidence of adverse experiences was 31 % (234 of 762) for cefpodoxime proxetil, 35% (66 of 190) for cefaclor and 21% (38 of 185) for amoxicillin (table VII); this includes all events, regardless of severity or relationship to drug. Only I patient, in the cefpodoxime proxetil group, experienced an adverse event (hypersensitivity reaction) that was considered both serious and drug related, and which led to withdrawal from the study. The most frequently reported adverse events, judged to be moderate or severe in intensity and possibly or probably drug related, were associated with the gastrointestinal (e.g. diarrhoea and nausea) and genital tracts (table VII). Gastrointestinal adverse experiences are typically observed with the administration of broad spectrum cephalosporins, and in the present studies the incidence tended to be higher for cefpodoxime proxetil than for the comparative agents. Nonetheless, there was no difference between the groups in the overall frequency of withdrawal from the trial as a result of adverse events (2% for all groups; table VIII) and no patient in these studies developed pseudomembranous colitis. Vaginal candidiasis, a typical adverse event associated with broad spectrum antibiotic use, was the most frequently reported genital tract problem. The incidence of this event was generally similar
49
Re view of Cefpodox ime Proxetil in Uncomplicated UTI
Table VII. Incidence of adverse events reported in 2 multicentre double-blind randomised comparisons of cefpodoxime proxetil in adults with uncomplicated urinary tract infections Adverse event
Overall a Drug related Moderate Severe Moderate/severe by system b Gastrointestinal Diarrhoea Nausea Genital tract Candidiasis/vaginitis
Cefpodoxirne proxetil 100mg bid (n = 762)
(n = 190)
Amoxicillin 250mg tid (n = 185)
234 (31 %)
66 (35%)
38 (21 %)
52 (7%)
19 (10%) 0
11 (6%) 1 « 1%)
5 « 1%) 29 (4%)C
Cefaclor 250mg tid
0 0 0
19 (3%) 9 (1%) 14 (2%)d
13(7%)
4 (2%) 1 « 1%) 2 (1%) 6(3%)
a Regardless of severity or relationship to drug. b Only events reported at an incidence of > 1% are listed. cOnly 2 patients had severe events . d Only 1 patient had a severe event. Abbreviations: bid = twice daily; tid = 3 times daily.
Table VIII. Patients withdrawn from study ·because of adverse events in 2 multicentre double-blind randomised comparisons of cefpodoxime proxetil in adults with uncomplicated urinary tract infections Adverse event
No. of patients cefpodoxime proxetil (n = 762)
Hypersensitivity Rash, pruritus Gastrointestinal Diarrhoea Nausea Vomiting Miscellaneous a Total a
3
cefaclor (n = 190)
amoxicillin (n = 185)
2
2
4(2%)
3(2%)
5 3
12 (2%)
Increased fever (cefpodoxime proxetil), ruptured appendix (cefaclor), and back pain (amoxicillin).
to that reported for other cephalosporins, but was highest in cefaclor-treated patients; no patients were withdrawn from the trial because of vaginal candidiasis and most were treated with topical antifungal drug therapy.
4. Conclusions The safety and efficacy of cefpodoxime proxetil in the treatment of patients with uncomplicated urinary tract infections have been established in
Drugs 42 (Suppl. 3) 1991
50
clinical trials conducted in Japan (Kumazawa 1991). This review, which reports the results of 2 controlled US clinical trials evaluating cefpodoxime proxetil at a dosage of IOOmg twice daily for 7 days, confirms those results. The bacteriological and clinical efficacy of cefpodoxime proxetil compared favourably with that of 2 established antibacterials, cefaclor and amoxicilIin. The type, severity, and incidence of adverse events observed in patients treated with cefpodoxime proxetil were typical of those associated with iJ-lactam antibacterial therapy. Furthermore, cefpodoxime proxetil offers a more convenient twice-daily dosage regimen compared with the 3 daily doses required for
cefaclor and amoxicillin. Thus, cefpodoxime proxetil has been shown to be a clinically useful therapeutic agent and is an effective alternative in the treatment of patients with uncomplicated urinary tract infections.
References Jones R. Barry A. Antimicrobial activity and disk diffusion susceptibility testing of U-76.523A (R-3746), the active metabolite of the new cephalosporin ester. U-76,252 (CS-807). Antimicrobial Agents and Chemotherapy 32: 443-449. 1988 Kumazawa J. Summary of clinical experience with cefpodoxime proxetil in adults in Japan. Drugs 42 (Suppl. 3): 1-5. 1991 Correspondence and reprints: Dr c.£. Cox. 956 Court Avenue Hl16. University of Tennessee. Memphis. TN 38163. USA.
