Cefpodoxime-Proxetil versus Trimethoprim-Sulfamethoxazole for Short-Term Therapy of Uncomplicated Acute Cystitis in Women

Abstract

One hundred sixty-three women with uncomplicated acute lower urinary tract infections were included in a multicenter randomized study comparing cefpodoxime-proxetil (one 100-mg tablet twice daily) with trimethoprim-sulfamethoxazole (one double-strength tablet [160/800 mg] twice daily) for 3 days. A total of 30 women in both arms were excluded from the study for various reasons. At 4 to 7 days after the discontinuation of therapy, 62 of 63 (98.4%) cefpodoxime-proxetil recipients and 70 of 70 (100%) trimethoprim-sulfamethoxazole patients were clinically cured and demonstrated bacteriological eradication, respectively. At 28 days after treatment, 48 of 55 (87.3%) and 43 of 50 (86%) cefpodoxime-proxetil recipients as well as 51 of 60 (85%) and 42 of 50 (84%) trimethoprim-sulfamethoxazole recipients were clinically cured and demonstrated bacteriological eradication, respectively. Independently of the prescribed regimen, a significant difference (P < 0.001) in failure rates was observed only for patients with a previous history of three or more episodes of acute cystitis per year. With the exception of one patient in the trimethoprim-sulfamethoxazole arm who discontinued therapy because of gastrointestinal pain, both antimicrobials were well tolerated. In conclusion, cefpodoxime-proxetil treatment for 3 days was as safe and effective as trimethoprim-sulfamethoxazole for 3 days for the treatment of uncomplicated acute cystitis in women.

Among pre- and postmenopausal women, uncomplicated lower urinary tract infections (UTIs) constitute a common reason for seeking medical assistance. Short-course, 3-day therapeutic regimens with trimethoprim-sulfamethoxazole (TMP-SMX) and fluoroquinolones have been proven to be as effective as longer courses of ≥5 days and are widely used (13, 22). Their advantages are based on increased patient compliance, with decreased adverse effects, decreased costs, and deceased rates of resistance development among the gut and vaginal flora (20). However, the increasing rates of TMP-SMX resistance in the community worldwide (2, 10, 17) as well as the adverse effects of TMP-SMX (3) are causes for concern. Thus, alternative short-course antimicrobial regimens are required. Unfortunately, amoxicillin and older cephalosporins are efficacious only when they are administered for ≥5 days, while nitrofurantoin requires at least 7 days of therapy (16).

Cefpodoxime-proxetil is an orally administered prodrug which is absorbed and deesterified by the intestinal mucosa to release the advanced cephalosporin cefpodoxime, which has approximately 50% systemic bioavailability (5). Cefpodoxime absorption is significantly increased by food, whereas it is reduced by agents that elevate the gastric pH (5). It has a broad spectrum of antibacterial activity encompassing both gram-negative and gram-positive bacteria and is stable against the most commonly found plasmid-mediated beta-lactamases including the TEM-2 and SHV-1 enzymes (5, 23); however, cefpodoxime is hydrolyzed by SHV-2, which is produced by some Klebsiella pneumoniae and Escherichia coli strains, and is also susceptible to hydrolysis by species-specific chromosomally mediated inducible cephalosporinases produced by strains of Pseudomonas aeruginosa, Morganella morganii, Serratia marcescens, Citrobacter spp., and Enterobacter spp. (23, 24). The extended half-life of cefpodoxime in plasma, which ranges from 1.9 to 3.7 h, permits twice-daily administration, while its elimination, primarily by renal excretion, renders cefpodoxime a promising candidate for the therapy of UTIs (4, 5).

The aim of the present study was to evaluate the efficacy and safety of a 3-day regimen of cefpodoxime-proxetil and to compare it with the established short-course 3-day regimen of oral TMP-SMX for the treatment of women with acute uncomplicated cystitis.

MATERIALS AND METHODS

This prospective, open, randomized multicenter study was performed at four medical centers throughout metropolitan Athens, Greece, including the island of Evia. Women between the ages of 18 and 70 years who were referred to relevant outpatient clinics because of symptoms compatible with acute cystitis were eligible for participation in the study. The study was approved by each institution's ethics committee, and before admission into the study, each patient gave oral witnessed informed consent. The diagnosis of uncomplicated cystitis was based upon clinical symptoms (i.e., dysuria, frequency, urgency, and burning pain on urination, as well as the absence of fever [temperature, ≤37.5°C] or flank pain), laboratory findings (i.e., pyuria in uncentrifuged urine of >8 leukocytes per mm³) and a positive urine culture yielding ≥10³ CFU/ml within 48 h before initiation of treatment (9). Exclusion criteria were as follows: serum creatinine concentration of >1.8 mg%, the presence of a permanent indwelling urinary catheter, diabetes or any immunosuppresive disease, a history or evidence of a functionally or anatomically abnormal urinary tract, asymptomatic bacteriuria, known hypersensitivity to β-lactams or TMP-SMX and any contraindication to the use of TMP-SMX (i.e., simultaneous treatment with anticoagulants or glucose-6-phosphate dehydrogenase deficiency), symptoms and signs of upper UTI, a history of acute pyelonephritis, a previous UTI episode with TMP-SMX treatment failure in the previous month or symptoms of lower UTI for longer than 3 days prior to presentation, any antimicrobial therapy within the previous 72 h or therapy with any antimicrobial except the study drugs during the trial, participation in a clinical trial within the previous 2 weeks, pregnancy or breast-feeding, failure to use effective contraception, evidence of hepatic dysfunction, any malabsorption syndrome, an inability to take drugs orally and suspicion of noncompliance, and the presence of urinary pathogens resistant to one of the agents used in the study (9).

Clean, voided midstream urine samples were collected, subjected to urinalysis, and cultured by conventional methods. All isolates were identified with an API system (bioMerieux, Marcy l' Etoile, France), and antimicrobial susceptibility testing was performed as described by the National Committee for Clinical Laboratory Standards (15). Treatment was given on an open randomized basis. Patients were assigned to receive either cefpodoxime-proxetil (one 100-mg tablet twice daily) or a double-strength tablet of TMP-SMX (160/800 mg twice daily) for 3 days. Each patient was monitored clinically and bacteriologically at the baseline visit as well as at 4 to 7 and 28 days after the discontinuation of therapy. Before therapy and at the second follow-up visit, a clinical assessment and urinalysis were performed, urine was obtained for culture, and a blood sample was obtained for routine hematology and serum chemistry, while at the first follow-up visit, only the clinical evaluation and urinalysis were performed and urine was obtained for culture. Only patients who returned for at least the first follow-up visit were eligible for the study.

The effectiveness of the study drugs was evaluated as follows (11). The patients were considered to be clinically cured when all symptoms had subsided and to have treatment failure when symptoms persisted during therapy or relapsed after the discontinuation of therapy. Bacteriological cure was defined as eradication of the causative pathogen, with sterile urine at both follow-ups, while isolation of any microorganism in urine cultures, as determined below, was considered bacteriological failure. Persistence was defined as the presence of the initial causative organisms at the first follow-up visit, superinfection was defined as the isolation of a new pathogen from the culture of urine obtained at the first follow-up, relapse was defined as the presence of the initial causative pathogen at the second follow-up visit with sterile urine at the first follow-up visit, and reinfection was defined as the isolation of a new microorganism at the second follow-up visit with sterile urine at the first follow-up visit. For bacteriological evaluation and whenever symptoms of a lower UTI were present, bacteriological failure was considered a cutoff of ≥10³ CFU/ml, whereas in the case of asymptomatic bacteriuria, a cutoff of ≥10⁵ CFU/ml was necessary. In the case of treatment failure, the patients were subjected to ultrasound of the urinary tract or intravenous pyelography and gynecological examination.

Side effects were recorded after each woman was asked at the follow-up visits about the appearance of any symptoms during the previous week(s) and specifically of symptoms related to the drug treatment, such as abdominal disturbances, nausea, vomiting, rash, and fever.

Statistical analysis was performed by the chi-square test, and P values of ≤0.05 were considered statistically significant (21).

RESULTS

A total of 163 women entered the study. Of these women, 81 received cefpodoxime-proxetil and 82 received TMP-SMX. However, 30 patients were excluded: 15 patients in the cefpodoxime arm were excluded because pretreatment urine cultures were negative, 2 patients in the cefpodoxime arm were excluded because of unstable neurogenic bladder, and 1 patient in the cefpodoxime arm was excluded because of ultrasound findings compatible with underlying chronic pyelonephritis, whereas 8 patients in the TMP-SMX arm were excluded because the pretreatment urine culture was negative and 4 patients in the TMP-SMX arm were excluded because the isolated microorganisms were resistant to the drug tested.

The demographic and clinical characteristics of the evaluable patients in both treatment groups were similar (Table 1). None of the women studied used a diaphragm or a vaginal spermicide; contraception was based on the use of condoms by their sexual partners. Clinical and bacteriological results are listed in Tables 2 and 3. There were no statistically significant differences in either the clinical or bacteriological efficacies of the two drugs (P = 0.54). Compared to those who were cured, all patients in the two treatment groups who failed bacteriologically had histories of three or more episodes of lower UTIs per year (P < 0.001). No significant difference in the cure rates between pre- and postmenopausal women was noted (P = 0.98). Among the seven cefpodoxime-proxetil recipients who failed bacteriologically (one at the first follow-up visit and six at the second follow-up visit), E. coli persisted in one patient and the E. coli infections relapsed in five patients, whereas in one patient a reinfection caused by Enterococcus faecalis was observed. Eight patients in the TMP-SMX arm were considered bacteriological failures (all at the second follow-up visit). Among those eight patients, six had relapses caused by E. coli, one had a relapse caused by Staphylococcus saprophyticus, and one was reinfected with E. faecalis. With the exception of one E. coli strain isolated from a patient given TMP-SMX that was resistant to SMX, the remaining E. coli strains isolated from patients with bacteriological failures in both arms were susceptible to the relevant antimicrobial administered. No superinfection was observed in any of the individuals participating in the study (Table 2). It should be mentioned that all patients who failed bacteriologically had symptoms compatible with a lower UTI. Gynecological examination and ultrasound studies were normal for all patients who failed therapies except for one given TMP-SMX; that patient showed a thickened urinary bladder wall compatible with relapsing cystitis.

TABLE 1.

Demographic characteristics of the two treatment groups

Characteristic	Cefpodoxime-proxetil	TMP-SMX
No. of patients	63	70
Age (yr)
Mean ± SD	43.63 ± 15.25	42.23 ± 15.58
Range	29-59	26-58
No. of premenopausal patients	37	45
No. of postmenopausal patients	26	25
No. of episodes of lower UTIs/pyra
0-1	16	22
2-3	29	32
>3	18	16

^aNone of the patients had chronic cystitis.

TABLE 2.

Bacteriological findings for the two treatment groups

Time of isolation and species isolated	No. of patients infected with the indicated species
	Cefpodoxime-proxetil	TMP-SMX
Initial pretherapy isolates
Escherichia coli	58	59
Proteus mirabilis	2	4
Klebsiella pneumoniae	2	3
Enterobacter cloacae	1	1
Staphylococcus saprophyticus		1
Failure at follow-up
Escherichia coli	6a	6b
Enterococcus faecalis	1	1
Staphylococcus saprophyticus		1c

^aAll isolates were susceptible to cefpodoxime.

^bFive isolates were susceptible to TMP-SMX, and one isolate was resistant to TMP-SMX.

^cThe isolate was susceptible to TMP-SMX.

TABLE 3.

Clinical and bacteriological results at the first and second follow-up visits for the two treatment groups

Visit and treatment	Clinical evaluation (total no. of patients treated/no. cured [%])	Bacteriological evaluation (total no. of patients treated/no. with bacterial eradication [%])
First follow-up
Cefpodoxime-proxetil	63/62 (98.4)	63/62 (98.4)
TMP-SMX	70/70 (100)	70/70 (100)
Second follow-upa
Cefpodoxime-proxetil	55/48 (87.3)	50b/43 (86)
TMP-SMX	60/51 (85)	50b/42 (84)

^aFor the clinical evaluation, 8 patients in the cefpodoxime-proxetil arm and 10 patients in the TMP-SMX were lost to the second follow-up.

^bThe numbers do not coincide with those from the clinical evaluation for the second follow-up visit because urine cultures were not repeated for the relevant patients after they became permanently asymptomatic.

Both drugs were well tolerated. In the cefpodoxime-proxetil arm, one patient each experienced mild gastrointestinal pain and an allergic maculopapular rash, but they did not discontinue therapy, whereas one patient in the TMP-SMX arm stopped treatment because of intense epigastric pain and vomiting. Pre- and posttherapy toxicity profiles were found to be within normal limits in both groups.

DISCUSSION

TMP-SMX is one of the most widely used and efficacious antibacterial agents for the short-term treatment of acute uncomplicated UTIs in women (9, 13, 16, 22). However, hypersensitivity reactions and the emergence of resistant isolates worldwide necessitate the search for other short-term treatment options (2, 3, 10, 17). Because of their advantageous bioavailabilities, high concentrations in urine, excellent in vitro activities, and in vivo efficacies against gram-negative urinary pathogens, fluoroquinolones are increasingly being used for short-term therapeutic regimens (11). Hooton et al. (9) obtained bacteriological cure rates of 92 and 89% at 1 and 5 weeks, respectively, after the discontinuation of therapy with 200 mg of ofloxacin once daily for 3 days. These results were almost the same as those obtained with TMP-SMX for the treatment of acute cystitis (1, 22). However, single-dose regimens with the newer quinolones as well as with fosfomycin trometamol had failure rates slightly higher than those obtained with the 3-day regimens (8, 16). On the other hand, the increasing rates of resistance of E. coli to quinolones in European countries (6, 7) as well as the increasing rates of resistance of E. coli isolates from urine in the Greek community, which exceeds 15% among strains derived from infectious disease outpatient clinics in the Athens area (H. Giamarellou, personal communication), necessitate the evaluation of short-term regimens with advanced cephalosporins. A 5-day treatment regimen with older β-lactams such as amoxicillin and narrow-spectrum cephalosporins had efficacy superior to that of a 3-day regimen, and there was an even greater risk of treatment failure with single-dose regimens (16). In contrast to the latter findings, Sandberg et al. (19) reported similar cure rates of 75 and 72% at late follow-up after treatment with 1 g of cefadroxil once daily for 3 and 7 days, respectively, whereas Greenberg et al. (8) obtained a bacteriological cure rate of 68% at early follow-up after treatment with cefadroxil (0.5 g twice a day) for 3 days and a cure rate of 83% when it was given for 7 days; however, at late follow-up the cure rates were lower (58 and 70%, respectively).

Although amoxicillin and older oral narrow-spectrum cephalosporins are efficacious when they are administered for at least 5 days (16), it seems that newer β-lactams may be more effective for short-term therapy. In a multicenter study, a 3-day regimen of cefuroxime-axetil proved to be as effective as a 3-day regimen of ofloxacin for the treatment of uncomplicated UTIs in 163 women (14). In the latter study, clinical cure and improvement were registered in 84.8 and 95.2% of the patients, respectively, at 7 to 9 days posttherapy, whereas bacteriuria (<10³/ml) was eliminated from 80.3 and 89.1% of the evaluable patients receiving cefuroxime-axetil and ofloxacin, respectively, with no statistically significant difference between treatment groups. On the other hand, in a double-blind randomized study, a 3-day regimen of 400 mg of cefixime once daily was as effective as a 3-day regimen of 200 mg of ofloxacin twice a day for the treatment of 99 women with uncomplicated cystitis (18). In the latter study, the respective clinical cure rates were 89 and 92% at early follow-up and 81 and 84% at late follow-up, with bacteriological cure rates of 83 and 86%, respectively, 7 days after the discontinuation of therapy and 77 and 80%, respectively, 4 weeks after the discontinuation of therapy (18).

In the present study, cefpodoxime-proxetil at a dose of 100 mg has been shown to be as effective and safe as TMP-SMX at a dose of 160/800 mg when both regimens are given twice daily for 3 days. At 28 days after the discontinuation of therapy, clinical cures were observed in 87.3 and 85% of the patients in the cefpodoxime-proxetil and TMP-SMX arms, respectively, and the rates of overall bacteriological eradication were 86 and 84% in the two arms, respectively. Although there is some evidence that short-term ciprofloxacin therapy may be more efficient for the eradication of urinary pathogens (11), the regimens used in the present study were better than those obtained with a short course of cefixime (18) and were similar to those obtained by Cox et al. (4) when cefpodoxime-proxetil was administered for 7 days (14). Two double-blind multicenter trials (4) compared cefpodoxime-proxetil (100 mg twice daily) with cefaclor (250 mg three times daily) or amoxicillin (250 mg three times daily) in 463 evaluable adult patients with uncomplicated UTIs. Cefpodoxime-proxetil proved to be as effective as cefaclor or amoxicillin, with no significant differences in the clinical cure rates between treatment arms (79, 79, and 72%, respectively) or in the bacteriological eradication rates (80, 82, and 70%, respectively). In the present study, independently of the prescribed regimen, a statistically significant difference in failure rates with the 3-day therapeutic course was observed only in patients with a previous history of three or more episodes of acute cystitis per year. In contrast to the results of previous studies with older oral β-lactams (5), the fact that in this study short-term therapy with cefpodoxime-proxetil was as effective as the established 3-day regimen of TMP-SMX could probably be based on the slower elimination of cefpodoxime from urine because of its prolonged half-life. Surveillance cultures for vaginal reservoir flora, which were not performed in the present study, could also offer another explanation for the low bacteriological failure rates observed in the cefpodoxime arm (12).

The tolerance of both antimicrobials was satisfactory. Only two patients in the cefpodoxime-proxetil arm reported mild adverse events, whereas one patient in the TMP-SMX arm discontinued therapy because of gastrointestinal side effects. Hematologic and biochemical results did not show any important differences pre- and posttherapy. However, if one considers the fact that a 3-day course of cefpodoxime proxetil costs $10.4 but a 3-day course of TMP-SMX costs $1.95, i.e., 5.3 times more (according to pharmacy prices in Athens), and if one considers the possibility of the emergence in the community of E. coli strains resistant even to advanced cephalosporins, it seems that the use of cefpodoxime-proxetil should be restricted to multiresistant gram-negative organisms.

This study has reported for the first time in the available literature that a short 3-day course of therapy with cefpodoxime-proxetil is as safe and effective as a 3-day course of TMP-SMX for the treatment of acute uncomplicated lower UTIs in women.