In vitro phase II comparison of the cytotoxicity of a novel platinum analog, nedaplatin (254-S), with that of cisplatin and carboplatin against fresh, human ovarian cancers.

PURPOSE: To compare the in vitro cytotoxicity of nedaplatin, an investigational platinum analog, with that of the standard platinum agents, cisplatin and carboplatin, against fresh human, epithelial ovarian cancers. METHODS: The Hamburger-Salmon human tumor colony-forming assay (HTCA) was used to measure the chemosensitivity of 36 fresh tumor samples obtained during initial exploratory laparotomy from patients with newly diagnosed stage III-IV epithelial ovarian cancer who had received no prior chemotherapy or radiation therapy. Tumor samples were exposed to the platinum analogs for 1 h at concentrations of 10 and 100 micrograms/ml of nedaplatin and cisplatin and 100 and 1000 micrograms/ml of carboplatin. The resulting survival data were used to estimate the IC50 (drug concentration associated with 50% inhibition of tumor colony forming units, TCFUs) of each of the platinum analogs for each of the tumor samples, as well as the estimated survival following exposure to clinically achievable drug levels (i.e. the ultrafiltrable platinum area under the plasma disappearance curve, AUC, achieved in cancer patients following administration of standard or phase II doses). RESULTS: At the lowest concentration tested (i.e. 10 micrograms/ml nedaplatin and cisplatin and 100 micrograms/ml carboplatin) the percentages of tumor samples which were sensitive (as defined by 50% or less survival of TCFUs as compared with controls) were 42, 50, and 40% for nedaplatin, cisplatin and carboplatin, respectively. The median IC50 values were 28.5, 12 and 121 micrograms/ml for nedaplatin, cisplatin and carboplatin, respectively. The estimated percentage of tumors sensitive to clinically achievable dose levels was 42% for nedaplatin and 36% for cisplatin and carboplatin. Nedaplatin and carboplatin proved relatively crossresistant with cisplatin in vitro; of the 18 tumor samples which were resistant to cisplatin, only 5 (28%) were sensitive to nedaplatin and 3 of 17 (18%) were sensitive to carboplatin. CONCLUSION: Nedaplatin was associated with cytotoxicity similar to cisplatin and carboplatin in this study. Although nedaplatin appears to be crossresistant with cisplatin, its high rate of in vitro cytotoxicity, relative lack of neurotoxicity and nephrotoxicity, and large in vivo biovailability establish nedaplatin as a promising platinum analog for further clinical development as a salvage and primary chemotherapeutic agent for patients with advanced ovarian cancer.

Trimethoprim-sulfamethoxazole for acute dysuria in women: a single-dose or 10-day course. A double-blind, randomized trial.

STUDY OBJECTIVE: To compare single-dose and 10-day treatment regimens of trimethoprim-sulfamethoxazole in women with acute dysuria, urgency, or urinary frequency. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Student health center at a major university. PATIENTS: Consecutive sample of 255 young women including 216 with a bacteriologically documented urinary tract infection. INTERVENTION: Single-dose treatment (trimethoprim, 320 mg and sulfamethoxazole, 1600 mg) given to 116 women and 10-day treatment (trimethoprim, 160 mg and sulfamethoxazole, 800 mg, twice daily) given to 125 women. Women with a history of sulfonamide allergy were given trimethoprim alone: 10 received single-dose treatment (200 mg) and 5 received 10-day treatment (100 mg, twice daily). MEASUREMENTS AND MAIN RESULTS: The rates for resolution of symptoms at 3 days, 13 days, and 6 weeks after entry into the study were not significantly different between treatment groups. Among women with urinary tract infections, cumulative crude rates of recurrence in the single-dose and 10-day treatment groups, respectively, were 24% compared with 5% at 13 days after entry (P = 0.0002; 95% confidence interval [CI] for difference in proportions, 10%, 28%) and 32% compared with 21% at 6 weeks after entry (P = 0.07; 95% Cl, -2%, 24%). Factors independently associated with lower cure rates were a history of a urinary tract infection within the previous 6 weeks (adjusted odds ratio [OR], 3.8; 95% Cl, 1.4 to 10.6) and presence of 10(5) bacteria/mL or greater in an initial midstream culture (adjusted OR, 2.9; 95% Cl, 1.2 to 7.0). After controlling for these factors, the risk of failure after single-dose treatment was not statistically significantly different from 10-day treatment at 6 weeks (adjusted OR, 1.6; 95% Cl, 0.8 to 3.2; P = 0.21). Compared to 10-day treatment, single-dose treatment less effectively eradicated Escherichia coli from the vaginal flora (P less than 0.001) and led more often to early same-strain recurrences (P = 0.003). Meaningful adverse effects occurred in 12% of women given single-dose treatment compared with 25% of women receiving 10-day treatment (P = 0.009). CONCLUSIONS: Compared with single-dose treatment, 10-day treatment yields a superior cure rate at 2 weeks after the start of treatment, but by 6 weeks the advantage of longer treatment no longer exists. This effect may be explained by the lesser effectiveness of single-dose treatment in eradicating vaginal E. coli, resulting in more frequent same-strain recurrences within 2 weeks of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Association between diaphragm use and urinary tract infection.

We conducted independent case-control and retrospective cohort investigations to assess the relationship between diaphragm use and urinary tract infection (UTI). In the former, we compared diaphragm use and vaginal flora among 114 women with acute UTI and 85 women with acute urinary tract symptoms and no UTI. In the latter study, we ascertained the incidence of UTI in 192 diaphragm users and 182 women taking oral contraceptives during a mean follow-up of 9.4 months. Both studies demonstrated a significantly increased risk of UTI in diaphragm users: relative odds were 2.0 in the case-control study and the relative risk was 2.5 in the retrospective cohort study. Vaginal colonization with Escherichia coli was significantly greater in diaphragm users. The incidence of UTI in the cohort study was 26.6 per 1,000 patient-months for diaphragm users and 8.9 per 1,000 patient-months for women taking oral contraceptives. The increased risk of UTI in diaphragm users could not be attributed to differences in age, parity, sexual activity, or previous UTI.

Management of recurrent urinary tract infections with patient-administered single-dose therapy.

In a randomized crossover trial, 38 women with recurrent urinary tract infections were assigned to use either continuous prophylaxis with trimethoprim-sulfamethoxazole or intermittent self-administered therapy (single-dose trimethoprim-sulfamethoxazole taken for acute urinary symptoms). The infection rate for patients on prophylaxis was 0.2 episodes/patient-year compared with 2.2 infections/patient-year for patients on self-administered therapy (p less than 0.001). Thirty-five of thirty-eight symptomatic episodes diagnosed by patients as infection were confirmed microbiologically, and 30 of the 35 infections responded clinically and microbiologically to patient-administered therapy with single-dose trimethoprim-sulfamethoxazole. No complications were seen in the 5 patients in whom therapy failed. The annual costs of prophylaxis and self-therapy were similar ($256 and $239, respectively) and both were less expensive than conventional therapy in women having 2 or more infections per year. In selected women, self-therapy is efficacious and economical compared with conventional therapy or prophylaxis.

Single-dose therapy for cystitis in women. A comparison of trimethoprim-sulfamethoxazole, amoxicillin, and cyclacillin.

We evaluated single-dose regimens of trimethoprim-sulfamethoxazole, amoxicillin, and cyclacillin as treatment for acute cystitis in 38 women. The trial was prematurely stopped because of frequent treatment failures. At two days after treatment, all 13 patients given trimethoprim-sulfamethoxazole were cured, while four (31%) of 13 given amoxicillin and four (33%) of 12 given cyclacillin had persistent bacteriuria. At two weeks, 11 (85%) of 13 patients given trimethoprim-sulfamethoxazole, six (50%) of 12 given amoxicillin, and three (30%) of ten given cyclacillin were cured. One patient with positive results of antibody-coated bacteria testing who was treated with cyclacillin had signs and symptoms of acute pyelonephritis three days after treatment, and two patients treated with amoxicillin and one treated with trimethoprim-sulfamethoxazole converted antibody-coated bacteria test results from negative to positive after therapy. We conclude that single-dose treatment of cystitis in unselected women with cyclacillin and amoxicillin may result in low cure rates and that progression to acute pyelonephritis may occur following ineffective single-dose therapy.

Urinary tract infections in young adult women caused by Staphylococcus saprophyticus.

We evaluated and compared 81 urinary tract infections (UTIs) with Staphylococcus saprophyticus occurring in 72 college women with Escherichia coli UTIs. During the 14-month study period, S saprophyticus was the second most common cause of UTIs, accounting for 11% of the total. Staphylococcus saprophyticus infections occurred more frequently during the late summer and early fall. Age, history of previous UTI, signs and symptoms of infection, and findings on urinalysis were similar in patients with S saprophyticus and E coli infections. Nine (41%) of 22 S saprophyticus infections were localized to the upper urinary tract by the antibody-coated bacteria technique compared with 18 (16%) of 115 infections with E coli (P = .01). Rectal, vaginal, and urethral colonization with S saprophyticus was associated with UTI caused by these organisms, suggesting that their pathogenesis resembles that of E coli UTIs. In vitro susceptibility testing showed almost uniform sensitivity of S saprophyticus to most antimicrobials used to treat UTIs, but recurrent infections occurred in six of the 72 women despite adequate therapy. Physicians and microbiologists must be aware that S saprophyticus is an important cause of UTIs in young women.

Etiologic role of Mycoplasma hominis and Ureaplasma urealyticum in women with the acute urethral syndrome.

In an assessment of the possible etiologic role of Mycoplasma hominis and Ureaplasma urealyticum in the acute urethral syndrome (AUS) in women, 79 women with AUS, 35 women with acute bacterial cystitis, and 66 asymptomatic volunteers were studied. Evidence against an etiologic role for M. hominis in AUS included: (1) a similar prevalence of the organism among women with AUS (18%), women with cystitis (29%), and asymptomatic women (15%); (2) a lack of association of M. hominis with AUS cases for which no other infectious cause was found; (3) a lack of association of pyuria with cases of infection in which M. hominis was isolated; and (4) an absence of M. hominis from cultures of bladder urine obtained by suprapubic aspiration. A possible etiologic role for U. urealyticum in some cases of AUS was suggested by the association of counts of this organism of greater than or equal to 10(3)/ml with pyuria in women whose AUS had no other apparent etiology and by the isolation of the organism from suprapubic aspirates from four of 15 women with AUS of unknown etiology. Further studies, similar to those done in men with nongonococcal urethritis, are necessary for confirmation of the causative role of U. urealyticum in AUS.

Diagnosis of coliform infection in acutely dysuric women.

We reevaluated conventional criteria for diagnosing coliform infection of the lower urinary tract in symptomatic women by obtaining cultures of the urethra, vagina, midstream urine, and bladder urine. The traditional diagnostic criterion, greater than or equal to 10(5) bacteria per milliliter of midstream urine, identified only 51 per cent of women whose bladder urine contained coliformis. We found the best diagnostic criterion to be greater than or equal to 10(2) bacteria per milliliter (sensitivity, 0.95; specificity, 0.85). Although isolation of less than 10(5) coliforms per milliliter of midstream urine has had a low predictive value of previous studies of asymptomatic women, the predictive value of the criterion of greater than or equal to 10(2) per milliliter was high (0.88) among symptomatic women the prevalence of coliform infection exceeded 50 per cent. In view of these findings, clinicians and microbiologists should alter their approach to the diagnosis and treatment of women with acute symptomatic coliform infection of the lower urinary tract.

Treatment of cystitis in women with a single dose of trimethoprim-sulfamethoxazole.

The efficacy of a single dose (four tablets) and of 10-day courses of trimethoprim-sulfamethoxazole (TMP-SMZ) was studied in 77 women with symptomatic cystitis and negative tests for antibody-coated bacteria. Cure rates after six weeks were 76% for single-dose therapy and 87% for 10 days of treatment. For Escherichia coli infections, cure rates after six weeks were 80% and 86%, respectively. However, 10-day treatment eliminated enteric bacilli from urethral and vaginal sites more often than did single-dose therapy. Two weeks after completion of treatment, perineal colonization was observed more often in the women who developed recurrent infections than in those who did not (P = 0.01). During these two weeks, recurrent infections were found somewhat more often in the women who had received single-dose therapy than in those who had undergone 10-day treatment (5 of 38 vs. 2 of 39; P = 0.07). With conventional courses of antibiotics, retreatment of all recurrent infections was less successful in women previously given single-dose therapy. Recurrent infections were also more frequent in women infected with bacteria other than E. coli. Both drug regimens were well tolerated. However, serious adverse reactions were fewer in patients treated with a single dose (8.5%) than in patients treated for 10 days (15%). Single-dose therapy with TMP-SMZ appears as effective as 10-day therapy in acute uncomplicated cystitis caused by E. coli.