1386. Efficacy of Repeat Dosing of Oral Fosfomycin in a Dynamic Bladder Infection In Vitro Model

Background Oral fosfomycin is indicated for uncomplicated urinary tract infections with activity against MDR-uropathogens. Despite off-label use of giving three doses every 2–3 days, limited supporting data are available. We performed pharmacodynamic profiling using a dynamic bladder infection in vitro model to assess adequacy of repeat doses of fosfomycin. Methods A bladder infection in vitro model simulating urinary fosfomycin concentrations after 3 g (equiv.) oral doses was used with Mueller–Hinton broth (MHB) with 25 mg/L glucose-6-phosphate. Fosfomycin exposures were validated by LC–MS/MS measurements. Pharmacodynamic response of 16 clinical Enterobacteriaceae isolates were examined (eight E. coli, four E. cloacae, four K. pneumoniae; agar dilution MIC 0.25–64 mg/L) following three doses of fosfomycin given every 72, 48 or 24 hours, compared with single dose therapy. Pathogen kill and resistance was assessed by quantitative cultures on drug-free and fosfomycin-containing Mueller–Hinton agar (MHA +64 mg/L, +512 mg/L). Results Fosfomycin exposure following single and multiple doses were accurately reproduced (mean deviation from target 5.0 ± 3.4%, max 11.8%) with minimal variability (mean relative SD 2.7 ± 1.7%, max 8.8%). Fosfomycin high-level heteroresistance was detected prior to drug exposure in 8/16 isolates (proportion 0.00002–0.001% of total population). All isolates with high-level heteroresistance regrew following single dose fosfomycin. Following three doses given every 72 hours, one additional K. pneumoniae isolate was killed. All other isolates regrew with amplification of HLR subpopulation (median proportion: 71.4%, IQR 57.5–100%). Despite dosing 48 and 24 hourly, the same isolates regrew, although HLR subpopulation amplification was reduced (48 hours dosing: 32.0%, IQR 0.005–83.3%; 24 hours dosing: 0.3%, IQR 0.0004–81.3%). Conclusion Dynamic in vitro modeling of multiple doses of oral fosfomycin fails to additionally suppress regrowth in the majority of isolates compared with single dose therapy. Baseline high-level heteroresistance is an important predictor for regrowth. These results suggest that giving multiple doses of fosfomycin is not necessarily better than standard single dose therapy. Earlier timing of repeat doses may help suppress the emergence of resistance. Disclosures All authors: No reported disclosures.

A recommendation for timing of repeat Chlamydia trachomatis test following infection and treatment in pregnant and nonpregnant women

The objective of this study was to describe the time required to obtain a negative chlamydia test in pregnant and nonpregnant women following treatment to inform test-of-cure collection and recommend an abstinence period to avoid reinfection. Seventy-two women with Chlamydia trachomatis infection, 36 pregnant and 36 nonpregnant, were enrolled in a prospective cohort study. Women were excluded less than 18 years of age, if they had been treated for chlamydia, reported an allergy to macrolide antibiotics, or if they had Myasthenia Gravis. Women were treated for chlamydia with single-dose therapy and submitted weekly vaginal chlamydia nucleic acid amplification tests (NAATs). Once NAAT were negative, the participants completed the study. Forty-seven women completed the study per protocol. The primary outcome was to determine the time to a negative chlamydia NAAT following treatment, with secondary outcomes of determining the appropriate time to collect a test-of-cure following chlamydia treatment and to recommend an appropriate abstinence period following treatment to avoid reinfection. Results showed that the time to a negative chlamydia NAAT was significantly different between groups (log-rank p = 0.0013). The median number of days to obtain a negative chlamydia NAAT was 8 days (IQR 7–14) in pregnant and 7 days (IQR 6–10) in nonpregnant women (WRST p = 0.04). All participants had a negative chlamydia NAAT by day 29 post-treatment. Following single-dose treatment for chlamydia, both pregnant and nonpregnant women should test negative with NAAT by 30 days post-treatment. Clinicians should collect a test-of-cure in pregnant women no earlier than 1 month. To avoid reinfection, women should avoid condomless intercourse for at least 1 month.