PBPK Modeling of Azithromycin Systemic Exposure in a Roux-en-Y Gastric Bypass Surgery Patient Population.

In this investigation, PBPK modeling using the Simcyp® Simulator was performed to evaluate whether Roux-en-Y gastric bypass (RYGB) surgery impacts the oral absorption and bioavailability of azithromycin. An RYGB surgery patient population was adapted from the published literature and verified using the same probe medications, atorvastatin and midazolam. Next, a PBPK model of azithromycin was constructed to simulate changes in systemic drug exposure after the administration of different oral formulations (tablet, suspension) to patients pre- and post-RYGB surgery using the developed and verified population model. Clinically observed changes in azithromycin systemic exposure post-surgery following oral administration (single-dose tablet formulation) were captured using PBPK modeling based on the comparison of model-predicted exposure metrics (Cmax, AUC) to published clinical data. Model simulations predicted a 30% reduction in steady-state AUC after surgery for three- and five-day multiple dose regimens of an azithromycin tablet formulation. The relative bioavailability of a suspension formulation was 1.5-fold higher than the tablet formulation after multiple dosing. The changes in systemic exposure observed after surgery were used to evaluate the clinical efficacy of azithromycin against two of the most common pathogens causing community acquired pneumonia based on the corresponding AUC24/MIC pharmacodynamic endpoint. The results suggest lower bioavailability of the tablet formulation post-surgery may impact clinical efficacy. Overall, the research demonstrates the potential of a PBPK modeling approach as a framework to optimize oral drug therapy in patients post-RYGB surgery.

Meropenem plus Ceftaroline Is Active against Enterococcus faecalis in an In Vitro Pharmacodynamic Model Using Humanized Dosing Simulations.

The standard of care for serious Enterococcus faecalis infections is ampicillin plus ceftriaxone. Ampicillin's inconvenient dosing schedule, drug instability, allergy potential, along with ceftriaxone's high risk for Clostridioides difficile infection and its promotion of vancomycin-resistant enterococci (VRE), led our team to explore alternative options. This work aimed to understand the role of carbapenems in combination with cephalosporins in these infections. We selected two ampicillin and penicillin susceptible E. faecalis strains (AMP-MIC 0.5-2 µg/mL; PCN-MIC 2 µg/mL) and simulated human therapeutic dosing regimens in a 48-h in vitro pharmacodynamic model (IVPD) with ampicillin (2g q4h), ertapenem (1g q24h), meropenem (2g q8h), ceftriaxone (2g q12h), and ceftaroline (600 mg q8h). As expected, ampicillin plus ceftriaxone demonstrated enhanced activity compared with ampicillin monotherapy with no MIC increases in either isolate. Meropenem and ceftaroline demonstrated significant kill against both isolates, with no regrowth or MIC increases occurring. Meropenem plus ceftriaxone also demonstrated significant kill, and while no MIC increases were identified for meropenem, there was minor regrowth and larger standard deviations. Ertapenem combined with either ceftriaxone or ceftaroline enhanced activity at 24 h, but at 48 h, regrowth occurred, and ertapenem MIC increases were noted. Meropenem-based combination therapy against E. faecalis may provide clinicians with another regimen to treat severe E. faecalis infections. Meropenem plus ceftaroline was as active as the standard of care treatment (ampicillin plus ceftriaxone) and may serve as an alternative for serious E. faecalis infections. Further studies are warranted to determine the clinical efficacy.

Evaluation of post-flexible cystoscopy urinary tract infection rates.

PURPOSE: The risk of urinary tract infection (UTI) development after flexible cystoscopy (FC) is not well described. It remains difficult to assess the role of pre-FC antimicrobial prophylaxis to reduce UTI risk. METHODS: In fall 2017, the urology service at the Providence Veterans Affairs Medical Center implemented routine oral antimicrobial prophylaxis in its outpatient FC clinic. Outpatients were randomly selected for a retrospective chart review to compare patients who received pre-FC antimicrobials (cefuroxime 500 mg tablet or sulfamethoxazole/trimethoprim [800 mg/160 mg] tablet) and those who underwent FC prior to fall 2017 and did not receive prophylaxis. The primary outcome was presence of symptomatic UTI within 30 days post FC. Secondary outcomes included symptomatic UTI that met colony-forming unit (CFU)/mL guideline requirements, and UTI treatment received. Potential risk factors for UTI were also assessed. RESULTS: A total of 296 patients were included in the final analysis: 139 who did not receive and 157 who received a prophylactic antimicrobial before FC. Rates of symptomatic UTI, symptomatic UTI meeting CFU/mL guideline requirements, and postprocedure treatment for UTI were similar with and without antimicrobial prophylaxis (2.5% vs 2.2% [P > 0.99], 1.9% vs 1.4% [P > 0.99], and 2.5% vs 4.3% [P = 0.53], respectively). The mean number of days from FC to the start of UTI treatment was 7.9 (range, 1-18 days). Age over 65 years was the only risk factor present in all patients with a post-FC UTI, irrespective of antimicrobial prophylaxis. CONCLUSION: The rate of post-FC symptomatic UTI was lower than rates previously described in the literature. The role of antimicrobial prophylaxis prior to FC warrants further exploration.