Pharmacodynamic evaluation of suppression of in vitro resistance in Acinetobacter baumannii strains using polymyxin B-based combination therapy

The emergence of polymyxin resistance in Gram-negative bacteria infections has motivated the use of combination therapy. This study determined the mutant selection window (MSW) of polymyxin B alone and in combination with meropenem and fosfomycin against A. baumannii strains belonging to clonal lineages I and III. To evaluate the inhibition of in vitro drug resistance, we investigate the MSW-derived pharmacodynamic indices associated with resistance to polymyxin B administrated regimens as monotherapy and combination therapy, such as the percentage of each dosage interval that free plasma concentration was within the MSW (%TMSW) and the percentage of each dosage interval that free plasma concentration exceeded the mutant prevention concentration (%T>MPC). The MSW of polymyxin B varied between 1 and 16 µg/mL for polymyxin B-susceptible strains. The triple combination of polymyxin B with meropenem and fosfomycin inhibited the polymyxin B-resistant subpopulation in meropenem-resistant isolates and polymyxin B plus meropenem as a double combination sufficiently inhibited meropenem-intermediate, and susceptible strains. T>MPC 90% was reached for polymyxin B in these combinations, while %TMSW was 0 against all strains. TMSW for meropenem and fosfomycin were also reduced. Effective antimicrobial combinations significantly reduced MSW. The MSW-derived pharmacodynamic indices can be used for the selection of effective combination regimen to combat the polymyxin B-resistant strain.

The Effect of Ibuprofen Dosing Interval on Post-Tonsillectomy Outcomes in Children: A Quality Improvement Study

Objective: In this Quality Improvement (QI project) it was hypothesized that an increase in dosing intervals for postoperative analgesia when alternating Ibuprofen and Acetaminophen would reduce post-tonsillectomy hemorrhage (PTH) rates for those undergoing tonsillectomies with or without adenoidectomy, while maintaining the standard of postoperative analgesia and reducing visits to the Emergency Room (ER) for reasons other than PTH. Data was collected from 353 children. Utilizing run chart analysis, it was determined that patients experiencing the 4-hour dosing interval had lower rates of PTH, fewer ER visits, and no increase in postoperative phone calls from caregivers. Patients and Methods: Patients were treated with standing Acetaminophen 15 mg/kg q6h and Ibuprofen 10 mg/kg q6h for postoperative analgesia from July of 2017 until January of 2018. Starting January of 2018 through November of 2018, the dosage interval was lengthened 1 hour. Data relating to PTH, ER visits for reasons other than bleeding, and phone calls from caregivers was collected. Results: Run charts were used to assess outcomes regarding PTH, postoperative visits to the ER for reasons other than PTH, and phone calls from caregivers. Our results suggest that a standing protocol of alternating Acetaminophen and Ibuprofen given every 4 hours improves the post-tonsillectomy hemorrhage rate without increasing ER visits or calls about pain. Conclusions: This data shows promise in reducing PTH and ER visits with a longer dose interval when alternating Acetaminophen and Ibuprofen for postoperative analgesia in tonsillectomy patients. A randomized clinical trial should be carried out to further validate these claims.

DOP26 Real-life dosing patterns and concomitant drug use among ustekinumab-treated patients with Crohn’s disease

Background Real-life long-term evidence on ustekinumab treatment in patients with Crohn’s disease (CD) is limited. We performed a retrospective non-interventional nation-wide chart review study of dosing and long-term clinical outcomes in Finnish CD patients treated with ustekinumab (FINUSTE2, EUPAS30920). Methods FINUSTE2 was carried out in 17 Finnish centres. Eligible patients were adults with CD, receiving an intravenous (IV) first dose of ustekinumab during 2017 or 2018. Data on disease activity, dosage, and concomitant medications were collected at baseline, 16 weeks, and 1 year from treatment initiation. All measurements on ustekinumab trough concentrations (TC) were recorded. Results The study included 155 patients (48% female) with a mean age of 44 and disease duration of 14 years. The disease was stricturing or penetrating in 69% of patients, 59% had prior CD-related surgeries, and 96% had a treatment history of at least one biologic agent. After one IV dose and one to two subcutaneous (SC) doses at 8 to 16 weeks, 140 patients (93%) continued to maintenance treatment with SC ustekinumab, of which nearly three-quarters with a dosage interval of 8 weeks (Figure 1). Of 93 patients with a follow-up of at least 1 year, 77 were still on ustekinumab. During follow-up, 55 patients (39%) had their ustekinumab dose adjusted, mostly (n = 44, 31.4%) as a shortening of the dosage interval. Forty-nine patients had in total 65 ustekinumab TC measurements performed, with a mean of 2.2 µg/ml at 16 weeks (n = 23) and 2.7 µg/ml at 1 year (n = 25). In 67% of cases, the reason for measuring TC was lack of or insufficient response. No anti-drug antibodies appeared at any time point. The proportion of patients on ustekinumab monotherapy increased significantly, from 34% (n = 52) at baseline to 54% (n = 79/146; p < 0.001) at 16 weeks and 64% (n = 49/77; p < 0.01) at 1 year. Correspondingly, corticosteroid use decreased significantly, and a trend towards reduced use of immunomodulators was observed (Figure 2). Conclusion In this nationwide real-life study, treatment with ustekinumab in patients with longstanding and complicated CD was persistent and allowed for significant corticosteroid tapering. A vast majority started the maintenance treatment with an 8-week dosage interval and nearly one-third of all patients required a dose increase, suggesting a highly refractory disease phenotype. The lack of detected antidrug antibodies during follow-up indicates low immunogenicity for ustekinumab.

In Vitro Resistance Selection in Shigella flexneri by Azithromycin, Ceftriaxone, Ciprofloxacin, Levofloxacin, and Moxifloxacin

ABSTRACT Shigella flexneri continues to be a major cause of diarrhea-associated illness, and increasing resistance to first-line antimicrobials complicates the treatment of infections caused by this pathogen. We investigated the pharmacodynamics of current antimicrobial treatments for shigellosis to determine the likelihood of resistance promotion with continued global antimicrobial use. The mutant prevention concentration (MPC) and mutant selection window (MSW) were determined for azithromycin, ceftriaxone, ciprofloxacin, levofloxacin, and moxifloxacin against a wild-type strain of S. flexneri (ATCC 12022) and an isogenic gyrA mutant (m-12022). Time-kill assays were performed to determine antimicrobial killing. Concentrations of approved doses of ciprofloxacin, levofloxacin, and moxifloxacin are predicted to surpass the MPC for a majority of the dosage interval against ATCC 12022. However, against m-12022, concentrations of all fluoroquinolones are predicted to fall below the MPC and remain in the MSW for a majority of the dosage interval. Concentrations of ceftriaxone fall within the MSW for the majority of the dosage interval for both strains. All agents other than azithromycin displayed bactericidal activity in time-kill assays. Results of pharmacodynamic analyses suggest that all tested fluoroquinolones would achieve a favorable area under the concentration-time curve (AUC)/MPC ratio for ATCC 12022 and would restrict selective enrichment of mutants but that mutant selection in m-12022 would be likely if ciprofloxacin were used. Based on pharmacodynamic analyses, azithromycin and ceftriaxone are predicted to promote mutant selection in both strains. Confirmation of these findings and examination of novel treatment regimens using in vivo studies are warranted.

Evaluation of Meropenem Regimens Suppressing Emergence of Resistance in Acinetobacter baumannii with Human Simulated Exposure in anIn VitroIntravenous-Infusion Hollow-Fiber Infection Model

ABSTRACTThe emergence of resistance to carbapenems inPseudomonas aeruginosacan be suppressed by optimizing the administration of meropenem. However, whether the same is true forAcinetobacter baumanniiis not fully understood. We assessed the bactericidal activity of meropenem and its potency to suppress the emergence of resistance inA. baumanniiwith human simulated exposure in anin vitrointravenous-infusion hollow-fiber infection model (HFIM). Two clinical strains of carbapenem-susceptible multidrug-resistantA. baumannii(CS-MDRAB), CSRA24 and CSRA91, were used, and their MICs and mutant prevention concentrations (MPCs) were determined. Six meropenem dosage regimens (0.5, 1.0, or 2.0 g given every 8 h [q8h] with a 0.5-h or 3-h infusion for seven consecutive days) were simulated and then evaluated in the HFIM. Both the total population and resistant subpopulations of the two strains were quantified. Drug concentrations were measured by high-performance liquid chromatography. All dosage regimens, except for the lowest dosage (0.5 g for both the 0.5-h and 3-h infusions), showed 3-log CFU/ml bacterial killing. Dosage regimens of 2.0 g with 0.5-h and 3-h infusions exhibited an obvious bactericidal effect and suppressed resistance. Selective amplification of subpopulations with reduced susceptibility to meropenem was suppressed with a percentage of the dosage interval in which meropenem concentrations exceeded the MPC (T>MPC) of ≥20% or with a ratio ofT>MPC to the percentage of the dosage interval in which drug concentrations are within the mutant selection window of ≥0.25. Ourin vitrodata support the use of a high dosage of meropenem (2.0 g q8h) for the treatment of severe infection caused by CS-MDRAB.

Effects of Etravirine Alone and with Ritonavir-Boosted Protease Inhibitors on the Pharmacokinetics of Dolutegravir

ABSTRACTDolutegravir (DTG) is an unboosted, once-daily integrase inhibitor currently in phase 3 trials. Two studies evaluated the effects of etravirine (ETR) alone and in combination with ritonavir (RTV)-boosted protease inhibitors (PIs) on DTG pharmacokinetics (PK) in healthy subjects. DTG 50 mg every 24 h (q24h) was administered alone for 5 days in period 1, followed by combination with ETR at 200 mg q12h for 14 days in period 2 (study 1) or with ETR/lopinavir (LPV)/RTV at 200/400/100 mg q12h or ETR/darunavir (DRV)/RTV at 200/600/100 mg q12h for 14 days in period 2 (study 2). PK samples were collected on day 5 in period 1 and day 14 in period 2. All of the treatments were well tolerated. ETR significantly decreased exposures of DTG, with geometric mean ratios of 0.294 (90% confidence intervals, 0.257 to 0.337) for the area under the curve from time zero until the end of the dosage interval (AUC0-τ), 0.484 (0.433 to 0.542) for the observed maximum plasma concentration (Cmax), and 0.121 (0.093 to 0.157) for the plasma concentration at the end of the dosage interval (Cτ). ETR combined with an RTV-boosted PI affected the exposure of DTG to a lesser degree: ETR/LPV/RTV treatment had no effect on the DTG plasma AUC0-τandCmax, whereas theCτincreased by 28%. ETR/DRV/RTV modestly decreased the plasma DTG AUC0-τ,Cmax, andCτby 25, 12, and 37%, respectively. Such effects of ETR/LPV/RTV and ETR/DRV/RTV are not considered clinically relevant. The combination of DTG and ETR alone should be avoided; however, DTG may be coadministered with ETR without a dosage adjustment if LPV/RTV or DRV/RTV is concurrently administered.