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Social emotional learning (SEL) aims to promote student well-being, including healthy relationships that are free from harm like gender-based-violence (GBV). We investigated U.S. SEL policy through the lens of GBV, and how policy in the New York State (NYS) context operates to actualize or constrain SEL aims. To do so, we developed and applied a novel feminist critical policy analysis (FCPA) heuristic. Key findings revealed that the NYS policy neglected to address GBV experienced by adolescent girls, and the overall absent presence of gender within the policy underscores concern for implementable SEL best practices. We conclude with implications for research, policy, and practice.

The late December sun blushes on the western horizon as I walk home along Toronto's Don River trail. 2020 will be over in a few days--my first year back after [...]

AbstractThis paper explores the definition of, and perceived community attitudes, toward kudanga, a Swahili street term for a type of transactional sex practised in Dar es Salaam, Tanzania. Rooted in economic and gender disparity, transactional sex increases adolescent girls’ and young women’s vulnerability to HIV and gender-based violence. We sought to understand perceived community attitudes about kudanga, and how the internalisation of norms surrounding gender-based violence relate to the experiences of young women who practise kudanga. Using qualitative data from focus group discussions with 37 young women, we found that community perceptions of kudanga were largely negative, and those who engaged in it were looked down upon and despised. Violence and lack of sexual agency were normalised when doing kudanga. However, young women understood kudanga to often be their best option to obtain economic stability and felt strongly that those who practised kudanga should not be stigmatised. Our research provides further evidence that transactional sex exists on a continuum and highlights the importance of reducing community stigma surrounding transactional sex as a means of decreasing risk of HIV and gender-based violence for young women. To our knowledge, this article is the first to explore kudanga. [ABSTRACT FROM AUTHOR]

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Elizabeth Greene Toronto: Inanna Publications and Education, 2018. REVIEWED BY KATE ROGERS In its first sentence, the novel A Season Among Psychics entices the reader with empathy, wit, and anticipation: [...]

We investigated responses of adult, novice practitioners (n = 9) to an 8-week traditional mat Pilates program (P) that met 1 hr/day three times/week. Classes consisted primarily of beginner and intermediate level exercises. Compared to an active control group (C; n = 13) that showed no improvements, those in P significantly (p less than 0.05) improved relative body fat (-1.2%BF), sit-and-reach (+7.5 cm), shoulder reach (+6.9 cm), curl-up (+14 reps), and low back extension (+7 reps) scores, as well as circumferences at the waist (-2.7 cm), chest (-1.7 cm), and arm (-0.5 cm). Baseline differences were noted only for curl-ups and low back extensions, with P being lower than C. Body composition, muscular endurance, and flexibility significantly improved after 8 weeks of traditional mat Pilates. (Contains 2 tables and 1 figure.)

Box 1 The Global strategy for women's, children's and adolescents' health (2016-2030) Objectives of the global strategy: * Survive: end preventable mortality; * Thrive: promote health and well-being; and * [...]

Background: Acute rheumatic fever (ARF), an autoimmune reaction to Group A Streptococcus (Streptococcus pyogenes; Strep A) infection, can cause rheumatic heart disease (RHD). New formulations of long-acting penicillins are being developed for secondary prophylaxis of ARF and RHD.Objectives: To evaluate the penicillin G concentrations required to suppress growth of Strep A.Methods: Broth microdilution MIC and MBC for Strep A strains M75611024, M1T15448 and M18MGAS8232 were determined. All strains were studied in a hollow fibre model (initial inoculum 4 log10 cfu/mL). Constant penicillin G concentrations of 0.008, 0.016 and 0.05 mg/L were examined against all strains, plus 0.012 mg/L against M18MGAS8232. Viable counts were determined over 144 h. Subsequently, all penicillin G-treated cartridges were emptied, reinoculated with 5 log10 cfu/mL and counts determined over a further 144 h. Mathematical modelling was performed.Results: MIC and MBC were 0.008 mg/L for all strains; small subpopulations of M75611024 and M1T15448, but not M18MGAS8232, grew at 1× MIC. Following the first inoculation, 0.008 mg/L achieved limited killing and/or stasis against M75611024 and M1T15448, with subsequent growth to ∼6 log10 cfu/mL. Following both inocula, concentrations ≥0.016 mg/L suppressed M75611024 and M1T15448 to <1 log10 cfu/mL from 6 h onwards with eradication. Concentrations ≥0.008 mg/L suppressed M18MGAS8232 to <1 log10 cfu/mL from 24 h onwards with eradication after both inoculations. Mathematical modelling well described all strains using a single set of parameter estimates, except for different maximum bacterial concentrations and proportions of bacteria growing at 1× MIC.Conclusions: In the absence of validated animal and human challenge models, the study provides guidance on penicillin G target concentrations for development of new penicillin formulations. [ABSTRACT FROM AUTHOR]

Based on the mid-20th century activities of three Western eugenists, this paper will demonstrate that there was a concerted, and ultimately successful, transnational effort to keep the eugenics movement alive during its most socially unacceptable period. I will argue that this success rested on the ability of eugenists to fuse the mid-century image and ideology of eugenics with respectable medical and public health agendas, and align this new adaptation of eugenics with the then increasingly fashionable social issues of democracy, environmentalism and family. Further to this, I will tentatively question the future bio-ethical implications of this historical reinterpretation., What became of the eugenics movement? For the great majority of us, the comfortable answer is that the ideology died a death some time during the mid-20th century. Supporting evidence [...]

Sonia Di Placido Toronto: Guernica Editions, 2018 REVIEWED BY KATE ROGERS At its best, poet Sonia Di Placido's Flesh is visceral. Associations tumble loose like the innards of a gutted [...]

Objectives: Pegfilgrastim is a granulocyte colony-stimulating factor (G-CSF) used as primary prophylaxis in patients receiving myelosuppressive chemotherapy regimens that have greater than 20% risk of developing febrile neutropenia (FN). Historically, pegfilgrastim has been administered 24 to 72 hours after chemotherapy, necessitating a return to clinic to receive the provider-administered injection. An alternative option is the pegfilgrastim on-body injector (OBI). With the OBI device, patients have their pegfilgrastim administered 27 hours after receiving chemotherapy while remaining at home, avoiding an additional clinic appointment. Concerns with pegfilgrastim OBI include lack of experience with the device in both the patient and provider, device-related failures, and the success of delivery. This study evaluates pegfilgrastim OBI failure rates through associated patient outcomes among cancer patients receiving chemotherapy requiring G-CSF. Methods: A retrospective electronic chart review was conducted of adult patients with cancer who received chemotherapy and pegfilgrastim OBI from July 1, 2016, to July 31, 2018. The primary objective of this study was the incidence of FN in patients receiving pegfilgrastim OBI. Results: There were no reported cases of hospitalization due to FN in patients who received pegfilgrastim OBI. Dose delays and dosage modifications were not observed in our review. The OBI device failure rate was found to be low (1.92%). Conclusion: The low device failure rate from this study suggests that the OBI is a viable option for administration of pegfilgrastim in patients receiving chemotherapy requiring G-CSF. [ABSTRACT FROM AUTHOR]

Augmented renal clearance (ARC, creatinine clearance > 130 mL/minute) makes difficult achievement of effective concentrations of renally cleared antibiotics in critically ill patients. This study examined the synergistic killing and resistance suppression for meropenem‐ciprofloxacin combination dosage regimens against Pseudomonas aeruginosa isolates within the context of ARC. Clinically relevant meropenem and ciprofloxacin concentrations, alone and in combinations, were studied against three clinical isolates with a range of susceptibilities to each of the antibiotics. Isolate Pa1280 was susceptible to both meropenem and ciprofloxacin, Pa1284 had intermediate susceptibility to meropenem and was susceptible to ciprofloxacin, and CR380 was resistant to meropenem and had intermediate susceptibility to ciprofloxacin. Initially, isolates were studied in 72‐hour static‐concentration time‐kill (SCTK) studies. Subsequently, the pharmacokinetic profiles expected in patients with ARC receiving dosage regimens, including at the highest approved daily doses (meropenem 6 g daily divided and administered as 0.5‐hour infusions every 8 hours, or as a continuous infusion; ciprofloxacin 0.4 g as 1‐hour infusions every 8 hours), were examined in a dynamic hollow‐fiber infection model (HFIM) over 7–10 days. In both SCTK and HFIM, combination regimens were generally synergistic and suppressed growth of less‐susceptible subpopulations, these effects being smaller for isolate CR380. The time‐courses of total and less‐susceptible bacterial populations in the HFIM were well‐described by mechanism‐based models, which enabled conduct of Monte Carlo simulations to predict likely effectiveness of approved dosage regimens at different creatinine clearances. Optimized meropenem‐ciprofloxacin combination dosage regimens may be a viable consideration for P. aeruginosa infections in critically ill patients with ARC. [ABSTRACT FROM AUTHOR]

I have told too many people now. My words weave a story which I must hold away from my body to retell. It is about women I know and don't [...]

This paper explores the incorporation of eugenic objectives within family focused and psychologically based public health initiatives throughout the 1940s–1970s. By focusing on three of Australia’s enduring public health initiatives – family planning, marriage guidance and sex education – I consider how post-war eugenic rhetoric in Australia was initially dominated by educational services which centred on creating a conducive environment for eugenically aligned reproductive choices within the nuclear family structure. The fact the term ‘eugenics’ was increasingly omitted from what remained eugenically aligned public health activities will also be considered. [ABSTRACT FROM PUBLISHER]

Background: Pathophysiological changes in critically ill patients can cause severely altered pharmacokinetics and widely varying antibiotic exposures. The impact of altered pharmacokinetics on bacterial killing and resistance has not been characterized in the dynamic hollow-fibre in vitro infection model (HFIM).Methods: A clinical Pseudomonas aeruginosa isolate (piperacillin MIC 4 mg/L) was studied in the HFIM (inoculum ∼10(7) cfu/mL). Pharmacokinetic profiles of three piperacillin dosing regimens (4 g 8-, 6- and 4-hourly, 30 min intravenous infusion) as observed in critically ill patients with augmented renal clearance (ARC), normal renal function or impaired renal function (creatinine clearances of 250, 110 or 30 mL/min, respectively) were simulated over 7 days. The time courses of total and less-susceptible populations and MICs were determined. Mechanism-based modelling was performed in S-ADAPT.Results: For all regimens with ARC and regimens with 8- or 6-hourly dosing with normal renal function, initial killing of ≤∼2 log10 was followed by regrowth to 10(8)-10(9) cfu/mL at 48 h. For 8- and 6-hourly dosing at normal renal function, the proportion of less-susceptible colonies increased ∼10-100-fold above those in ARC and control arms. Regimens achieving an fCmin of ≥5× MIC resulted in bacterial killing of 3-4 log10 without regrowth and suppressed less-susceptible populations to ≤∼2 log10. The mechanism-based model successfully quantified the time course of bacterial growth, killing and regrowth.Conclusions: Only high piperacillin concentrations prevented regrowth of P. aeruginosa. Individualized dosing regimens that account for altered pharmacokinetics and aim for higher-than-standard antibiotic exposures to achieve an fCmin of ≥5× MIC were required to maximize bacterial killing and suppress emergence of resistance. [ABSTRACT FROM AUTHOR]

Objective Treatment outcome was compared among non-Hispanic White and racial/ethnic minority participants with trichotillomania (TTM), or hair-pulling disorder. Method Symptom severity, quality of life, and TTM-related disability were compared in a behavior therapy trial with a stepped care approach: web-based self-help and then individual behavior therapy. The sample comprised 72% ( n = 38) non-Hispanic White participants and 28% ( n = 15) minority participants. Results The ethnic groups responded differently to treatment, with fewer minority participants showing improvement during web-based self-help. Response rates were equivalent between ethnic groups during the in-person behavior therapy. These results should be interpreted with caution because of the small sample size of minorities in the study and consequent inability to analyze results for each racial/ethnic group individually. Conclusions Future studies should focus on the investigation of factors that may enable or hinder racial and ethnic minority participants to benefit from online and/or self-help behavior therapy for TTM. [ABSTRACT FROM AUTHOR]

We evaluated piperacillin-tazobactam and tobramycin regimens against Pseudomonas aeruginosa isolates from critically ill patients. Static-concentration time-kill studies (SCTK) assessed piperacillin-tazobactam and tobramycin monotherapies and combinations against four isolates over 72 h. A 120 h-dynamic in vitro infection model (IVM) investigated isolates Pa1281 (MICpiperacillin 4 mg/L, MICtobramycin 0.5 mg/L) and CR380 (MICpiperacillin 32 mg/L, MICtobramycin 1 mg/L), simulating the pharmacokinetics of: (A) tobramycin 7 mg/kg q24 h (0.5 h-infusions, t1/2 = 3.1 h); (B) piperacillin 4 g q4 h (0.5 h-infusions, t1/2 = 1.5 h); (C) piperacillin 24 g/day, continuous infusion; A + B; A + C. Total and less-susceptible bacteria were determined. SCTK demonstrated synergy of the combination for all isolates. In the IVM, regimens A and B provided initial killing, followed by extensive regrowth by 72 h for both isolates. C provided >4 log10 CFU/mL killing, followed by regrowth close to initial inoculum by 96 h for Pa1281, and suppressed growth to <4 log10 CFU/mL for CR380. A and A + B initially suppressed counts of both isolates to <1 log10 CFU/mL, before regrowth to control or starting inoculum and resistance emergence by 72 h. Overall, the combination including intermittent piperacillin-tazobactam did not provide a benefit over tobramycin monotherapy. A + C, the combination regimen with continuous infusion of piperacillin-tazobactam, provided synergistic killing (counts <1 log10 CFU/mL) of Pa1281 and CR380, and suppressed regrowth to <2 and <4 log10 CFU/mL, respectively, and resistance emergence over 120 h. The shape of the concentration–time curve was important for synergy of the combination. [ABSTRACT FROM AUTHOR]

The poem "The Unnamed Bird" by Kate Rogers is presented. First Line: The long notes of the adhan; Last Line: their colours beyond words.

The poem "Alone, Birding the Mountain" by Kate Rogers is presented. First Line: All the birds have flown up and gone; Last Line: to be real.

Plain Language Statement: Gender norms that centre men and disadvantage women create gender inequality, which can lead to risky sexual behaviour. This study examined how both community and individual attitudes toward gender norms influenced risky sexual behaviour in adolescents, and whether that influence was different between males and females. We found that higher gender-equitable attitudes were linked to increased odds of HIV testing in the last 12 months, and decreased odds of engaging in a sexual relationship with a much older partner. Individual high gender-equitable attitudes among girls were also linked to higher odds of them using condoms and contraceptives. Gender-equitable attitudes did not seem to influence early sexual debut, engagement in transactional sex, having multiple sexual partners at the same time, or the number of sexual partners a participant had in the last 12 months. Based on these findings, programming designed to increase gender-equitable attitudes might be helpful in increasing HIV testing and condom and contraceptive use, but it needs to involve the entire community, not just individual boys and girls.

Pseudomonas aeruginosa remains a challenge in chronic respiratory infections in cystic fibrosis (CF). Ceftolozane-tazobactam has not yet been evaluated against multidrug-resistant hypermutable P. aeruginosa isolates in the hollow-fiber infection model (HFIM). Isolates CW41, CW35, and CW44 (ceftolozane-tazobactam MICs of 4, 4, and 2 mg/L, respectively) from adults with CF were exposed to simulated representative epithelial lining fluid pharmacokinetics of ceftolozane-tazobactam in the HFIM. Regimens were continuous infusion (CI; 4.5 g/day to 9 g/day, all isolates) and 1-h infusions (1.5 g every 8 hours and 3 g every 8 hours, CW41). Whole-genome sequencing and mechanism-based modeling were performed for CW41. CW41 (in four of five biological replicates) and CW44 harbored preexisting resistant subpopulations; CW35 did not. For replicates 1 to 4 of CW41 and CW44, 9 g/day CI decreased bacterial counts to <3 log 10 CFU/mL for 24 to 48 h, followed by regrowth and resistance amplification. Replicate 5 of CW41 had no preexisting subpopulations and was suppressed below ~3 log 10 CFU/mL for 120 h by 9 g/day CI, followed by resistant regrowth. Both CI regimens reduced CW35 bacterial counts to <1 log 10 CFU/mL by 120 h without regrowth. These results corresponded with the presence or absence of preexisting resistant subpopulations and resistance-associated mutations at baseline. Mutations in ampC , algO , and mexY were identified following CW41 exposure to ceftolozane-tazobactam at 167 to 215 h. Mechanism-based modeling well described total and resistant bacterial counts. The findings highlight the impact of heteroresistance and baseline mutations on the effect of ceftolozane-tazobactam and limitations of MIC to predict bacterial outcomes. The resistance amplification in two of three isolates supports current guidelines that ceftolozane-tazobactam should be utilized together with another antibiotic against P. aeruginosa in CF., Competing Interests: The authors declare no conflict of interest.

Augmented renal clearance (ARC) is common in critically ill patients and is associated with subtherapeutic concentrations of renally eliminated antibiotics. We investigated the impact of ARC on bacterial killing and resistance amplification for meropenem and tobramycin regimens in monotherapy and combination. Two carbapenem-resistant Pseudomonas aeruginosa isolates were studied in static-concentration time-kill studies. One isolate was examined comprehensively in a 7-day hollow-fiber infection model (HFIM). Pharmacokinetic profiles representing substantial ARC (creatinine clearance of 250 ml/min) were generated in the HFIM for meropenem (1 g or 2 g administered every 8 h as 30-min infusion and 3 g/day or 6 g/day as continuous infusion [CI]) and tobramycin (7 mg/kg of body weight every 24 h as 30-min infusion) regimens. The time courses of total and less-susceptible bacterial populations and MICs were determined for the monotherapies and all four combination regimens. Mechanism-based mathematical modeling (MBM) was performed. In the HFIM, maximum bacterial killing with any meropenem monotherapy was ∼3 log 10 CFU/ml at 7 h, followed by rapid regrowth with increases in resistant populations by 24 h (meropenem MIC of up to 128 mg/liter). Tobramycin monotherapy produced extensive initial killing (∼7 log 10 at 4 h) with rapid regrowth by 24 h, including substantial increases in resistant populations (tobramycin MIC of 32 mg/liter). Combination regimens containing meropenem administered intermittently or as a 3-g/day CI suppressed regrowth for ∼1 to 3 days, with rapid regrowth of resistant bacteria. Only a 6-g/day CI of meropenem combined with tobramycin suppressed regrowth and resistance over 7 days. MBM described bacterial killing and regrowth for all regimens well. The mode of meropenem administration was critical for the combination to be maximally effective against carbapenem-resistant P. aeruginosa ., (Copyright © 2019 American Society for Microbiology.)

Hypermutable Pseudomonas aeruginosa organisms are prevalent in chronic respiratory infections and have been associated with reduced lung function in cystic fibrosis (CF); these isolates can become resistant to all antibiotics in monotherapy. This study aimed to evaluate the time course of bacterial killing and resistance of meropenem and ciprofloxacin in combination against hypermutable and nonhypermutable P. aeruginosa Static concentration time-kill experiments over 72 h assessed meropenem and ciprofloxacin in mono- and combination therapies against PAO1 (nonhypermutable), PAOΔ mutS (hypermutable), and hypermutable isolates CW8, CW35, and CW44 obtained from CF patients with chronic respiratory infections. Meropenem (1 or 2 g every 8 h [q8h] as 3-h infusions and 3 g/day as a continuous infusion) and ciprofloxacin (400 mg q8h as 1-h infusions) in monotherapies and combinations were further evaluated in an 8-day hollow-fiber infection model study (HFIM) against CW44. Concentration-time profiles in lung epithelial lining fluid reflecting the pharmacokinetics in CF patients were simulated and counts of total and resistant bacteria determined. All data were analyzed by mechanism-based modeling (MBM). In the HFIM, all monotherapies resulted in rapid regrowth with resistance at 48 h. The maximum daily doses of 6 g meropenem (T >MIC of 80% to 88%) and 1.2 g ciprofloxacin (area under the concentration-time curve over 24 h in the steady state divided by the MIC [AUC/MIC], 176), both given intermittently, in monotherapy failed to suppress regrowth and resulted in substantial emergence of resistance (≥7.6 log 10 CFU/ml resistant populations). The combination of these regimens achieved synergistic killing and suppressed resistance. MBM with subpopulation and mechanistic synergy yielded unbiased and precise curve fits. Thus, the combination of 6 g/day meropenem plus ciprofloxacin holds promise for future clinical evaluation against infections by susceptible hypermutable P. aeruginosa ., (Copyright © 2018 American Society for Microbiology.)

Objective: To examine if North Carolina (NC) opioid prescribing guidelines were associated with changes in opioid prescribing., Method: Retrospective secondary analysis of the Medicare Provider Utilization and Payment Data: Part D Prescriber datasets from 2013 to 2015., Participants: Providers who prescribed at least one opioid from 2013 to 2015 and paid by Medicare Part D., Main Outcome Measure: Per-prescriber Medicare-population adjusted number of analgesic opioid claims and per-prescriber average day supply. Generalized estimating equations (GEE) were used to analyze the data., Results: There were significantly higher per-prescriber Medicare adjusted opioid claims in 2014 compared to 2015 (p < 0.001) but no difference between 2013 and 2015 (p = 0.584). GEE results also indicated that there was a significant increase in 2015 in per-prescriber average day supply, compared to 2013 and 2014 (both p < 0.0001)., Conclusions: State opioid prescribing guidelines published in mid-2014 may have slowed the escalation of numbers of opioid prescriptions in NC. Future research should examine whether the guidelines were associated with changes in morphine equivalent dosing in NC during the same timeframe.

Augmented renal clearance (ARC) in critically ill patients can result in suboptimal drug exposures and treatment failure. Combination dosage regimens accounting for ARC have never been optimized and evaluated against Pseudomonas aeruginosa by use of the hollow-fiber infection model (HFIM). Using a P. aeruginosa isolate from a critically ill patient and static-concentration time-kill experiments (SCTKs), we studied clinically relevant piperacillin and tobramycin concentrations, alone and in combinations, against two inocula (10 5.8 and 10 7.6 CFU/ml) over 72 h. We subsequently evaluated the effects of optimized piperacillin (4 g every 4 h [q4h], given as 0.5-h infusions) plus tobramycin (5 mg/kg of body weight q24h, 7 mg/kg q24h, or 10 mg/kg q48h, given as 0.5-h infusions) regimens on killing and regrowth in the HFIM, simulating a creatinine clearance of 250 ml/min. Mechanism-based modeling was performed in S-ADAPT. In SCTKs, piperacillin plus tobramycin (except combinations with 8 mg/liter tobramycin and against the low inoculum) achieved synergistic killing (≥2 log 10 versus the most active monotherapy at 48 h and 72 h) and prevented regrowth. Piperacillin monotherapy (4 g q4h) in the HFIM provided 2.4-log 10 initial killing followed by regrowth at 24 h and resistance emergence. Tobramycin monotherapies displayed rapid initial killing (≥5 log 10 at 13 h) followed by extensive regrowth. As predicted by mechanism-based modeling, the piperacillin plus tobramycin dosage regimens were synergistic and provided ≥5-log 10 killing with resistance suppression over 8 days in the HFIM. Optimized piperacillin-tobramycin regimens provided significant bacterial killing and suppressed resistance emergence. These regimens appear to be highly promising for effective and early treatment, even in the near-worst-case scenario of ARC., (Copyright © 2018 American Society for Microbiology.)

We aimed to prospectively validate an optimized combination dosage regimen against a clinical carbapenem-resistant Acinetobacter baumannii (CRAB) isolate (imipenem MIC, 32 mg/liter; tobramycin MIC, 2 mg/liter). Imipenem at constant concentrations (7.6, 13.4, and 23.3 mg/liter, reflecting a range of clearances) was simulated in a 7-day hollow-fiber infection model (inoculum, ∼10 7.2 CFU/ml) with and without tobramycin (7 mg/kg q24h, 0.5-h infusions). While monotherapies achieved no killing or failed by 24 h, this rationally optimized combination achieved >5 log 10 bacterial killing and suppressed resistance., (Copyright © 2018 American Society for Microbiology.)

Hypermutable Pseudomonas aeruginosa strains are prevalent in patients with cystic fibrosis and rapidly become resistant to antibiotic monotherapies. Combination dosage regimens have not been optimized against such strains using mechanism-based modeling (MBM) and the hollow-fiber infection model (HFIM). The PAO1 wild-type strain and its isogenic hypermutable PAOΔ mutS strain (MIC meropenem of 1.0 mg/liter and MIC tobramycin of 0.5 mg/liter for both) were assessed using 96-h static-concentration time-kill studies (SCTK) and 10-day HFIM studies (inoculum, ∼10 8.4 CFU/ml). MBM of SCTK data were performed to predict expected HFIM outcomes. Regimens studied in the HFIM were meropenem at 1 g every 8 h (0.5-h infusion), meropenem at 3 g/day with continuous infusion, tobramycin at 10 mg/kg of body weight every 24 h (1-h infusion), and both combinations. Meropenem regimens delivered the same total daily dose. Time courses of total and less susceptible populations and MICs were determined. For the PAOΔ mutS strain in the HFIM, all monotherapies resulted in rapid regrowth to >10 8.7 CFU/ml with near-complete replacement by less susceptible bacteria by day 3. Meropenem every 8 h with tobramycin caused >7-log 10 bacterial killing followed by regrowth to >6 log 10 CFU/ml by day 5 and high-level resistance (MIC meropenem , 32 mg/liter; MIC tobramycin , 8 mg/liter). Continuous infusion of meropenem with tobramycin achieved >8-log 10 bacterial killing without regrowth. For PAO1, meropenem monotherapies suppressed bacterial growth to <4 log 10 over 7 to 9 days, with both combination regimens achieving near eradication. An MBM-optimized meropenem plus tobramycin regimen achieved synergistic killing and resistance suppression against a difficult-to-treat hypermutable P. aeruginosa strain. For the combination to be maximally effective, it was critical to achieve the optimal shape of the concentration-time profile for meropenem., (Copyright © 2018 American Society for Microbiology.)

Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharmacokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. A Pseudomonas aeruginosa isolate (MIC meropenem 0.25 mg/liter) was studied in the hollow-fiber infection model (inoculum ∼10 7.5 CFU/ml; 10 days). Pharmacokinetic profiles representing critically ill patients with augmented renal clearance (ARC), normal, or impaired renal function (creatinine clearances of 285, 120, or ∼10 ml/min, respectively) were generated for three meropenem regimens (2, 1, and 0.5 g administered as 8-hourly 30-min infusions), plus 1 g given 12 hourly with impaired renal function. The time course of total and less-susceptible populations and MICs were determined. Mechanism-based modeling (MBM) was performed using S-ADAPT. All dosing regimens across all renal functions produced similar initial bacterial killing (≤∼2.5 log 10 ). For all regimens subjected to ARC, regrowth occurred after 7 h. For normal and impaired renal function, bacterial killing continued until 23 to 47 h; regrowth then occurred with 0.5- and 1-g regimens with normal renal function ( fT >5×MIC = 56 and 69%, fC min /MIC < 2); the emergence of less-susceptible populations (≥32-fold increases in MIC) accompanied all regrowth. Bacterial counts remained suppressed across 10 days with normal (2-g 8-hourly regimen) and impaired (all regimens) renal function ( fT >5×MIC ≥ 82%, fC min /MIC ≥ 2). The MBM successfully described bacterial killing and regrowth for all renal functions and regimens simultaneously. Optimized dosing regimens, including extended infusions and/or combinations, supported by MBM and Monte Carlo simulations, should be evaluated in the context of ARC to maximize bacterial killing and suppress resistance emergence., (Copyright © 2017 American Society for Microbiology.)