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BACKGROUND: HIV remains a leading cause of death for adolescents and young people aged 10-24 years. HIV prevention requires multisectoral approaches that target adolescents and young people, addressing HIV risk pathways (e.g., transactional sex, gender-based violence, and school attendance) through bundled interventions that combine economic strengthening, health capabilities, and gender equality education. However, best practices are unknown because evidence on multisectoral programming targeted to adolescents and combining these components has not been systematically reviewed. METHODS: We conducted a systematic review to summarize the evidence on bundled interventions combining health and economic strengthening components for adolescents and young people and their effects on HIV/STI incidence and risk factors. We included studies from Africa published between 2005 and 2023, combining at least one economic strengthening and one health component, directed toward adolescents and young people aged 10-24 years. Included studies measured programmatic impacts on primary outcomes: HIV and STI incidence/prevalence; and mediators as secondary outcomes: sexual behaviours, sexual and reproductive health, school attendance, health-seeking behaviours, and violence. We conducted key word searches in PubMed, EMBASE, and Web of Science, imported titles/abstracts from the initial search, and reviewed them using the inclusion criteria. Full texts of selected articles were reviewed and information was extracted for analysis. Findings from the full texts identified were summarized. RESULTS: We reviewed 58 studies, including 43 quantitative studies and 15 qualitative studies, evaluating 26 unique interventions. A majority of studies reviewed were conducted in Eastern and Southern Africa. Interventions reviewed showed a greater number of significant results in improving economic outcomes; mental health and psychosocial outcomes; sexual and reproductive health knowledge and services utilization; and HIV prevention knowledge and testing. They showed fewer significant results in improving outcomes related to HIV incidence/prevalence; sexual risk behaviours; gender-based violence; gender attitudes; education; STI incidence, prevalence and testing; and sexual debut. CONCLUSIONS: Our review demonstrated the potential for bundled, multisectoral interventions for preventing HIV and facilitating safe transitions to adulthood. Findings have implications for designing HIV sensitive programmes on a larger scale, including how interventions may need to address multiple strata of the social ecological model to achieve success in the prevention of HIV and related pathways.
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Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Infecções Sexualmente Transmissíveis , Humanos , Adolescente , Infecções Sexualmente Transmissíveis/epidemiologia , Infecções Sexualmente Transmissíveis/prevenção & controle , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Comportamento Sexual/psicologia , África AustralRESUMO
This 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.
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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 log10 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 log10 CFU/mL for 120 h by 9 g/day CI, followed by resistant regrowth. Both CI regimens reduced CW35 bacterial counts to <1 log10 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.
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Fibrose Cística , Infecções por Pseudomonas , Adulto , Humanos , Pseudomonas aeruginosa , Fibrose Cística/tratamento farmacológico , Fibrose Cística/microbiologia , Cefalosporinas/farmacocinética , Tazobactam/farmacologia , Antibacterianos/farmacocinética , Mitomicina/farmacologia , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Farmacorresistência Bacteriana Múltipla/genéticaRESUMO
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 4â log10 cfu/mL). Constant penicillin G concentrations of 0.008, 0.016 and 0.05â mg/L were examined against all strains, plus 0.012â mg/L against M18MGAS8232. Viable counts were determined over 144â h. Subsequently, all penicillin G-treated cartridges were emptied, reinoculated with 5â log10 cfu/mL and counts determined over a further 144â h. Mathematical modelling was performed. RESULTS: MIC and MBC were 0.008â mg/L for all strains; small subpopulations of M75611024 and M1T15448, but not M18MGAS8232, grew at 1× MIC. Following the first inoculation, 0.008â mg/L achieved limited killing and/or stasis against M75611024 and M1T15448, with subsequent growth to â¼6â log10 cfu/mL. Following both inocula, concentrations ≥0.016â mg/L suppressed M75611024 and M1T15448 to <1â log10 cfu/mL from 6â h onwards with eradication. Concentrations ≥0.008â mg/L suppressed M18MGAS8232 to <1â log10 cfu/mL from 24â 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.
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Penicilina G , Infecções Estreptocócicas , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Testes de Sensibilidade Microbiana , Penicilina G/farmacologia , Penicilinas/farmacologia , Penicilinas/uso terapêutico , Infecções Estreptocócicas/tratamento farmacológico , Infecções Estreptocócicas/prevenção & controle , Streptococcus pyogenesRESUMO
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.
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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 â¼3 log10 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 (â¼7 log10 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 â¼1 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.
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Meropeném/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Tobramicina/farmacologia , Antibacterianos/farmacologia , Carbapenêmicos/farmacologia , Estado Terminal , Humanos , Testes de Sensibilidade Microbiana , Modelos Teóricos , Infecções por Pseudomonas/microbiologiaRESUMO
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), PAOΔmutS (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 log10 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.
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Ciprofloxacina/uso terapêutico , Fibrose Cística/tratamento farmacológico , Meropeném/uso terapêutico , Pseudomonas aeruginosa/efeitos dos fármacos , Infecções Respiratórias/tratamento farmacológico , Antibacterianos/uso terapêutico , Fibrose Cística/microbiologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Quimioterapia Combinada/métodos , Humanos , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Testes de Sensibilidade Microbiana/métodos , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/metabolismo , Infecções Respiratórias/microbiologiaRESUMO
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, â¼107.2 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 log10 bacterial killing and suppressed resistance.
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Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Carbapenêmicos/farmacologia , Imipenem/farmacologia , Modelos Teóricos , Tobramicina/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
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 PAOΔmutS strain (MICmeropenem of 1.0 mg/liter and MICtobramycin of 0.5 mg/liter for both) were assessed using 96-h static-concentration time-kill studies (SCTK) and 10-day HFIM studies (inoculum, â¼108.4 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 PAOΔmutS strain in the HFIM, all monotherapies resulted in rapid regrowth to >108.7 CFU/ml with near-complete replacement by less susceptible bacteria by day 3. Meropenem every 8 h with tobramycin caused >7-log10 bacterial killing followed by regrowth to >6 log10 CFU/ml by day 5 and high-level resistance (MICmeropenem, 32 mg/liter; MICtobramycin, 8 mg/liter). Continuous infusion of meropenem with tobramycin achieved >8-log10 bacterial killing without regrowth. For PAO1, meropenem monotherapies suppressed bacterial growth to <4 log10 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.
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Antibacterianos/farmacologia , Meropeném/farmacologia , Modelos Teóricos , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Tobramicina/farmacologia , Testes de Sensibilidade Microbiana , Mutação/genéticaRESUMO
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 (105.8 and 107.6 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 log10 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-log10 initial killing followed by regrowth at 24 h and resistance emergence. Tobramycin monotherapies displayed rapid initial killing (≥5 log10 at 13 h) followed by extensive regrowth. As predicted by mechanism-based modeling, the piperacillin plus tobramycin dosage regimens were synergistic and provided ≥5-log10 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.
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Antibacterianos/farmacologia , Piperacilina/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Tobramicina/farmacologia , Antibacterianos/farmacocinética , Humanos , Testes de Sensibilidade Microbiana , Modelos Teóricos , Piperacilina/farmacocinética , Tobramicina/farmacocinéticaRESUMO
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 (MICmeropenem 0.25 mg/liter) was studied in the hollow-fiber infection model (inoculum â¼107.5 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 â¼10 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 (≤â¼2.5 log10). 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%, fCmin/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%, fCmin/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.
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Antibacterianos/uso terapêutico , Taxa de Depuração Metabólica/fisiologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Tienamicinas/farmacocinética , Tienamicinas/uso terapêutico , Antibacterianos/farmacocinética , Creatinina/metabolismo , Estado Terminal , Relação Dose-Resposta a Droga , Feminino , Humanos , Testes de Função Renal , Masculino , Meropeném , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/isolamento & purificaçãoRESUMO
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 â¼10(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 ≤â¼2 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 â¼10-100-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 ≤â¼2 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.
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Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Rim/fisiopatologia , Piperacilina/farmacologia , Piperacilina/farmacocinética , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Antibacterianos/administração & dosagem , Estado Terminal , Humanos , Testes de Sensibilidade Microbiana , Modelos Teóricos , Piperacilina/administração & dosagemRESUMO
Certain autoimmune diseases as well as asthma have increased in recent decades, particularly in developed countries. The hygiene hypothesis has been the prevailing model to account for this increase; however, epidemiology studies also support the contribution of diet and obesity to inflammatory diseases. Diet affects the composition of the gut microbiota, and recent studies have identified various molecules and mechanisms that connect diet, the gut microbiota, and immune responses. Herein, we discuss the effects of microbial metabolites, such as short chain fatty acids, on epithelial integrity as well as immune cell function. We propose that dysbiosis contributes to compromised epithelial integrity and disrupted immune tolerance. In addition, dietary molecules affect the function of immune cells directly, particularly through lipid G-protein coupled receptors such as GPR43.
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Bactérias/imunologia , Infecções Bacterianas/imunologia , Ácidos Graxos/imunologia , Doenças do Sistema Imunitário/imunologia , Mucosa Intestinal/imunologia , Animais , Bactérias/metabolismo , Infecções Bacterianas/complicações , Infecções Bacterianas/microbiologia , Dieta , Suplementos Nutricionais , Ácidos Graxos/metabolismo , Humanos , Doenças do Sistema Imunitário/etiologia , Doenças do Sistema Imunitário/microbiologia , Tolerância Imunológica , Inflamação/imunologia , Inflamação/microbiologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Receptores Acoplados a Proteínas G/metabolismoRESUMO
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.
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Terapia Comportamental/métodos , Etnicidade/etnologia , Resultado do Tratamento , Tricotilomania/etnologia , Tricotilomania/terapia , População Branca/etnologia , Feminino , Humanos , Internet , Masculino , Autocuidado/métodosRESUMO
OBJECTIVES: Meropenem is commonly used against Pseudomonas aeruginosa. Traditionally, the time unbound antibiotic concentration exceeds the MIC (fT>MIC) is used to select carbapenem regimens. We aimed to characterize the effects of different baseline resistance mechanisms on bacterial killing and resistance emergence; evaluate whether fT>MIC can predict these effects; and, develop a novel Quantitative and Systems Pharmacology (QSP) model to describe the effects of baseline resistance mechanisms on the time-course of bacterial response. METHODS: Seven isogenic P. aeruginosa strains with a range of resistance mechanisms and MICs were used in 10-day hollow-fiber infection model studies. Meropenem pharmacokinetic profiles were simulated for various regimens (t1/2,meropenem = 1.5 h). All viable counts on drug-free, 3 × MIC, and 5 × MIC meropenem-containing agar across all strains, five regimens, and control (n = 90 profiles) were simultaneously subjected to QSP modeling. Whole genome sequencing was completed for total population samples and emergent resistant colonies at 239 h. RESULTS: Regimens achieving ≥98%fT>1×MIC suppressed resistance emergence of the mexR knockout strain. Even 100%fT>5 × MIC failed to achieve this against the strain with OprD loss and the ampD and mexR double-knockout strain. Baseline resistance mechanisms affected bacterial outcomes, even for strains with the same MIC. Genomic analysis revealed that pre-existing resistant subpopulations drove resistance emergence. During meropenem exposure, mutations in mexR were selected in strains with baseline oprD mutations, and vice versa, confirming these as major mechanisms of resistance emergence. Secondary mutations occurred in lysS or argS, coding for lysyl and arginyl tRNA synthetases, respectively. DISCUSSION: The QSP model well-characterized all bacterial outcomes of the seven strains simultaneously, which fT>MIC could not.
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OBJECTIVE: Hypermutable Pseudomonas aeruginosa strains are highly prevalent in chronic lung infections of patients with cystic fibrosis (CF). Acute exacerbations of these infections have limited treatment options. This study aimed to investigate inhaled aztreonam and tobramycin against clinical hypermutable P. aeruginosa strains using the CDC dynamic in vitro biofilm reactor (CBR), mechanism-based mathematical modelling (MBM) and genomic studies. METHODS: Two CF multidrug-resistant strains were investigated in a 168 h CBR (n = 2 biological replicates). Regimens were inhaled aztreonam (75 mg 8-hourly) and tobramycin (300 mg 12-hourly) in monotherapies and combination. The simulated pharmacokinetic profiles of aztreonam and tobramycin (t1/2 = 3 h) were based on published lung fluid concentrations in patients with CF. Total viable and resistant counts were determined for planktonic and biofilm bacteria. MBM of total and resistant bacterial counts and whole genome sequencing were completed. RESULTS: Both isolates showed reproducible bacterial regrowth and resistance amplification for the monotherapies by 168 h. The combination performed synergistically, with minimal resistant subpopulations compared to the respective monotherapies at 168 h. Mechanistic synergy appropriately described the antibacterial effects of the combination regimen in the MBM. Genomic analysis of colonies recovered from monotherapy regimens indicated noncanonical resistance mechanisms were likely responsible for treatment failure. CONCLUSION: The combination of aztreonam and tobramycin was required to suppress the regrowth and resistance of planktonic and biofilm bacteria in all biological replicates of both hypermutable multidrug-resistant P. aeruginosa CF isolates. The developed MBM could be utilised for future investigations of this promising inhaled combination.
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Antibacterianos , Aztreonam , Biofilmes , Fibrose Cística , Sinergismo Farmacológico , Infecções por Pseudomonas , Pseudomonas aeruginosa , Tobramicina , Sequenciamento Completo do Genoma , Tobramicina/administração & dosagem , Tobramicina/farmacologia , Aztreonam/farmacologia , Aztreonam/administração & dosagem , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Biofilmes/efeitos dos fármacos , Fibrose Cística/microbiologia , Fibrose Cística/complicações , Humanos , Antibacterianos/farmacologia , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Administração por Inalação , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Testes de Sensibilidade Microbiana , Farmacorresistência Bacteriana Múltipla/genética , Modelos Teóricos , Quimioterapia CombinadaRESUMO
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.
Assuntos
Equidade de Gênero , Pessoa Solteira , Masculino , Humanos , Feminino , Adolescente , Tanzânia , Estudos Longitudinais , Comportamento SexualRESUMO
OBJECTIVE: Acute exacerbations of biofilm-associated Pseudomonas aeruginosa infections in cystic fibrosis (CF) have limited treatment options. Ceftolozane/tazobactam (alone and with a second antibiotic) has not yet been investigated against hypermutable clinical P. aeruginosa isolates in biofilm growth. This study aimed to evaluate, using an in vitro dynamic biofilm model, ceftolozane/tazobactam alone and in combination with tobramycin at simulated representative lung fluid pharmacokinetics against free-floating (planktonic) and biofilm states of two hypermutable P. aeruginosa epidemic strains (LES-1 and CC274) from adolescents with CF. METHODS: Regimens were intravenous ceftolozane/tazobactam 4.5 g/day continuous infusion, inhaled tobramycin 300 mg 12-hourly, intravenous tobramycin 10 mg/kg 24-hourly, and both ceftolozane/tazobactam-tobramycin combinations. The isolates were susceptible to both antibiotics. Total and less-susceptible free-floating and biofilm bacteria were quantified over 120-168 h. Ceftolozane/tazobactam resistance mechanisms were investigated by whole-genome sequencing. Mechanism-based modelling of bacterial viable counts was performed. RESULTS: Monotherapies of ceftolozane/tazobactam and tobramycin did not sufficiently suppress emergence of less-susceptible subpopulations, although inhaled tobramycin was more effective than intravenous tobramycin. Ceftolozane/tazobactam resistance development was associated with classical (AmpC overexpression plus structural modification) and novel (CpxR mutations) mechanisms depending on the strain. Against both isolates, combination regimens demonstrated synergy and completely suppressed the emergence of ceftolozane/tazobactam and tobramycin less-susceptible free-floating and biofilm bacterial subpopulations. CONCLUSION: Mechanism-based modelling incorporating subpopulation and mechanistic synergy well described the antibacterial effects of all regimens against free-floating and biofilm bacterial states. These findings support further investigation of ceftolozane/tazobactam in combination with tobramycin against biofilm-associated P. aeruginosa infections in adolescents with CF.
Assuntos
Infecções por Pseudomonas , Tobramicina , Humanos , Adolescente , Tobramicina/farmacologia , Tobramicina/uso terapêutico , Pseudomonas aeruginosa , Cefalosporinas/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Tazobactam/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Biofilmes , Testes de Sensibilidade Microbiana , Farmacorresistência Bacteriana MúltiplaRESUMO
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.