RESUMO
BACKGROUND: Nine-valent human papillomavirus (9vHPV) vaccines can be administered in 2 doses 6 to 12 months apart in adolescents. The impact of extended dose intervals is unknown. We report immunogenicity and safety data in adolescents of a second 9vHPV vaccine dose administered ≥1 year after the first. METHODS: This open-label safety and immunogenicity study (NCT04708041) assessed extended-interval 2-dose regimens of 9vHPV vaccine among adolescents (10 to 15 years) who received 2 9vHPV vaccine doses: the first ≥1 year before enrollment, and second, at enrollment (day 1). We measured serologic responses to vaccine-targeted human papillomavirus (HPV) types at enrollment day 1 (pre-dose 2) and 1 month post-dose 2 (month 1) using a competitive LuminexV® immunoassay. We estimated effects of dose interval on geometric mean titers (GMTs) using regression modeling. Participants reported adverse events (AEs) through 15 days after vaccination. RESULTS: We enrolled 146 adolescents (mean age 13.3 years) with median 25 months since first 9vHPV vaccine dose (range: 12-53 months). Across vaccine-targeted HPV types, GMTs increased from day 1 to month 1; seropositivity at month 1 was 100%. Anti-HPV GMTs at month 1 were not affected by differences in dose interval of 12 to 53 months, based on regression modeling. The most common AEs were mild-to-moderate injection site reactions; no serious AEs were reported. CONCLUSIONS: Extending the interval between first and second 9vHPV vaccine doses to 12 to 53 months did not affect antibody responses, with favorable safety profile. These results support feasibility of extended interval regimens for 9vHPV vaccine.
Assuntos
Esquemas de Imunização , Imunogenicidade da Vacina , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Humanos , Adolescente , Feminino , Masculino , Criança , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/efeitos adversos , Vacinas contra Papillomavirus/imunologia , Infecções por Papillomavirus/prevenção & controle , Anticorpos Antivirais/sangueRESUMO
Immunocompetent adults with certain medical and behavioral factors are at increased risk of pneumococcal disease. In some countries, sequential vaccination with 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for at-risk adults. This subgroup analysis from a phase 3 study evaluated the safety, tolerability, and immunogenicity of sequential administration of either V114 (a 15-valent PCV containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) or PCV13, followed 6 months later by PPSV23, in immunocompetent adults 18-49 years of age with pre-defined risk factors for pneumococcal disease. Safety and immunogenicity post-vaccination were analyzed by type and baseline number of risk factors for pneumococcal disease (1 and ≥2 risk factors). This analysis included 1,131 participants randomized 3:1 to receive either V114 or PCV13, followed by PPSV23. The majority (73.1%) of participants had at least one risk factor. Safety and tolerability profiles of V114 and PCV13 were similar across risk factor groups. V114 administered either alone or sequentially with PPSV23 6 months later was immunogenic for all 15 serotypes, including those not contained in PCV13, regardless of the number of baseline risk factors. V114 has the potential to broaden serotype coverage for at-risk adults.
Assuntos
Infecções Pneumocócicas , Streptococcus pneumoniae , Humanos , Adulto , Vacinas Conjugadas , Método Duplo-Cego , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/efeitos adversos , Anticorpos Antibacterianos , Imunogenicidade da VacinaRESUMO
BACKGROUND AND OBJECTIVES: Current strategies for obesity management in primary care leave many patients inadequately treated or unable to access treatment entirely. We aimed to evaluate a comprehensive, primary care clinic-based weight management program's clinical effectiveness in a community practice setting. Methods: This was an 18-month pre/postintervention study. We collected demographic and anthropometric data on patients enrolled in a primary care-based weight management program. The primary outcomes were percent weight loss postintervention and the proportion of patients who achieved a clinically significant total body weight loss (TBWL) of 5% or greater. Results: Our program served 550 patients over 1,952 visits from March 2019 through October 2020. A total of 209 patients had adequate program exposure, defined as four or more completed visits. Among these, all received targeted lifestyle counseling and 78% received antiobesity medication. Patients who attended at least four visits had an average TBWL of 5.7% compared to an average gain of 1.5% total body weight for those with only one visit. Fifty-three percent of patients (n=111) achieved greater than 5% TBWL, and 20% (n=43) achieved greater than 10% TBWL. CONCLUSION: We demonstrated that a community-based weight management program delivered by obesity medicine-trained primary care providers effectively produces clinically significant weight loss. Future work will include wider implementation of this model to increase patient access to evidence-based obesity treatments in their communities.
Assuntos
Obesidade , Programas de Redução de Peso , Humanos , Obesidade/terapia , Obesidade/psicologia , North Carolina , Redução de Peso , Atenção à SaúdeRESUMO
BACKGROUND: Adults with certain medical and behavioral factors are at increased risk for pneumococcal disease (PD). Sequential vaccination with 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for at-risk adults in some countries. METHODS: This phase 3 trial evaluated the safety, tolerability, and immunogenicity of sequential administration of either V114 (a 15-valent PCV containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) or PCV13, followed 6 months later by PPSV23, in immunocompetent adults aged 18-49 years with or without predefined risk factors for PD (NCT03547167). Overall, 1515 participants were randomized 3:1 to receive either V114 or PCV13, followed by PPSV23. RESULTS: Most common solicited adverse events (AEs) following administration of V114 or PCV13 as well as PPSV23 were injection-site pain and fatigue. The proportion of participants with AEs was comparable in both groups. V114 and PCV13 were immunogenic based on opsonophagocytic activity (OPA) geometric mean titers (GMTs) 30 days postvaccination for all serotypes contained in each respective vaccine. OPA GMTs to the 2 unique serotypes in V114 were robust in the V114 group. PPSV23 was immunogenic for all 15 serotypes contained in V114 in both vaccination groups, including 22F and 33F. CONCLUSIONS: V114 administered alone or sequentially with PPSV23 is well tolerated and immunogenic for all 15 serotypes, including those not contained in PCV13, in immunocompetent adults aged 18-49 years with or without certain medical or behavioral risk factors for PD. CLINICAL TRIALS REGISTRATION: NCT03547167 and EudraCT 2017-004915-38.
RESUMO
HPV vaccines are widely licensed as two-dose regimens, 6-12 months apart, for adolescents. Extended intervals between doses may be necessary due to resource constraints or vaccination program disruption. This international, multicenter, open-label study (NCT04708041) will evaluate the safety and immunogenicity of two-dose 9vHPV vaccine regimens with extended intervals of 1-5 years between doses in boys/girls compared with a standard three-dose regimen in women. Participants (planned N = 700) will be enrolled into six cohorts; Cohort 0: boys/girls aged 10-15 years who received one 9vHPV vaccine dose ≥1 year before enrollment without completing the series will receive one study dose of 9vHPV vaccine at day 1; Cohorts 1-4: HPV vaccination-naïve boys/girls aged 9-14 years will receive two doses (day 1 and month 12, 24, 36, or 60); Cohort 5: HPV vaccination-naïve women aged 16-26 years will receive three doses (day 1, months 2 and 6). Primary analyses will be based on serological responses 1 month after final vaccine dose. Co-primary objectives will (1) evaluate non-inferiority of geometric mean titers in each of Cohorts 1-4 versus Cohort 5, and (2) characterize antibody responses in Cohort 0, accounting for the interval between commercial and study vaccine dose. Injection-site and systemic adverse events (AEs) will be collected for 15 days and serious AEs for 12 months post-vaccination; vaccine-related serious AEs and deaths will be collected throughout the study. Results will inform completion of vaccination in individuals who did not complete the recommended series and guide implementation of vaccination programs in resource-limited settings.
Assuntos
Alphapapillomavirus , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Adolescente , Anticorpos Antivirais , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Masculino , Papillomaviridae , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/efeitos adversosRESUMO
BACKGROUND: The nine-valent human papillomavirus (9vHPV) vaccine protects against infection and disease related to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. The pivotal 36-month Phase III immunogenicity study of 9vHPV vaccine in 9- to 15-year-old girls and boys was extended to assess long-term immunogenicity and effectiveness through approximately 10 years after vaccination. We describe results of an interim analysis based on approximately 8 years of follow-up after vaccination. METHODS: Participants aged 9-15 years who received three doses of 9vHPV vaccine (at day 1, month 2, and month 6) in the base study and consented to follow-up were enrolled in the long-term follow-up study extension (N = 1272 [females, n = 971; males, n = 301]). Serum was collected at months 66 and 90 to assess antibody responses. For effectiveness analysis, genital swabs were collected (to assess HPV DNA by polymerase chain reaction [PCR]) and external genital examination was conducted (to detect external genital lesions) every 6 months starting when the participant reached 16 years of age. Cervical cytology tests were conducted annually when female participants reached 21 years of age; participants with cytological abnormalities were triaged to colposcopy based on a protocol-specified algorithm. External genital and cervical biopsies of abnormal lesions were performed, and histological diagnoses were adjudicated by a pathology panel. Specimens were tested by PCR to detect HPV DNA. RESULTS: Geometric mean titers for each 9vHPV vaccine HPV type peaked around month 7 and gradually decreased through month 90. Seropositivity rates remained >90% through month 90 for each of the 9vHPV vaccine types by HPV immunoglobulin Luminex Immunoassay. No cases of HPV6/11/16/18/31/33/45/52/58-related high-grade intraepithelial neoplasia or genital warts were observed in the per-protocol population (n = 1107) based on a maximum follow-up of 8.2 years (median 7.6 years) post-Dose 3. Incidence rates of HPV6/11/16/18/31/33/45/52/58-related 6-month persistent infection in females and males were 49.2 and 37.3 per 10,000 person-years, respectively, which were within ranges expected in vaccinated cohorts. There were no vaccine-related SAEs or deaths during the period covered by this interim analysis. CONCLUSIONS: The 9vHPV vaccine provided sustained immunogenicity and durable effectiveness through approximately 7 and 8 years, respectively, following vaccination of girls and boys aged 9-15 years.
Assuntos
Anticorpos Antivirais/sangue , Imunogenicidade da Vacina , Papillomaviridae/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Adolescente , Criança , Feminino , Seguimentos , Humanos , Masculino , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/classificação , Fatores de Tempo , Vacinação/estatística & dados numéricosRESUMO
Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including Haemophilus influenzae, which is one of the leading causes of community-acquired bacterial pneumonia (CABP). The evaluation of antimicrobial agents against H. influenzae using standard murine infection models is challenging due to the low pathogenicity of this species in mice. Therefore, 24-h dose-ranging studies using a one-compartment in vitro infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five H. influenzae isolates. These five isolates, for which MIC values were 1 or 2 mg/liter, were exposed to omadacycline total-drug epithelial lining fluid (ELF) concentration-time profiles based on those observed in healthy volunteers following intravenous omadacycline administration. Relationships between change in log10 CFU/ml from baseline at 24 h and the total-drug ELF AUC/MIC ratios for each isolate and for the isolates pooled were evaluated using Hill-type models and nonlinear least-squares regression. As evidenced by the high coefficients of determination (r2) of 0.88 to 0.98, total-drug ELF AUC/MIC ratio described the data well for each isolate and the isolates pooled. The median total-drug ELF AUC/MIC ratios associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 6.91, 8.91, and 11.1, respectively. These data were useful to support the omadacycline dosing regimens selected for the treatment of patients with CABP, as well as susceptibility breakpoints for H. influenzae.
Assuntos
Haemophilus influenzae , Streptococcus pneumoniae , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Humanos , Camundongos , Testes de Sensibilidade Microbiana , TetraciclinasRESUMO
We previously demonstrated that for tazobactam administered in combination with ceftolozane, the pharmacokinetic-pharmacodynamic (PK-PD) index that best described tazobactam efficacy was the percentage of the dosing interval that tazobactam concentrations were above a threshold (%T>threshold). Using data from studies of Enterobacteriaceae producing extended-spectrum ß-lactamases (ESBLs), a relationship between tazobactam %T>threshold and reduction in log10 CFU/ml from baseline, for which the tazobactam threshold concentration was the product of the isolate's ceftolozane-tazobactam MIC value and 0.5, was identified. However, since the kinetics of cephalosporin hydrolysis vary among ESBLs and compounds, it is likely that the translational relationship used to derive the tazobactam threshold concentration varies among enzymes and compounds. Using a one-compartment in vitro infection model, the PK-PD of tazobactam administered in combination with cefepime was characterized, and a translational relationship across ESBL-producing Enterobacteriaceae was developed. Four clinical isolates, two Escherichia coli and two Klebsiella pneumoniae isolates, known to produce CTX-M-15 ß-lactamase enzymes and displaying cefepime MIC values of 2 to 4 mg/liter in the presence of 4 mg/liter tazobactam, were evaluated. Tazobactam threshold concentrations from 0.0625× to 1× the tazobactam-potentiated cefepime MIC value were considered. The threshold that best described the relationship between tazobactam %T>threshold and change in log10 CFU/ml from the baseline at 24 h was the product of 0.125 and the cefepime-tazobactam MIC (R2 = 0.813). The magnitudes of %T>threshold associated with net bacterial stasis and a 1-log10 CFU/ml reduction from baseline at 24 h were 21.9% and 52.8%, respectively. These data will be useful in supporting the identification of tazobactam dosing regimens in combination with cefepime for evaluation in future clinical studies.
Assuntos
Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Ácido Penicilânico/análogos & derivados , Inibidores de beta-Lactamases/farmacologia , Antibacterianos/farmacocinética , Proteínas de Bactérias/metabolismo , Cefepima , Cefalosporinas/farmacocinética , Farmacorresistência Bacteriana Múltipla/fisiologia , Quimioterapia Combinada , Escherichia coli/isolamento & purificação , Proteínas de Escherichia coli/metabolismo , Klebsiella pneumoniae/isolamento & purificação , Lipoproteínas/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Testes de Sensibilidade Microbiana , Modelos Biológicos , Ácido Penicilânico/farmacocinética , Ácido Penicilânico/farmacologia , Tazobactam , Inibidores de beta-Lactamases/farmacocinética , beta-Lactamases/metabolismoRESUMO
A major clinical challenge for treating infectious diseases is the duration of antimicrobial therapy required to eradicate the pathogen. We hypothesized that modulation of the bacterial replication rate in the context of an antimicrobial exposure is coupled with the rate and extent of bactericidal effects. Herein we describe results from in vitro infection model (one compartment, 24-h model; hollow fiber, 10-day model) studies designed to probe the relationship between the bacterial replication rate and the rate and extent of bactericidal effects in the context of an effective antibiotic exposure. The bacterial replication rate was modulated by adjusting the sodium chloride concentration (0 to 8%) in the growth media (Mueller-Hinton II broth). The study drug selected was levofloxacin, and the challenge isolate was Staphylococcus aureus ATCC 29213 (levofloxacin MIC, 0.125 mg/liter). Within each in vitro infection model, human levofloxacin concentration-time profiles (half-life, 7 h) were simulated and the challenge isolate was subjected to an effective exposure (free-drug area under the concentration-time curve over 24 h divided by the MIC [AUC/MIC ratio], 65; administered as a single dose or daily for 10 days). Over the course of each study, samples were taken from each model for bacterial density determinations and drug concentration assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In the 24-h one-compartment in vitro infection model studies, as the bacterial replication rate increased, so too did the rate (slope, 0 to 4 h) and extent (24-h CFU count per milliliter) of bacterial killing. In the 10-day hollow-fiber infection model studies, the times until a reduction of bacterial density to 1 × 102 CFU/ml occurred were 10 days in the media in which the challenge isolate grew slowly and approximately 2 days in the media in which the challenge isolate grew rapidly. Together, these data provide a proof of concept for new adjunctive therapeutic options with respect to the use of antimicrobial agents alone that reduce treatment durations. Such adjunctive therapies hold promise for marked reductions in the tonnage of antimicrobial agents administered to patient populations and selection pressure toward antimicrobial resistance.
Assuntos
Anti-Infecciosos/farmacologia , Levofloxacino/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Cromatografia Líquida , Testes de Sensibilidade Microbiana , Mutação , Staphylococcus aureus/genética , Espectrometria de Massas em TandemRESUMO
Understanding the relationship between antibiotic exposure and amplification of bacterial subpopulations with reduced drug susceptibility over time is important for evaluating the adequacy of dosing regimens. We utilized a hollow-fiber infection model to identify the fosfomycin intravenous dosing regimens that prevented the amplification of Escherichia coli bacterial subpopulations with reduced fosfomycin susceptibility. The challenge isolate was E. coli ATCC 25922 (agar MIC with glucose-6-phosphate, 1 mg/liter; agar MIC without glucose-6-phosphate, 32 mg/liter). The fosfomycin dosing regimens studied were 1 to 12 g every 8 h for 10 days to approximate that planned for clinical use. The studies included a no-treatment control regimen. Two bacterial subpopulations were identified, one with reduced susceptibility with agar MIC values ranging from 32 to 128 mg/liter and the other resistant with agar MIC values of 256 to >1,024 mg/liter on plates containing 5× and 256× the baseline MIC value, respectively. An inverted-U-shaped function best described the relationship between the amplification of the two bacterial subpopulations and drug exposure. The lowest fosfomycin dosing regimen that did not amplify a bacterial subpopulation with reduced susceptibility was 4 g administered every 8 h. Nearly immediate amplification of bacterial subpopulations with reduced susceptibility was observed with fosfomycin dosing regimens consisting of 1 to 2 g every 8 h. These data will be useful to support the selection of fosfomycin dosing regimens that minimize the potential for on-therapy amplification of bacterial subpopulations with reduced susceptibility.
Assuntos
Antibacterianos/farmacocinética , Escherichia coli/efeitos dos fármacos , Fosfomicina/farmacocinética , Modelos Biológicos , Antibacterianos/farmacologia , Cultura em Câmaras de Difusão , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Farmacorresistência Bacteriana , Escherichia coli/crescimento & desenvolvimento , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Fosfomicina/farmacologia , Humanos , Testes de Sensibilidade MicrobianaRESUMO
The usefulness of ß-lactam antimicrobial agents is threatened as never before by ß-lactamase-producing bacteria. For this reason, there has been renewed interest in the development of broad-spectrum ß-lactamase inhibitors. Herein we describe the results of dose fractionation and dose-ranging studies carried out using a one-compartment in vitro infection model to determine the exposure measure for CB-618, a novel ß-lactamase inhibitor, most predictive of the efficacy when given in combination with meropenem. The challenge panel included Enterobacteriaceae clinical isolates, which collectively produced a wide range of ß-lactamase enzymes (KPC-2, KPC-3, FOX-5, OXA-48, SHV-11, SHV-27, and TEM-1). Human concentration-time profiles were simulated for each drug, and samples were collected for drug concentration and bacterial density determinations. Using data from dose fractionation studies and a challenge Klebsiella pneumoniae isolate (CB-618-potentiated meropenem MIC = 1 mg/liter), relationships between change from baseline in log10 CFU/ml at 24 h and each of CB-618 area under the concentration-time curve over 24 h (AUC0-24), maximum concentration (Cmax), and percentage of the dosing interval that CB-618 concentrations remained above a given threshold were evaluated in combination with meropenem at 2 g every 8 h (q8h). The exposure measures most closely associated with CB-618 efficacy in combination with meropenem were the CB-618 AUC0-24 (r(2) = 0.835) and Cmax (r(2) = 0.826). Using the CB-618 AUC0-24 indexed to the CB-618-potentiated meropenem MIC value, the relationship between change from baseline in log10 CFU/ml at 24 h and CB-618 AUC0-24/MIC ratio in combination with meropenem was evaluated using the pooled data from five challenge isolates; the CB-618 AUC0-24/MIC ratio associated with net bacterial stasis and the 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 27.3, 86.1, and 444.8, respectively. These data provide a pharmacokinetics-pharmacodynamics (PK-PD) basis for evaluating potential CB-618 dosing regimens in combination with meropenem in future studies.
Assuntos
Antibacterianos/farmacologia , Klebsiella pneumoniae/efeitos dos fármacos , Tienamicinas/farmacologia , Inibidores de beta-Lactamases/farmacologia , Antibacterianos/farmacocinética , Klebsiella pneumoniae/metabolismo , Meropeném , Testes de Sensibilidade Microbiana , Tienamicinas/farmacocinética , Inibidores de beta-Lactamases/farmacocinéticaRESUMO
Fosfomycin, a phosphonic class antibiotic with a broad spectrum of antibacterial activity, has been used outside the United States since the early 1970s for the treatment of a variety of infections. In the United States, an oral (tromethamine salt) formulation is used for uncomplicated urinary tract infections. Recently, there has been interest in the use of an intravenous solution (ZTI-01) for the treatment of a broad range of infections associated with multidrug-resistant bacteria. In this era of multidrug-resistant bacteria with few treatment options, it is critical to understand the pharmacokinetic-pharmacodynamic (PK-PD) determinants for fosfomycin efficacy. Since such data are limited, a one-compartment in vitro infection model was used to determine the PK-PD index associated with efficacy and the magnitude of this measure necessary for various levels of effect. One challenge isolate (Escherichia coli ATCC 25922, for which the fosfomycin agar MIC is 0.5 mg/liter and the broth microdilution MIC is 1 mg/liter) was evaluated in the dose fractionation studies, and two additional clinical E. coli isolates were evaluated in the dose-ranging studies. Mutation frequency studies indicated the presence of an inherently fosfomycin resistant E. coli subpopulation (agar MIC = 32 to 64 mg/liter) within the standard starting inoculum of a susceptibility test. Due to the presence of this resistant subpopulation, we identified the percentage of the dosing interval that drug concentrations were above the inherent resistance inhibitory concentration found at baseline to be the PK-PD index associated with efficacy (r(2) = 0.777). The magnitudes of this PK-PD index associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 11.9, 20.9, and 32.8, respectively. These data provide useful information for modernizing and optimizing ZTI-01 dosing regimens for further study.
Assuntos
Antibacterianos/farmacocinética , Escherichia coli/efeitos dos fármacos , Fosfomicina/farmacocinética , Modelos Estatísticos , Antibacterianos/farmacologia , Área Sob a Curva , Contagem de Colônia Microbiana , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/fisiologia , Escherichia coli/crescimento & desenvolvimento , Fosfomicina/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Modelos Biológicos , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologiaRESUMO
It is important to understand the relationship between antibiotic exposure and the selection of drug resistance in the context of therapy exposure. We sought to identify the ceftolozane-tazobactam exposure necessary to prevent the amplification of drug-resistant bacterial subpopulations in a hollow-fiber infection model. Two Pseudomonas aeruginosa challenge isolates were selected for study, a wild-type ATCC strain (ceftolozane-tazobactam MIC, 0.5 mg/liter) and a clinical isolate (ceftolozane-tazobactam MIC, 4 mg/liter). The experiment duration was 10 days, and the ceftolozane-tazobactam dose ratio (2:1) and dosing interval (every 8 h) were selected to approximate those expected to be used clinically. The studied ceftolozane-tazobactam dosing regimens ranged from 62.5/31.25 to 2,000/1,000 mg per dose in step fold dilutions. Negative-control arms included no treatment and tazobactam at 500 mg every 8 h. Positive-control arms included ceftolozane at 1 g every 8 h and piperacillin-tazobactam dosed at 4.5 g every 6 h. For the wild-type ATCC strain, resistance was not selected by any ceftolozane-tazobactam regimen evaluated. For the clinical isolate, an inverted-U-shaped function best described the relationship between the amplification of a drug-resistant subpopulation and drug exposure. The least (62.5/31.25 mg) and most (2,000/1,000 mg) intensive ceftolozane-tazobactam dosing regimens did not select for drug resistance. Drug resistance selection was observed with intermediately intensive dosing regimens (125/62.5 through 1,000/500 mg). For the intermediately intensive ceftolozane-tazobactam dosing regimens, the duration until the selection for drug resistance increased with dose regimen intensity. These data support the selection of ceftolozane-tazobactam dosing regimens that minimize the potential for on-therapy drug resistance selection.
Assuntos
Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Ácido Penicilânico/análogos & derivados , Pseudomonas aeruginosa/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Ácido Penicilânico/farmacologia , TazobactamRESUMO
We recently investigated the pharmacokinetics-pharmacodynamics (PK-PD) of tazobactam in combination with ceftolozane against an isogenic CTX-M-15-producing Escherichia coli triplet set, genetically engineered to transcribe different levels of blaCTX-M-15. The percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold) was identified as the PK-PD exposure measure that was most closely associated with efficacy. Moreover, the tazobactam concentration was dependent upon the enzyme transcription level. Given that the aforementioned strains were genetically engineered to transcribe a single ß-lactamase enzyme and that clinical isolates typically produce multiple ß-lactamase enzymes with various transcription levels, it is likely that the tazobactam threshold concentration is isolate/enzyme dependent. Our first objective was to characterize the relationship between the tazobactam %Time>threshold in combination with ceftolozane and efficacy using clinical isolates in an in vitro PK-PD infection model. Our second objective was to identify a translational relationship that would allow for the comodeling across clinical isolates. The initial challenge panel included four well-characterized ß-lactamase-producing E. coli strains with variable enzyme expression and other resistance determinants. As evidenced by r(2) values of ranging from 0.90 to 0.99 for each clinical isolate, the observed data were well described by fitted functions describing the relationship between the tazobactam %Time>threshold and change in log10 CFU from baseline; however, the data from the four isolates did not comodel well. The threshold concentration identified for each isolate ranged from 0.5 to 4 mg/liter. We identified an enabling translational relationship for the tazobactam threshold that allowed comodeling of all four clinical isolates, which was the product of the individual isolate's ceftolozane-tazobactam MIC value and 0.5. As evidenced by an r(2) value of 0.90, the transformed data were well described by a fitted function describing the relationship between tazobactam %Time>threshold and change in log10 CFU from baseline. Due to these findings, the challenge panel was expanded to include three well-characterized ß-lactamase-producing Klebsiella pneumoniae strains with variable enzyme expression and other resistance determinants. The translational relationship for the tazobactam threshold that allowed for the comodeling of the four E. coli isolates performed well for the expanded data set (seven isolates in total; four E. coli and three K. pneumoniae), as evidenced by an r(2) value of 0.84. This simple translational relationship is especially useful as it is directly linked to in vitro susceptibility test results, which are used to guide the clinician's choice of drug and dosing regimen.
Assuntos
Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Modelos Estatísticos , Ácido Penicilânico/análogos & derivados , Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Contagem de Colônia Microbiana , Simulação por Computador , Esquema de Medicação , Combinação de Medicamentos , Cálculos da Dosagem de Medicamento , Escherichia coli/enzimologia , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Expressão Gênica , Meia-Vida , Humanos , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/enzimologia , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Ácido Penicilânico/farmacocinética , Ácido Penicilânico/farmacologia , Plasmídeos , Tazobactam , beta-Lactamases/genética , beta-Lactamases/metabolismoRESUMO
In an era of rapidly emerging antimicrobial-resistant bacteria, it is critical to understand the importance of the relationships among drug exposure, duration of therapy, and selection of drug resistance. Herein we describe the results of studies designed to determine the ceftolozane-tazobactam exposure necessary to prevent the amplification of drug-resistant bacterial subpopulations in a hollow-fiber infection model. The challenge isolate was a CTX-M-15-producing Escherichia coli isolate genetically engineered to transcribe a moderate level of blaCTX-M-15. This organism's blaCTX-M-15 transcription level was confirmed by relative quantitative reverse transcription-PCR (qRT-PCR), ß-lactamase hydrolytic assays, and a ceftolozane MIC value of 16 mg/liter. In these studies, the experimental duration (10 days), ceftolozane-tazobactam dose ratio (2:1), and dosing interval (every 8 h) were selected to approximate those expected to be used clinically. The ceftolozane-tazobactam doses studied ranged from 125-62.5 to 1,500-750 mg. Negative- and positive-control arms included no treatment and piperacillin-tazobactam at 4.5 g every 6 h, respectively. An inverted-U-shaped function best described the relationship between bacterial drug resistance amplification and drug exposure. The least- and most-intensive ceftolozane-tazobactam dosing regimens, i.e., 125-62.5, 750-375, 1,000-500, and 1,500-750 mg, did not amplify drug resistance, while drug resistance amplification was observed with intermediate-intensity dosing regimens (250-125 and 500-250 mg). For the intermediate-intensity ceftolozane-tazobactam dosing regimens, the drug-resistant subpopulation became the dominant population by days 4 to 6. The more-intensive ceftolozane-tazobactam dosing regimens (750-375, 1,000-500, and 1,500-750 mg) not only prevented drug resistance amplification but also virtually sterilized the model system. These data support the selection of ceftolozane-tazobactam dosing regimens that minimize the potential for on-therapy drug resistance amplification.