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1.
J Antimicrob Chemother ; 76(1): 179-183, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33035321

RESUMO

OBJECTIVES: Reduced in vitro ß-lactam activity against a dense bacterial population is well recognized. It is commonly attributed to the presence of ß-lactamase(s) and it is unknown whether the inoculum effect could be diminished by a ß-lactamase inhibitor. We evaluated different ß-lactam/ß-lactamase inhibitor combinations in suppressing a high inoculum of ESBL-producing bacteria. METHODS: Three clinical isolates expressing representative ESBLs (CTX-M-15 and SHV-12) were examined. The impact of escalating ß-lactamase inhibitor (tazobactam or avibactam) concentrations on ß-lactam (piperacillin or ceftazidime) MIC reduction was characterized by an inhibitory sigmoid Emax model. The effect of various dosing regimens of ß-lactam/ß-lactamase inhibitor combinations was predicted using %T>MICi and selected exposures were experimentally validated in a hollow-fibre infection model over 120 h. The threshold exposure to suppress bacterial regrowth was identified using recursive partitioning. RESULTS: A concentration-dependent reduction in ß-lactam MIC was observed (r2 ≥0.93). Regrowth could be suppressed in all six experiments using %T>MICi ≥73.6%, but only one out of six experiments below the threshold (P = 0.015). The exposures to suppress regrowth might be attained using the clinical dose of avibactam, but a much higher dose than the standard dose would be needed for tazobactam. CONCLUSIONS: A dense population of ESBL-producing bacteria could be suppressed by an optimized dosing regimen of selected ß-lactam/ß-lactamase inhibitor combinations. The reversibility of enzyme inhibition could play an important role in diminishing the inoculum effect. In vivo investigations to validate these findings are warranted.


Assuntos
Lactamas , Inibidores de beta-Lactamases , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bactérias , Testes de Sensibilidade Microbiana , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases
2.
Comput Chem Eng ; 1552021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34924641

RESUMO

Combination therapy for treatment of multi-drug resistant bacterial infections is becoming common. In vitro testing of drug combinations under realistic pharmacokinetic conditions is needed before a corresponding combination is eventually put into clinical use. The current standard for design of such in vitro simulations for drugs with different half-lives is heuristic and limited to two drugs. To address that void, we develop a rigorous design method suitable for an arbitrary number of N drugs with different half-lives. The method developed offers substantial flexibility and produces novel designs even for two drugs. Explicit design equations are rigorously developed and are suitable for immediate use by experimenters. These equations were used in experimental verification using a combination of three antibiotics with distinctly different half-lives. In addition to antibiotics, the method is applicable to any anti-infective or anti-cancer drugs with distinct elimination pharmacokinetics.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32571819

RESUMO

Despite excellent in vitro activity, aminoglycosides are used conservatively to treat multidrug-resistant bacterial infections due to their associated nephrotoxicity. Aminoglycosides are known to accumulate in the kidneys, but the quantitative relationship between drug exposures and nephrotoxicity is not well established. To bridge the knowledge gap, the objective of this study was to develop an animal model with clinically relevant conditions to mimic human disease progression. Single-dose pharmacokinetics were studied in Sprague-Dawley rats dosed either with 100 or 500 mg/kg of body weight of amikacin subcutaneously. Serial blood samples were collected, and serum amikacin concentrations were measured using liquid chromatography tandem mass spectrometry. Rats were also dosed with amikacin once daily for up to 10 days; blood samples were taken at baseline and daily to detect nephrotoxicity (defined as doubling of serum creatinine from baseline). Kidneys from both studies were harvested from selected rats, and amikacin concentrations in renal tissues were measured. A dose-dependent increase in systemic area under the curve (AUC) was observed, which ranged from approximately 1/3 (AUC of 53 mg·h/liter) to 3 times (AUC of 650 mg·h/liter) the expected exposure resulting from standard dosing in humans. Nephrotoxicity was significantly higher in rats given 500 mg/kg (100% versus 30%, P = 0.003). Kaplan-Meier analysis also showed a significant difference in nephrotoxicity onset between the two groups (P = 0.001). Finally, analysis of the renal tissues showed that the accumulation of amikacin could be associated with nephrotoxicity. These results are consistent with clinical observations, which support using this model in the future to investigate an intervention(s) that can be used clinically to alleviate nephrotoxicity.


Assuntos
Amicacina , Preparações Farmacêuticas , Amicacina/toxicidade , Aminoglicosídeos , Animais , Antibacterianos/toxicidade , Modelos Animais de Doenças , Ratos , Ratos Sprague-Dawley
4.
Artigo em Inglês | MEDLINE | ID: mdl-31871078

RESUMO

Subcutaneous administration is a novel way to deliver antibiotics for an infection, but intolerability has been reported. Evaluating the local tolerability of subcutaneously administered antibiotics is not standardized. The goal of this study was to develop an animal model to assess the subcutaneous administration of ceftriaxone. Sprague-Dawley rats were given daily subcutaneous injections for 12 days. The back of each animal was divided into 4 quadrants, with injections rotating each day among the quadrants. Ceftriaxone (1,000 mg/kg of body weight daily) was given in different concentrations and durations. Normal saline and potassium chloride solutions (2 meq/2 ml) were used as negative and positive controls, respectively. After the treatment course, skin samples were biopsied, and the local inflammatory response was assessed histologically using a semiquantitative scoring system. The histopathology scores were compared using a Kruskal-Wallis test. Injections with potassium chloride resulted in full-thickness skin necrosis with subcutaneous atrophy that was not seen in the saline-injected animals; inflammation of the muscular panniculus was observed, with various degrees of myocyte injury. Serosanguinous cavity formation in the subcutaneous compartment was observed when ceftriaxone (125 mg/ml) was given as a bolus injection, but the extent of the local tissue response was remarkably reduced when the same ceftriaxone dose was given at a lower concentration (25 mg/ml) over 120 min (P = 0.63, compared to saline controls). At a low concentration, ceftriaxone infusion was found to be well tolerated in this animal tissue necrosis model. If validated, the model could be an instrumental platform to evaluate different pharmaceutical formulations for subcutaneous delivery.


Assuntos
Antibacterianos/uso terapêutico , Ceftriaxona/uso terapêutico , Animais , Antibacterianos/administração & dosagem , Ceftriaxona/administração & dosagem , Feminino , Inflamação/tratamento farmacológico , Injeções Subcutâneas , Masculino , Ratos , Ratos Sprague-Dawley
5.
Microbiol Immunol ; 62(4): 291-294, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29418013

RESUMO

The virulence of an isogenic pair of Pseudomonas aeruginosa strains was studied under similar experimental conditions in two animal infection models. The time to death was significantly longer for the multidrug resistant (MDR) than the wild-type strain. The transcriptional profiles of 84 innate immune response genes in the lungs of immune competent Balb/C mice were further compared. Significantly weaker expression of genes involved in production of soluble pattern recognition receptor and complement were observed in animals infected with the MDR strain. Altered patterns of innate immune system activation may explain the attenuated virulence in MDR bacteria.


Assuntos
Antibacterianos/imunologia , Suscetibilidade a Doenças/imunologia , Imunidade Inata/imunologia , Pulmão/imunologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/imunologia , Fatores de Transcrição/imunologia , Animais , Antibacterianos/farmacologia , Grupo dos Citocromos b/metabolismo , Modelos Animais de Doenças , Farmacorresistência Bacteriana Múltipla/imunologia , Feminino , Expressão Gênica , Larva/imunologia , Larva/microbiologia , Lepidópteros/imunologia , Lepidópteros/microbiologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/patogenicidade , Fatores de Transcrição/genética , Virulência
6.
Artigo em Inglês | MEDLINE | ID: mdl-28264853

RESUMO

Multidrug-resistant (MDR) Acinetobacter baumannii is increasingly more prevalent in nosocomial infections. Although in vitro susceptibility of A. baumannii to minocycline is promising, the in vivo efficacy of minocycline has not been well established. In this study, the in vivo activity of minocycline was evaluated in a neutropenic murine pneumonia model. Specifically, we investigated the relationship between minocycline exposure and bactericidal activity using five A. baumannii isolates with a broad range of susceptibility (MIC ranged from 0.25 mg/liter to 16 mg/liter). The pharmacokinetics of minocycline (single dose of 25 mg/kg of body weight, 50 mg/kg, 100 mg/kg, and a humanized regimen, given intraperitoneally) in serum and epithelial lining fluid (ELF) were characterized. Dose linearity was observed for doses up to 50 mg/kg and pulmonary penetration ratios (area under the concentration-time curve in ELF from 0 to 24 h [AUCELF,0-24]/area under the concentration time curve in serum from 0 to 24 h [AUCserum,0-24]) ranged from 2.5 to 2.8. Pharmacokinetic-pharmacodynamics (PK-PD) index values in ELF for various dose regimens against different A. baumannii isolates were calculated. The maximum efficacy at 24 h was approximately 1.5-log-unit reduction of pulmonary bacterial burdens from baseline. The AUC/MIC ratio was the PK-PD index most closely correlating to the bacterial burden (r2 = 0.81). The required AUCELF,0-24/MIC for maintaining stasis and achieving 1-log-unit reduction were 140 and 410, respectively. These findings could guide the treatment of infections caused by A. baumannii using minocycline in the future. Additional studies to examine resistance development during therapy are warranted.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Minociclina/farmacocinética , Minociclina/uso terapêutico , Neutropenia/imunologia , Pneumonia/tratamento farmacológico , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/isolamento & purificação , Animais , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/microbiologia , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Minociclina/sangue , Neutropenia/induzido quimicamente , Pneumonia/microbiologia
7.
Artigo em Inglês | MEDLINE | ID: mdl-28096166

RESUMO

Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250 g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg, and 20 mg/kg) subcutaneously once daily. The onset of nephrotoxicity over 7 days and renal drug concentrations 24 h after the first dose were assessed. The effects of sodium maleate (400 mg/kg intraperitoneally) on megalin homeostasis were evaluated by determining the urinary megalin concentration and electron microscopic study of renal tissue. The serum/renal pharmacokinetics of polymyxin B were assessed in megalin-shedding rats. The onset of nephrotoxicity was correlated with the daily dose of polymyxin B. Renal polymyxin B concentrations were found to be 3.6 ± 0.4 µg/g, 9.9 ± 1.5 µg/g, and 21.7 ± 4.8 µg/g in the 5-mg/kg, 10-mg/kg, and 20-mg/kg dosing groups, respectively. In megalin-shedding rats, the serum pharmacokinetics of polymyxin B remained unchanged, but the renal exposure was attenuated by 40% compared to that of control rats. The onset of polymyxin B-induced nephrotoxicity is correlated with the renal drug exposure. In addition, megalin appears to play a pivotal role in the renal accumulation of polymyxin B, which might contribute to nephrotoxicity.


Assuntos
Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Rim/efeitos dos fármacos , Polimixina B/efeitos adversos , Polimixina B/farmacocinética , Animais , Antibacterianos/sangue , Rim/metabolismo , Maleatos/farmacologia , Polimixina B/sangue , Ratos , Ratos Sprague-Dawley
8.
J Antimicrob Chemother ; 72(5): 1421-1428, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28158470

RESUMO

Objectives: ß-Lactams are commonly used for nosocomial infections and resistance to these agents among Gram-negative bacteria is increasing rapidly. Optimized dosing is expected to reduce the likelihood of resistance development during antimicrobial therapy, but the target for clinical dose adjustment is not well established. We examined the likelihood that various dosing exposures would suppress resistance development in an in vitro hollow-fibre infection model. Methods: Two strains of Klebsiella pneumoniae and two strains of Pseudomonas aeruginosa (baseline inocula of ∼10 8  cfu/mL) were examined. Various dosing exposures of cefepime, ceftazidime and meropenem were simulated in the hollow-fibre infection model. Serial samples were obtained to ascertain the pharmacokinetic simulations and viable bacterial burden for up to 120 h. Drug concentrations were determined by a validated LC-MS/MS assay and the simulated exposures were expressed as C min /MIC ratios. Resistance development was detected by quantitative culture on drug-supplemented media plates (at 3× the corresponding baseline MIC). The C min /MIC breakpoint threshold to prevent bacterial regrowth was identified by classification and regression tree (CART) analysis. Results: For all strains, the bacterial burden declined initially with the simulated exposures, but regrowth was observed in 9 out of 31 experiments. CART analysis revealed that a C min /MIC ratio ≥3.8 was significantly associated with regrowth prevention (100% versus 44%, P = 0.001). Conclusions: The development of ß-lactam resistance during therapy could be suppressed by an optimized dosing exposure. Validation of the proposed target in a well-designed clinical study is warranted.


Assuntos
Antibacterianos/farmacologia , Klebsiella pneumoniae/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Resistência beta-Lactâmica , beta-Lactamas/farmacologia , Cefepima , Ceftazidima/farmacologia , Cefalosporinas/farmacologia , Humanos , Cinética , Klebsiella pneumoniae/crescimento & desenvolvimento , Meropeném , Testes de Sensibilidade Microbiana/métodos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Espectrometria de Massas em Tandem , Tienamicinas/farmacologia
9.
Antimicrob Agents Chemother ; 60(2): 1029-34, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26643340

RESUMO

Despite dose-limiting nephrotoxicity concerns, polymyxin B has resurged as the treatment of last resort for multidrug-resistant Gram-negative bacterial infections. However, the pharmacokinetic, pharmacodynamic, and nephrotoxic properties of polymyxin B still are not thoroughly understood. The objective of this study was to provide additional insights into the overall biodistribution and disposition of polymyxin B in an animal model. Sprague-Dawley rats were dosed with intravenous polymyxin B (3 mg/kg of body weight). Drug concentrations in the serum, urine, bile, and tissue (brain, heart, lungs, liver, spleen, kidneys, and skeletal muscle) samples over time were assayed by a validated methodology. Among all the organs evaluated, polymyxin B distribution was highest in the kidneys. The mean renal tissue/serum polymyxin B concentration ratios were 7.45 (95% confidence interval [CI], 4.63 to 10.27) at 3 h and 19.62 (95% CI, 5.02 to 34.22) at 6 h postdose. Intrarenal drug distribution was examined by immunostaining. Using a ratiometric analysis, proximal tubular cells showed the highest accumulation of polymyxin B (Mander's overlap coefficient, 0.998) among all cell types evaluated. Less than 5% of the administered dose was recovered in urine over 48 h, but all 4 major polymyxin B components were detected in the bile over 4 h. These findings corroborate previous results that polymyxin B is highly accumulated in the kidneys, but the elimination likely is via a nonrenal route. Biliary excretion could be one of the routes of polymyxin B elimination, and this should be further explored. The elucidation of mechanism(s) of drug uptake in proximal tubular cells is ongoing.


Assuntos
Polimixina B/farmacocinética , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Feminino , Injeções Intravenosas , Rim/efeitos dos fármacos , Rim/metabolismo , Polimixina B/administração & dosagem , Polimixina B/sangue , Ratos Sprague-Dawley , Distribuição Tecidual
10.
Antimicrob Agents Chemother ; 59(5): 2930-3, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25712358

RESUMO

The elevation of serum creatinine levels is a concern with telavancin therapy. We examined the onset of kidney injury associated with telavancin in an animal model. Urine samples were collected at baseline and daily to determine the concentrations of kidney injury molecule 1 (KIM-1), a marker for early kidney injury. When a clinically relevant exposure of telavancin was given daily to rats, some differences in kidney injury were attributed to the dosing regimen. Further investigations of alternative telavancin dosing regimens are warranted.


Assuntos
Aminoglicosídeos/efeitos adversos , Animais , Biomarcadores , Moléculas de Adesão Celular/urina , Modelos Animais de Doenças , Feminino , Rim/microbiologia , Lipoglicopeptídeos , Masculino , Ratos , Ratos Sprague-Dawley
11.
Antimicrob Agents Chemother ; 59(5): 2720-5, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25712362

RESUMO

Antimicrobial resistance among Acinetobacter baumannii is increasing worldwide, often necessitating combination therapy. The clinical utility of using minocycline with polymyxin B is not well established. In this study, we investigated the activity of minocycline and polymyxin B against 1 laboratory isolate and 3 clinical isolates of A. baumannii. Minocycline susceptibility testing was performed with and without an efflux pump inhibitor, phenylalanine-arginine ß-naphthylamide (PAßN). The intracellular minocycline concentration was determined with and without polymyxin B (0.5 µg/ml). Time-kill studies were performed over 24 h using approximately 10(6) CFU/ml of each strain with clinically relevant minocycline concentrations (2 µg/ml and 8 µg/ml), with and without polymyxin B (0.5 µg/ml). The in vivo efficacy of the combination was assessed in a neutropenic murine pneumonia model. Infected animals were administered minocycline (50 mg/kg), polymyxin B (10 mg/kg), or both to achieve clinically equivalent exposures in humans. A reduction in the minocycline MIC (≥ 4×) was observed in the presence of PAßN. The intracellular concentration and in vitro bactericidal effect of minocycline were both enhanced by polymyxin B. With 2 minocycline-susceptible strains, the bacterial burden in lung tissue at 24 h was considerably reduced by the combination compared to monotherapy with minocycline or polymyxin B. In addition, the combination prolonged survival of animals infected with a minocycline-susceptible strain. Polymyxin B increased the intracellular concentration of minocycline in bacterial cells and enhanced the bactericidal activity of minocycline, presumably due to efflux pump disruption. The clinical utility of this combination should be further investigated.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/patogenicidade , Antibacterianos/uso terapêutico , Minociclina/uso terapêutico , Polimixina B/uso terapêutico , Animais , Farmacorresistência Bacteriana Múltipla , Feminino , Camundongos , Testes de Sensibilidade Microbiana , Pneumonia/tratamento farmacológico , Pneumonia/microbiologia
12.
J Infect Chemother ; 20(3): 224-7, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24674388

RESUMO

Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae may display MICs to carbapenems within susceptible or intermediate ranges, prompting confirmatory testing. Four phenotypic methods to detect KPC producers were evaluated against a collection of clinical Enterobacteriaceae isolates. Meropenem-phenylboronic acid double disk synergy testing demonstrated the best performance with 100% sensitivity and specificity.


Assuntos
Proteínas de Bactérias/biossíntese , Técnicas de Tipagem Bacteriana/métodos , Klebsiella pneumoniae/classificação , Klebsiella pneumoniae/enzimologia , Resistência beta-Lactâmica/genética , beta-Lactamases/biossíntese , Antibacterianos/farmacologia , Ácidos Borônicos , Humanos , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/genética , Testes de Sensibilidade Microbiana , Fenótipo , Sensibilidade e Especificidade
13.
J Infect Dis ; 207(5): 786-93, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23242537

RESUMO

BACKGROUND: The prevalence of bla(KPC) among gram-negative bacteria continues to increase worldwide. Limited treatment options exist for this multidrug-resistant phenotype, often necessitating combination therapy. We investigated the in vitro and in vivo efficacy of multiple antimicrobial combinations. METHODS: Two clinical strains of Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae were studied. The killing activities of six 2-agent combinations of amikacin, doripenem, levofloxacin, and rifampin were quantitatively assessed using a validated mathematical model. Combination time-kill studies were conducted using clinically relevant concentrations; observed bacterial burdens were modeled using 3-dimensional response surfaces. Selected combinations were further validated in a neutropenic murine pneumonia model, using human-like dosing exposures. RESULTS: The most enhanced killing effect in time-kill studies was seen with amikacin plus doripenem. Compared with placebo controls, this combination resulted in significant reduction of the bacterial burden in tissue at 24 hours, along with prolonged animal survival. In contrast, amikacin plus levofloxacin was found to be antagonistic in time-kill studies, showing inferior animal survival, as predicted. CONCLUSIONS: Our modeling approach appeared to be robust in assessing the effectiveness of various combinations for KPC-producing isolates. Amikacin plus doripenem was the most effective combination in both in vitro and in vivo infection models. Empirical selection of combinations against KPCs may result in antagonism and should be avoided.


Assuntos
Antibacterianos/administração & dosagem , Proteínas de Bactérias/metabolismo , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/enzimologia , Viabilidade Microbiana/efeitos dos fármacos , beta-Lactamases/metabolismo , Animais , Antibacterianos/farmacologia , Carga Bacteriana , Modelos Animais de Doenças , Quimioterapia Combinada/métodos , Feminino , Humanos , Klebsiella pneumoniae/isolamento & purificação , Pulmão/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/microbiologia , Resultado do Tratamento
15.
Antimicrob Agents Chemother ; 56(11): 5724-7, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22908162

RESUMO

The increasing prevalence of multidrug-resistant Gram-negative infections has led to the resurgence of systemic polymyxin B, but little is known about its pharmacokinetics. The objective of this study was to characterize the pharmacokinetics and renal disposition of polymyxin B. Eight female Sprague-Dawley rats (weight, 225 to 250 g) were administered a single intravenous polymyxin B dose (4 mg/kg of body weight). Serial serum samples were collected and assayed for major polymyxin B components using a validated ultraperformance liquid chromatography-tandem mass spectrometry method. The best-fit pharmacokinetic parameters of each component were derived and compared using one-way analysis of variance. Cumulative urine was also collected daily for 48 h and assayed for polymyxin B. Kidney drug concentrations were measured at 6 h (n = 3) and 48 h (n = 3) after the same dose. Additionally, three rats were administered 2 doses of intravenous polymyxin B (4 mg/kg) 7 days apart. Serial serum samples were collected pre- and post-renal insufficiency (induced by uranyl nitrate) and assayed for polymyxin B. The pharmacokinetic parameters of the major components did not appear to be significantly different (P > 0.05). Less than 1% of the dose was recovered unchanged in urine collected over 48 h following administration. Therapeutic drug concentrations persisted in kidney tissue at 48 h. The post-renal insufficiency to pre-renal insufficiency ratio of the area under the serum concentration-time curve from time zero to infinity was 1.33 ± 0.04. Polymyxin B components appear to have similar pharmacokinetics. Polymyxin B preferentially persists in kidneys, which suggests a selective uptake process in renal cells. A mechanism(s) other than renal excretion could be involved in polymyxin B elimination, and dosing adjustment in renal insufficiency may not be necessary.


Assuntos
Injúria Renal Aguda/urina , Antibacterianos/farmacocinética , Antibacterianos/urina , Rim/efeitos dos fármacos , Polimixina B/farmacocinética , Polimixina B/urina , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/fisiopatologia , Animais , Antibacterianos/farmacologia , Área Sob a Curva , Transporte Biológico , Cromatografia Líquida , Feminino , Injeções Intravenosas , Rim/metabolismo , Rim/fisiopatologia , Taxa de Depuração Metabólica , Polimixina B/farmacologia , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Nitrato de Uranil
16.
Antimicrob Agents Chemother ; 56(5): 2237-40, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22330927

RESUMO

The scarcity of new antibiotics against drug-resistant bacteria has led to the development of inhibitors targeting specific resistance mechanisms, which aim to restore the effectiveness of existing agents. However, there are few guidelines for the optimal dosing of inhibitors. Extending the utility of mathematical modeling, which has been used as a decision support tool for antibiotic dosing regimen design, we developed a novel mathematical modeling framework to guide optimal dosing strategies for a beta-lactamase inhibitor. To illustrate our approach, MK-7655 was used in combination with imipenem against a clinical isolate of Klebsiella pneumoniae known to produce KPC-2. A theoretical concept capturing fluctuating susceptibility over time was used to define a novel pharmacodynamic index (time above instantaneous MIC [T>MIC(i)]). The MK-7655 concentration-dependent MIC reduction was characterized by using a modified sigmoid maximum effect (E(max))-type model. Various dosing regimens of MK-7655 were simulated to achieve escalating T>MIC(i) values in the presence of a clinical dose of imipenem (500 mg every 6 h). The effectiveness of these dosing exposures was subsequently validated by using a hollow-fiber infection model (HFIM). An apparent trend in the bacterial response was observed in the HFIM with increasing T>MIC(i) values. In addition, different dosing regimens of MK-7655 achieving a similar T>MIC(i) (69%) resulted in comparable bacterial killing over 48 h. The proposed framework was reasonable in predicting the in vitro activity of a novel beta-lactamase inhibitor, and its utility warrants further investigations.


Assuntos
Compostos Azabicíclicos/farmacologia , Imipenem/farmacologia , Klebsiella pneumoniae/efeitos dos fármacos , Modelos Estatísticos , Inibidores de beta-Lactamases , Compostos Azabicíclicos/farmacocinética , Simulação por Computador , Esquema de Medicação , Combinação de Medicamentos , Humanos , Imipenem/farmacocinética , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/crescimento & desenvolvimento , Membranas Artificiais , Testes de Sensibilidade Microbiana , Guias de Prática Clínica como Assunto
17.
Antimicrob Agents Chemother ; 56(4): 1680-5, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22232279

RESUMO

The emergence of resistance presents a debilitating change in the management of infectious diseases. Currently, the temporal relationship and interplay between various mechanisms of drug resistance are not well understood. A thorough understanding of the resistance development process is needed to facilitate rational design of countermeasure strategies. Using an in vitro hollow-fiber infection model that simulates human drug treatment, we examined the appearance of efflux pump (acrAB) overexpression and target topoisomerase gene (gyrA and parC) mutations over time in the emergence of quinolone resistance in Escherichia coli. Drug-resistant isolates recovered early (24 h) had 2- to 8-fold elevation in the MIC due to acrAB overexpression, but no point mutations were noted. In contrast, high-level (≥ 64× MIC) resistant isolates with target site mutations (gyrA S83L with or without parC E84K) were selected more readily after 120 h, and regression of acrAB overexpression was observed at 240 h. Using a similar dosing selection pressure, the emergence of levofloxacin resistance was delayed in a strain with acrAB deleted compared to the isogenic parent. The role of efflux pumps in bacterial resistance development may have been underappreciated. Our data revealed the interplay between two mechanisms of quinolone resistance and provided a new mechanistic framework in the development of high-level resistance. Early low-level levofloxacin resistance conferred by acrAB overexpression preceded and facilitated high-level resistance development mediated by target site mutation(s). If this interpretation is correct, then these findings represent a paradigm shift in the way quinolone resistance is thought to develop.


Assuntos
Farmacorresistência Bacteriana/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Mutação/genética , Mutação/fisiologia , Antibacterianos/farmacologia , Área Sob a Curva , Meios de Cultura , DNA Girase/biossíntese , DNA Girase/genética , DNA Topoisomerase IV/biossíntese , DNA Topoisomerase IV/genética , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/microbiologia , Deleção de Genes , Levofloxacino , Testes de Sensibilidade Microbiana , Ofloxacino/farmacologia , Reação em Cadeia da Polimerase , Quinolonas/farmacologia , Reação em Cadeia da Polimerase em Tempo Real
18.
Antimicrob Agents Chemother ; 56(7): 3753-7, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22526311

RESUMO

Carbapenem-resistant bacteria represent a significant treatment challenge due to the lack of active antimicrobials available. MK-7655 is a novel ß-lactamase inhibitor under clinical development. We investigated the combined killing activity of imipenem and MK-7655 against four imipenem-resistant bacterial strains, using a mathematical model previously evaluated in our laboratory. Time-kill studies (TKS) were conducted with imipenem and MK-7655 against a KPC-2-producing Klebsiella pneumoniae isolate (KP6339) as well as 3 Pseudomonas aeruginosa isolates (PA24226, PA24227, and PA24228) with OprD porin deletions and overexpression of AmpC. TKS were performed using 25 clinically achievable concentration combinations in a 5-by-5 array. Bacterial burden at 24 h was determined in triplicate by quantitative culture and mathematically modeled using a three-dimensional response surface. Mathematical model assessments were evaluated experimentally using clinically relevant dosing regimens of imipenem, with or without MK-7655, in a hollow-fiber infection model (HFIM). The combination of imipenem and MK-7655 was synergistic for all strains. Interaction indices were as follows: for KP6339, 0.50 (95% confidence interval [CI], 0.42 to 0.58); for PA24226, 0.60 (95% CI, 0.58 to 0.62); for PA24227, 0.70 (95% CI, 0.66 to 0.74); and for PA24228, 0.55 (95% CI, 0.49 to 0.61). In the HFIM, imipenem plus MK-7655 considerably reduced the bacterial burden at 24 h, while failure with imipenem alone was seen against all isolates. Sustained suppression of bacterial growth at 72 h was achieved with simulated doses of 500 mg imipenem plus 500 mg MK-7655 in 2 (KP6339 and PA24227) strains, and it was achieved in an additional strain (PA24228) when the imipenem dose was increased to 1,000 mg. Additional studies are being conducted to determine the optimal dose and combinations to be used in clinical investigations.


Assuntos
Antibacterianos/farmacologia , Compostos Azabicíclicos/farmacologia , Carbapenêmicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Imipenem/farmacologia , Inibidores de beta-Lactamases , Klebsiella pneumoniae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Teóricos
19.
J Antimicrob Chemother ; 67(4): 928-32, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22232512

RESUMO

OBJECTIVES: It has been proposed that antimicrobial resistance could be associated with a fitness cost in bacteria, which is often determined by competition experiments between isogenic strains (wild-type and mutant). However, this conventional approach is time consuming and labour intensive. An alternative method was developed to assess the fitness cost in drug-resistant bacteria. METHODS: Time-growth studies were performed with approximately 1 × 10(5) cfu/mL of Acinetobacter baumannii or Pseudomonas aeruginosa at baseline. Serial samples were obtained to quantify the bacterial burden over 24 h. The growth rates (K(g)) of isogenic strains (antibiotic susceptible and resistant) were determined individually and used to predict their relative abundance in a co-culture over an extended period of time. The predicted difference between the two strains was subsequently validated by in vitro growth competition experiments. RESULTS: The growth rates of A. baumannii were not significantly different in different strengths of growth medium. The difference in bacterial burden observed in competition studies was in general agreement with the predicted difference based on K(g) values, suggesting good predicting ability of the mathematical model. CONCLUSIONS: The proposed mathematical model was found to be reasonable in characterizing bacterial growth and predicting the fitness cost of resistance. This simple method appears robust in the assessment of fitness cost associated with drug resistance and warrants further investigations.


Assuntos
Acinetobacter baumannii/fisiologia , Farmacorresistência Bacteriana , Metabolismo Energético , Pseudomonas aeruginosa/fisiologia , Acinetobacter baumannii/crescimento & desenvolvimento , Carga Bacteriana , Humanos , Modelos Teóricos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Fatores de Tempo
20.
Virulence ; 13(1): 1920-1927, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36308002

RESUMO

Acinetobacter baumannii has emerged as a common cause of bloodstream infections, which is associated with high mortality and long periods of hospitalization. To advance the medical care of our patients, the study was designed to identify microbial characteristics associated with poor clinical outcomes. A collection of 32 A. baumannii bloodstream isolates with diverse genetic backgrounds (as determined by multilocus sequence typing) was studied. These isolates were recovered by unique patients (18 males, 14 females; age range: 17 days to 87 years) between 2011 and 2018. A sequential screening approach (cross-referencing analyses using different endpoints) was used to identify isolates with the best correlation between bacterial virulence and clinical prognosis. Isolates associated with more rapid in vitro growth rate, shorter median survival time in pre-clinical infection models, and hospital mortality were selected as candidates for high virulence, while those with opposite characteristics were selected as controls with low virulence. Whole genome sequencing was undertaken in the most promising clinical isolates. We found five virulence genes (beta-hemolysin/cytolysin, Cpi-1a + Cpi-1 (SPI-1 like), enhanced entry proteins, FbpABC, Paa) and 1 secretory system (T6SS) only present in a highly virulent isolate (AB23), compared to a low virulence control isolate (AB6). These genetic elements could be associated with the poor prognosis of A. baumannii bacteraemia and further investigations are warranted.


Assuntos
Infecções por Acinetobacter , Acinetobacter baumannii , Bacteriemia , Feminino , Humanos , Recém-Nascido , Masculino , Infecções por Acinetobacter/microbiologia , Antibacterianos/farmacologia , Bacteriemia/microbiologia , Farmacorresistência Bacteriana Múltipla/genética , Genômica , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus , Virulência/genética
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