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1.
J Antimicrob Chemother ; 78(9): 2254-2262, 2023 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-37527369

RESUMO

OBJECTIVES: To use a pre-clinical pharmacokinetic infection model to assess the antibacterial effect of ceftolozane/tazobactam alone or in combination with fosfomycin or tobramycin against Pseudomonas aeruginosa strains with MICs at or higher than the clinical breakpoint (MIC ≥ 4 mg/L). METHODS: An in vitro model was used to assess changes in bacterial load and population profiles after exposure to mean human serum concentrations of ceftolozane/tazobactam associated with doses of 2 g/1 g q8h, fosfomycin concentrations associated with doses of 8 g q8h or tobramycin at doses of 7 mg/kg q24 h over 168 h. RESULTS: Simulations of ceftolozane/tazobactam at 2 g/1 g q8h alone produced 3.5-4.5 log reductions in count by 6 h post drug exposure for strains with MIC ≤32 mg/L. The antibacterial effect over the first 24 h was related to ceftolozane/tazobactam MIC. There was subsequent regrowth with most strains to bacterial densities of >106 CFU/mL. Addition of either fosfomycin or tobramycin resulted in suppression of regrowth and in the case of tobramycin more rapid initial bacterial killing up to 6 h. These effects could not be related to either fosfomycin or tobramycin MICs. Changes in population profiles were noted with ceftolozane/tazobactam alone often after 96 h exposure but such changes were suppressed by fosfomycin and almost abolished by the addition of tobramycin. CONCLUSIONS: The addition of either fosfomycin or tobramycin to ceftolozane/tazobactam at simulated human clinically observed concentrations reduced P. aeruginosa bacterial loads and the risk of resistance to ceftolozane/tazobactam when strains had ceftolozane/tazobactam MIC values at or above the clinical breakpoint.


Assuntos
Fosfomicina , Infecções por Pseudomonas , Humanos , Pseudomonas aeruginosa , Tobramicina/farmacologia , Tobramicina/uso terapêutico , Fosfomicina/farmacologia , Fosfomicina/uso terapêutico , Antibacterianos/uso terapêutico , Cefalosporinas/uso terapêutico , Tazobactam/farmacocinética , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia
2.
J Antimicrob Chemother ; 78(12): 2869-2877, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37837411

RESUMO

BACKGROUND: Efflux pump inhibitors (EPIs) offer an attractive therapeutic option when combined with existing classes. However, their optimal dosing strategies are unknown. METHODS: MICs of ciprofloxacin (CIP)+/-chlorpromazine, phenylalanine-arginine ß naphthylamide (PAßN) and a developmental molecule MBX-4191 were determined and the pharmacodynamics (PD) was studied in an in vitro model employing Escherichia coli MG1655 and its isogenic MarR mutant (I1147). Exposure ranging experiments were performed initially then fractionation. Changes in bacterial load and population profiles were assessed. Strains recovered after EPI simulations were studied by WGS. RESULTS: The CIPMICs for E. coli MG1655 and I1147 were 0.08 and 0.03 mg/L. Chlorpromazine at a concentration of 60 mg/L, PAßN concentrations of 30 mg/L and MBX-4191 concentrations of 0.5-1.0 mg/L reduced CIP MICs for I1147 and enhanced bacterial killing. Using CIP at an AUC of 1.2 mg·h/L, chlorpromazine AUC was best related to reduction in bacterial load at 24 h, however, when the time drug concentration was greater than 25 mg/L (T > 25 mg/L) chlorpromazine was also strongly related to the effect. For PaßN with CIP AUC, 0.6 mg·h/L PaßN AUC was best related to a reduction in bacterial load. MBX-4191T > 0.5-0.75 mg·h/L was best related to reduction in bacterial load. Changes in population profiles were not seen in experiments of ciprofloxacin + EPIs. WGS of recovered strains from simulations with all three EPIs showed mutations in gyrA, gyrB or marR. CONCLUSIONS: AUC was the pharmacodynamic driver for chlorpromazine and PAßN while T > threshold was the driver for MBX-4191 and important in the activity of chlorpromazine and PAßN. Changes in population profiles did not occur with combinations of ciprofloxacin + EPIs, however, mutations in gyrA, gyrB and marR were detected.


Assuntos
Clorpromazina , Escherichia coli , Escherichia coli/genética , Clorpromazina/farmacologia , Farmacorresistência Bacteriana Múltipla , Antibacterianos/farmacologia , Ciprofloxacina/farmacologia , Testes de Sensibilidade Microbiana , Farmacorresistência Bacteriana
3.
J Antimicrob Chemother ; 77(5): 1306-1312, 2022 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-35137096

RESUMO

BACKGROUND: There is surprisingly little comparative published data on the bactericidal action of different sub-classes of ß-lactams against aerobic Gram-negative rods, and the assumption is that all behave in the same way. OBJECTIVES: To describe a systematic investigation of a representative penicillin, cephalosporin, monobactam and carbapenem against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa. METHODS: Concentration-time-kill curves (TKC) were determined for three strains each of E. coli, K. pneumoniae, A. baumannii and P. aeruginosa. All strains were susceptible to the agents used. The antibiotics were piperacillin/tazobactam, ceftazidime, aztreonam and meropenem. The initial inoculum was 106 cfu/mL and TKC were determined over 48 h. The area-under-the-bacterial-kill curve to 24 h (AUBKC 24 log cfu·h/mL) and 48 h (AUBKC 48) were used to measure antibacterial effect (ABE). Population profiles before and after antibiotic exposure were recorded. RESULTS: Against E. coli and K. pneumoniae meropenem had a maximal ABE at ≥MIC × 1 concentrations while piperacillin/tazobactam and ceftazidime had maximal effect at ≥MIC × 4 and aztreonam at ≥MIC × 8 concentrations. Ceftazidime, aztreonam and meropenem had less ABE against K. pneumoniae than E. coli. Against P. aeruginosa, meropenem was most bactericidal, with a maximum ABE at 8×/16 × MIC. Other ß-lactams had notably less ABE. In contrast, against A. baumannii, ceftazidime and meropenem had the greatest ABE, with a maximal effect at ≥MIC × 4, concentration changes in population profiles were least apparent with E. coli. CONCLUSIONS: ß-Lactam sub-classes (penicillins, cephalosporins, monobactams and carbapenems) have different antibacterial effects against E. coli, K. pneumoniae, A. baumannii and P. aeruginosa. Extrapolation of in vitro pharmacodynamic findings from one species to another or one sub-class of ß-lactam to another is not justified.


Assuntos
Acinetobacter baumannii , Antibacterianos/farmacologia , Aztreonam/farmacologia , Carbapenêmicos , Ceftazidima/farmacologia , Cefalosporinas/farmacologia , Escherichia coli , Klebsiella pneumoniae , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , Monobactamas , Piperacilina/farmacologia , Pseudomonas aeruginosa , Tazobactam , beta-Lactamas/farmacologia
4.
J Antimicrob Chemother ; 78(1): 196-204, 2022 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-36346710

RESUMO

OBJECTIVE: To estimate the effect of treatment duration on in-hospital mortality in patients with Staphylococcus aureus blood stream infection and demonstrate the biases that can arise when immortal-time bias is ignored. EXPOSURE: We compared three treatment strategies: short therapy (<10 days), intermediate (10-18 days) and long (>18 days). MAIN OUTCOME MEASURES: Twenty-eight-day all-cause in-hospital mortality. METHODS: Using data from the BSI-FOO study, we implemented an approach proposed by Hernán to overcome confounding and immortal-time biases. The first stage is to clone all participants, so that each participant is assigned to each treatment strategy. Second, observations are censored when their data becomes inconsistent with their assigned strategy. Finally, inverse-probability weights are applied to adjust for potential selection. We compared our results to a naïve approach where immortal-time bias is ignored. RESULTS: Of the 1903 participants in BSI-FOO, 587 were eligible and included in the analysis. After cloning, the weighted estimates of hazard ratio of mortality for short versus long therapy was 1.74 (95% CI 1.36, 2.24) and for intermediate versus long therapy was 1.09 (0.98, 1.22). In the naïve approach, the hazard ratios with reference to the long therapy group are 37.4 (95% CI 18.9 to 74.4) in the short therapy group and 4.1 (95% CI 1.9 to 8.9) in the intermediate therapy group. CONCLUSIONS: Our findings suggest that duration of therapy >18 days is beneficial with respect to 28-day in-hospital mortality, however, there remains uncertainty around the efficacy of reducing duration of treatment to 10-18 days.


Assuntos
Infecções Estafilocócicas , Staphylococcus aureus , Humanos , Duração da Terapia , Estudos de Coortes , Infecções Estafilocócicas/tratamento farmacológico , Viés , Clonagem Molecular
5.
Antimicrob Agents Chemother ; 65(8): e0241220, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-33972250

RESUMO

Meropenem is a clinically important antibacterial reserved for treatment of multiresistant infections. In meropenem-resistant bacteria of the family Enterobacterales, NDM-1 is considerably more common than IMP-1, despite both metallo-ß-lactamases (MBLs) hydrolyzing meropenem with almost identical kinetics. We show that blaNDM-1 consistently confers meropenem resistance in wild-type Enterobacterales, but blaIMP-1 does not. The reason is higher blaNDM-1 expression because of its stronger promoter. However, the cost of meropenem resistance is reduced fitness of blaNDM-1-positive Enterobacterales. In parallel, from a clinical case, we identified multiple Enterobacter spp. isolates carrying a plasmid-encoded blaNDM-1 having a modified promoter region. This modification lowered MBL production to a level associated with zero fitness cost, but, consequently, the isolates were not meropenem resistant. However, we identified a Klebsiella pneumoniae isolate from this same clinical case carrying the same blaNDM-1 plasmid. This isolate was meropenem resistant despite low-level NDM-1 production because of a ramR mutation reducing envelope permeability. Overall, therefore, we show how the resistance/fitness trade-off for MBL carriage can be resolved. The result is sporadic emergence of meropenem resistance in a clinical setting.


Assuntos
Microbioma Gastrointestinal , beta-Lactamases , Antibacterianos/farmacologia , Carbapenêmicos/farmacologia , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , beta-Lactamases/genética
6.
J Antimicrob Chemother ; 76(12): 3144-3150, 2021 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-34450630

RESUMO

BACKGROUND: Our primary aim was to test whether cattle-associated fluoroquinolone-resistant (FQ-R) Escherichia coli found on dairy farms are closely phylogenetically related to those causing bacteriuria in humans living in the same 50 × 50 km geographical region suggestive of farm-human sharing. Another aim was to identify risk factors for the presence of FQ-R E. coli on dairy farms. METHODS: FQ-R E. coli were isolated during 2017-18 from 42 dairy farms and from community urine samples. Forty-two cattle and 489 human urinary isolates were subjected to WGS, allowing phylogenetic comparisons. Risk factors were identified using a Bayesian regularization approach. RESULTS: Of 489 FQ-R human isolates, 255 were also third-generation-cephalosporin-resistant, with strong genetic linkage between aac(6')Ib-cr and blaCTX-M-15. We identified possible farm-human sharing for pairs of ST744 and ST162 isolates, but minimal core genome SNP distances were larger between farm-human pairs of ST744 and ST162 isolates (71 and 63 SNPs, respectively) than between pairs of isolates from different farms (7 and 3 SNPs, respectively). Total farm fluoroquinolone use showed a positive association with the odds of isolating FQ-R E. coli, while total dry cow therapy use showed a negative association. CONCLUSIONS: This work suggests that FQ-R E. coli found on dairy farms have a limited impact on community bacteriuria within the local human population. Reducing fluoroquinolone use may reduce the on-farm prevalence of FQ-R E. coli and this reduction may be greater when dry cow therapy is targeted to the ecology of resistant E. coli on the farm.


Assuntos
Bacteriúria , Infecções por Escherichia coli , Animais , Antibacterianos/farmacologia , Teorema de Bayes , Bovinos , Escherichia coli/genética , Infecções por Escherichia coli/epidemiologia , Infecções por Escherichia coli/veterinária , Fazendas , Feminino , Fluoroquinolonas/farmacologia , Humanos , Filogenia
7.
J Antimicrob Chemother ; 75(1): 65-71, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31538190

RESUMO

OBJECTIVES: Third-generation cephalosporin-resistant Escherichia coli from community-acquired urinary tract infections are increasingly reported worldwide. We sought to determine and characterize the mechanisms of cefotaxime resistance employed by urinary E. coli obtained from primary care, over 12 months, in Bristol and surrounding counties in South-West England. METHODS: Cefalexin-resistant E. coli isolates were identified from GP-referred urine samples using disc susceptibility testing. Cefotaxime resistance was determined by subsequent plating onto MIC breakpoint plates. ß-Lactamase genes were detected by PCR. WGS was performed on 225 isolates and analyses were performed using the Center for Genomic Epidemiology platform. Patient information provided by the referring general practices was reviewed. RESULTS: Cefalexin-resistant E. coli (n=900) isolates were obtained from urines from 146 general practices. Following deduplication by patient approximately 69% (576/836) of isolates were cefotaxime resistant. WGS of 225 isolates identified that the most common cefotaxime-resistance mechanism was blaCTX-M carriage (185/225), followed by plasmid-mediated AmpCs (pAmpCs) (17/225), AmpC hyperproduction (13/225), ESBL blaSHV variants (6/225) or a combination of both blaCTX-M and pAmpC (4/225). Forty-four STs were identified, with ST131 representing 101/225 isolates, within which clade C2 was dominant (54/101). Ciprofloxacin resistance was observed in 128/225 (56.9%) of sequenced isolates, predominantly associated with fluoroquinolone-resistant clones ST131 and ST1193. CONCLUSIONS: Most cefalexin-resistant E. coli isolates were cefotaxime resistant, predominantly caused by blaCTX-M carriage. The correlation between cefotaxime resistance and ciprofloxacin resistance was largely attributable to the high-risk pandemic clones ST131 and ST1193. Localized epidemiological data provide greater resolution than regional data and can be valuable for informing treatment choices in the primary care setting.


Assuntos
Antibacterianos/farmacologia , Cefotaxima/farmacologia , Farmacorresistência Bacteriana/genética , Infecções por Escherichia coli/urina , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Infecções Urinárias/microbiologia , Idoso , Proteínas de Bactérias/genética , Infecções Comunitárias Adquiridas/microbiologia , Inglaterra/epidemiologia , Infecções por Escherichia coli/epidemiologia , Infecções por Escherichia coli/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tipagem de Sequências Multilocus , Atenção Primária à Saúde/estatística & dados numéricos , Sequenciamento Completo do Genoma , beta-Lactamases/genética
8.
J Antimicrob Chemother ; 75(6): 1374-1389, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32083674

RESUMO

BACKGROUND: Pharmacokinetic (PK)-pharmacodynamic (PD) indices relate measures of drug exposure to antibacterial effect. Clinical PK-PD studies aim to correlate PK-PD indices with outcomes in patients. Optimization of dosing based on pre-clinical studies means that PK-PD relationships are difficult to establish; therefore studies need to be designed and reported carefully to validate pre-clinical findings. OBJECTIVES: To describe the methodological features of clinical antibacterial and antifungal PK-PD studies that reported the relationship between PK-PD indices and clinical or microbiological responses. METHODS: Studies published between 1980 and 2015 were identified through systematic searches. Methodological features of eligible studies were extracted. RESULTS: We identified 85 publications containing 97 PK-PD analyses. Most studies were small, with fewer than 100 patients. Around a quarter were performed on patients with infections due to a single specific pathogen. In approximately one-third of studies, patients received concurrent antibiotics/antifungals and in some other studies patients received other treatments that may confound the PK-PD-outcome relationship. Most studies measured antimicrobial concentrations in blood/serum and only four measured free concentrations. Most performed some form of regression, time-to-event analysis or used the Hill/Emax equation to examine the association between PK-PD index and outcome. Target values of PK-PD indices that predict outcomes were investigated in 52% of studies. Target identification was most commonly done using recursive partitioning or logistic regression. CONCLUSIONS: Given the variability in conduct and reporting, we suggest that an agreed set of standards for the conduct and reporting of studies should be developed.


Assuntos
Anti-Infecciosos , Antifúngicos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antifúngicos/farmacologia , Área Sob a Curva , Humanos
9.
J Antimicrob Chemother ; 74(7): 1945-1951, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31220257

RESUMO

OBJECTIVES: We assessed the antibacterial effect of human simulations of dosing with imipenem/relebactam (with or without amikacin) on Enterobacteriaceae or Pseudomonas aeruginosa over 7 or 14 day antibiotic exposures. METHODS: An in vitro pharmacokinetic model was used to assess changes in bacterial load and population profiles. RESULTS: Imipenem/relebactam produced an initial >4 log drop in viable counts followed by suppression for 7 days for Enterobacteriaceae whether the strain was WT, produced KPC enzymes or produced an AmpC enzyme with porin loss. Similarly, with the P. aeruginosa strains, there was an initial >4 log clearance over the first 24 h irrespective of whether the strain was WT, hyperexpressed AmpC or had OprD mutation with porin loss. However, with three of four strains there was modest regrowth over the 7 days. There were no changes in imipenem/relebactam MICs over the 7 days. Addition of amikacin in 7 day simulations resulted in more suppression of pseudomonal growth. In 14 day simulations with P. aeruginosa there was regrowth to 8 log10 by 14 days with imipenem/relebactam alone and associated increases in MICs. Addition of amikacin resulted in clearance from the model and prevented changes in population profiles. CONCLUSIONS: Imipenem/relebactam was highly effective at reducing the bacterial load of Enterobacteriaceae and there was no emergence of resistance. Against P. aeruginosa, the initial bacterial burden was also rapidly reduced, but there was subsequent regrowth, especially after 7 days of exposure. Addition of amikacin increased the clearance of P. aeruginosa and prevented emergence of resistance.


Assuntos
Antibacterianos/farmacologia , Compostos Azabicíclicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Imipenem/farmacologia , Simulação por Computador , Relação Dose-Resposta a Droga , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Fatores de Tempo
10.
Clin Infect Dis ; 67(12): 1922-1931, 2018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30107400

RESUMO

Innovations are urgently required for clinical development of antibacterials against multidrug-resistant organisms. Therefore, a European, public-private working group (STAT-Net; part of Combatting Bacterial Resistance in Europe [COMBACTE]), has reviewed and tested several innovative trials designs and analytical methods for randomized clinical trials, which has resulted in 8 recommendations. The first 3 focus on pharmacokinetic and pharmacodynamic modeling, emphasizing the pertinence of population-based pharmacokinetic models, regulatory procedures for the reassessment of old antibiotics, and rigorous quality improvement. Recommendations 4 and 5 address the need for more sensitive primary end points through the use of rank-based or time-dependent composite end points. Recommendation 6 relates to the applicability of hierarchical nested-trial designs, and the last 2 recommendations propose the incorporation of historical or concomitant trial data through Bayesian methods and/or platform trials. Although not all of these recommendations are directly applicable, they provide a solid, evidence-based approach to develop new, and established, antibacterials and address this public health challenge.


Assuntos
Antibacterianos/farmacocinética , Farmacorresistência Bacteriana Múltipla , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa/normas , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Teorema de Bayes , Interpretação Estatística de Dados , Medicina Baseada em Evidências , Humanos
11.
Artigo em Inglês | MEDLINE | ID: mdl-29263066

RESUMO

Fluoroquinolone resistance in Gram-negative bacteria is multifactorial, involving target site mutations, reductions in fluoroquinolone entry due to reduced porin production, increased fluoroquinolone efflux, enzymes that modify fluoroquinolones, and Qnr, a DNA mimic that protects the drug target from fluoroquinolone binding. Here we report a comprehensive analysis, using transformation and in vitro mutant selection, of the relative importance of each of these mechanisms for fluoroquinolone nonsusceptibility using Klebsiella pneumoniae as a model system. Our improved biological understanding was then used to generate 47 rules that can predict fluoroquinolone susceptibility in K. pneumoniae clinical isolates. Key to the success of this predictive process was the use of liquid chromatography-tandem mass spectrometry to measure the abundance of proteins in extracts of cultured bacteria, identifying which sequence variants seen in the whole-genome sequence data were functionally important in the context of fluoroquinolone susceptibility.


Assuntos
Cromatografia Líquida/métodos , Fluoroquinolonas/farmacologia , Espectrometria de Massas em Tandem/métodos , Sequenciamento Completo do Genoma/métodos , Antibacterianos/farmacologia , Genótipo , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/genética , Testes de Sensibilidade Microbiana
12.
J Antimicrob Chemother ; 73(9): 2411-2417, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30020472

RESUMO

Objectives: To use a pre-clinical infection model to assess the antibacterial effect of human simulations of dosing with ceftolozane/tazobactam (with or without amikacin) or meropenem against Enterobacteriaceae and Pseudomonas aeruginosa. Methods: An in vitro pharmacokinetic model was used to assess changes in bacterial load and profiles after exposure to mean human serum concentrations over 168 h. Changes in area under the bacterial kill curve (AUBKC; log cfu/mL·h) and growth on 4 × MIC recovery plates were the co-primary outcome measures. Results: Simulations of ceftolozane/tazobactam at 1 g/0.5 g or 2 g/1 g q8h or meropenem 2 g q8h all produced a >4 log reduction in bacterial load of Escherichia coli. Meropenem had smaller AUBKC values, indicating greater reduction in bacterial load than ceftolozane/tazobactam. Meropenem was also more effective than ceftolozane/tazobactam against Klebsiella pneumoniae strains. All regimens were equally effective in reducing P. aeruginosa bacterial load measured by AUBKC but growth on 4 × MIC recovery plates and changes in population profiles were only seen with meropenem. Addition of amikacin at 15 mg/kg q24h or 7.5 mg/kg q12h to 2 g/1 g of ceftolozane/tazobactam produced greater reductions in bacterial load but generated changes in amikacin population profiles with the 7.5 mg/kg q12h amikacin simulation. Conclusions: The doses of ceftolozane/tazobactam simulated were highly effective in reducing the bacterial load of E. coli (MIC ≤0.25 mg/L), but less so for K. pneumoniae (MIC 4 mg/L). For both species, meropenem produced an overall greater reduction in pathogen load. Ceftolozane/tazobactam and meropenem were equally effective as monotherapy against P. aeruginosa but emergence of resistance occurred with meropenem. Addition of amikacin to ceftolozane/tazobactam reduced the bacterial load of P. aeruginosa at the expense of emergence of resistance to amikacin.


Assuntos
Amicacina/administração & dosagem , Antibacterianos/administração & dosagem , Cefalosporinas/administração & dosagem , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Tazobactam/administração & dosagem , Inibidores de beta-Lactamases/administração & dosagem , Amicacina/farmacocinética , Amicacina/farmacologia , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Carga Bacteriana , Cefalosporinas/farmacocinética , Cefalosporinas/farmacologia , Quimioterapia Combinada/métodos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Meropeném/administração & dosagem , Meropeném/farmacocinética , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Modelos Teóricos , Tazobactam/farmacocinética , Tazobactam/farmacologia , Inibidores de beta-Lactamases/farmacocinética , Inibidores de beta-Lactamases/farmacologia
13.
J Antimicrob Chemother ; 73(5): 1305-1313, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29562340

RESUMO

Background: The pharmacodynamics of inhaled antimicrobials are poorly studied. Amikacin is being developed for inhalational therapy as BAY 41-6551. Objectives: We employed an in vitro pharmacokinetic model to study the pharmacokinetics/pharmacodynamics of amikacin. Methods: A dose-ranging design was used to establish fAUC/MIC and fCmax/MIC targets for static, -1 log drop and -2 log drop effects for strains of Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. We then modelled epithelial lining fluid (ELF) concentration associated with inhaled amikacin (400 mg every 12 h), over 5 days using mean human concentrations. Results: The 24 h static effect fAUC/MIC targets and -1 log drop targets were 51.0 ±âŸ26.7 and 71.6 ±âŸ27.6 for all species of aerobic Gram-negative bacilli. fAUC/MIC targets for static effect, -1 log drop or -2 log drop were smaller than the 24 h values at 12 h and larger at 48 h. Emergence of resistance occurred maximally with E. coli in the fAUC/MIC range 12-60; K. pneumoniae 0-60 (48 h) and P. aeruginosa 12-80. When human ELF concentrations were modelled for strains with MIC ≤8 mg/L, there was rapid clearance and no regrowth. For strains with MIC ≥32 mg/L, there was initial clearance followed by regrowth. If MIC values were related to bacterial clearance then at least a static effect or -1 log drop in count would be expected for bacterial strains with MICs of ≤180 mg/L (static effect) or ≤148 mg/L (-1 log drop effect). Conclusions: An fAUC/MIC amikacin target of 50-80 is appropriate for aerobic Gram-negative bacilli and mean ELF concentrations of BAY 41-6551 would produce a static to -1 log clearance with strains up to 128 mg/L.


Assuntos
Amicacina/farmacologia , Amicacina/farmacocinética , Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Administração por Inalação , Amicacina/administração & dosagem , Antibacterianos/administração & dosagem , Escherichia coli/efeitos dos fármacos , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Estatísticos , Modelos Teóricos , Pseudomonas aeruginosa/efeitos dos fármacos
14.
J Antimicrob Chemother ; 72(2): 323-329, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28115501

RESUMO

Susceptibility testing of bacteria is one of the most important tests performed in a clinical microbiology laboratory. Improvements in laboratory techniques, especially the move towards standardized susceptibility testing, has provided better consistency and accuracy of testing. When used in conjunction with the most recently developed interpretative criteria, the result is better prediction of the outcome of antimicrobial therapy for infected patients. Throughout the last four decades this Journal has published numerous articles evidencing improvements and new techniques, a valuable source of information for microbiology laboratories.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Testes de Sensibilidade Microbiana/métodos , Testes de Sensibilidade Microbiana/normas , Antibacterianos/uso terapêutico , Bactérias/isolamento & purificação , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Humanos , Resultado do Tratamento
15.
Antimicrob Agents Chemother ; 60(1): 515-21, 2016 01.
Artigo em Inglês | MEDLINE | ID: mdl-26552975

RESUMO

Ceftolozane plus tazobactam is an antipseudomonal cephalosporin combined with tazobactam, an established beta-lactamase inhibitor, and has in vitro potency against a range of clinically important ß-lactamase-producing bacteria, including most extended-spectrum-ß-lactamase (ESBL)-positive Enterobacteriaceae. The pharmacodynamics of ß-lactam-ß-lactamase inhibitor combinations presents a number of theoretical and practical challenges, including modeling different half-lives of the compounds. In this study, we studied the pharmacodynamics of ceftolozane plus tazobactam against Escherichia coli and Pseudomonas aeruginosa using an in vitro pharmacokinetic model of infection. Five strains of E. coli, including three clinical strains plus two CTX-M-15 (one high and one moderate) producers, and five strains of P. aeruginosa, including two with OprD overexpression and AmpC ß-lactamases, were employed. Ceftolozane MICs (E. coli, 0.12 to 0.25 mg/liter, and P. aeruginosa, 0.38 to 8 mg/liter) were determined in the presence of 4 mg/liter tazobactam. Dose ranging of ceftolozane (percentage of time in which the free-drug concentration exceeds the MIC [fT>MIC], 0 to 100%) plus tazobactam (human pharmacokinetics) was simulated every 8 hours, with half-lives (t1/2) of 2.5 and 1 h, respectively. Ceftolozane and tazobactam concentrations were confirmed by high-performance liquid chromatography (HPLC). The ceftolozane-plus-tazobactam fT>MIC values at 24 h for a static effect and a 1-log and 2-log drop in initial inoculum for E. coli were 27.8% ± 5.6%, 33.0% ± 5.6%, and 39.6% ± 8.5%, respectively. CTX-M-15 production did not affect the 24-h fT>MIC for E. coli strains. The ceftolozane-plus-tazobactam fT>MIC values for a 24-h static effect and a 1-log and 2-log drop for P. aeruginosa were 24.9% ± 3.0%, 26.6% ± 3.9%, and 31.2% ± 3.6%. Despite a wide range of absolute MICs, the killing remained predictable as long as the MICs were normalized to the corresponding fT>MIC. Emergence of resistance on 4× MIC plates and 8× MIC plates occurred maximally at an fT>MIC of 10 to 30% and increased as time of exposure increased. The fT>MIC for a static effect for ceftolozane plus tazobactam is less than that observed with other cephalosporins against E. coli and P. aeruginosa and is more similar to the fT>MIC reported for carbapenems.


Assuntos
Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Escherichia coli/efeitos dos fármacos , Modelos Estatísticos , Ácido Penicilânico/análogos & derivados , Pseudomonas aeruginosa/efeitos dos fármacos , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Reatores Biológicos , Cefalosporinas/farmacologia , Cromatografia Líquida de Alta Pressão , Contagem de Colônia Microbiana , Simulação por Computador , Escherichia coli/enzimologia , Escherichia coli/genética , Expressão Gênica , Meia-Vida , Bombas de Infusão , Testes de Sensibilidade Microbiana , Ácido Penicilânico/farmacocinética , Ácido Penicilânico/farmacologia , Porinas/genética , Porinas/metabolismo , Pseudomonas aeruginosa/enzimologia , Pseudomonas aeruginosa/genética , Tazobactam , beta-Lactamases/genética , beta-Lactamases/metabolismo
16.
J Antimicrob Chemother ; 71(10): 2704-12, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27334663

RESUMO

The monobactam aztreonam is currently being re-examined as a therapeutic agent in light of the global spread of carbapenem resistance in aerobic Gram-negative bacilli and aztreonam's stability to Ambler class B metallo-ß-lactamases. Of particular interest are the pharmacokinetic and pharmacodynamic properties of aztreonam alone and in combination with ß-lactamase inhibitors. The choice of inhibitor may vary depending on the spectrum of ß-lactamases produced by Enterobacteriaceae. The monobactam ring is also being used to produce new developmental monobactams. Thus, a greater understanding of aztreonam pharmacokinetics and dynamics is of great relevance in drug development. This review summarizes the pharmacokinetic profile of aztreonam in man and its pharmacodynamics in human and pre-clinical studies when studied alone and with ß-lactamase inhibitors.


Assuntos
Aztreonam/farmacocinética , Aztreonam/uso terapêutico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Inibidores de beta-Lactamases/farmacocinética , Inibidores de beta-Lactamases/uso terapêutico , Aztreonam/administração & dosagem , Aztreonam/farmacologia , Ensaios Clínicos como Assunto , Quimioterapia Combinada , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/enzimologia , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Inibidores de beta-Lactamases/administração & dosagem , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/biossíntese
17.
J Antimicrob Chemother ; 71(5): 1270-8, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26846209

RESUMO

OBJECTIVES: Dose-ranging experiments were performed to study the pharmacodynamics of ceftaroline against Enterobacteriaceae. METHODS: A range of fT>MIC values (0%-100%) were simulated over 96 h using a single-compartment dilutional in vitro pharmacokinetic model using Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Citrobacter koseri and Serratia marcescens (n = 16). Antibacterial effect was assessed by change in viable count and population profiles by growth on ceftaroline MIC ×2, ×4 and ×8 agar plates. The fT>MIC (%) was related to antibacterial effect using a sigmoid Emax model. RESULTS: The 24 h bacteriostatic effect fT>MIC was 39.7% ±â€Š15.7% and 43.2% ±â€Š15.6% for a -1 log drop for all strains. E. coli required lower exposures than K. pneumoniae, i.e. 24 h fT>MIC for a -3 log drop in viable count was 40.0% ±â€Š9.6% and 84.8% ±â€Š15.2% for K. pneumoniae. Similarly at 96 h, fT>MIC was >100% for K. pneumoniae (for four of five strains), 27.2%-66.2% for E. coli and 16.2%-86.6% for P. mirabilis. Strain-to-strain variation within species in the fT>MIC for static and cidal effect was marked; the 24 h bacteriostatic range was 14.1%-73.4% for P. mirabilis, 34.2%-44.6% for E. coli and 42.2%-62.5% for K. pneumoniae. Changes in ceftaroline population analysis profiles were observed with E. coli, K. pneumoniae and C. koseri, especially at fT>MIC values just below the bacteriostatic effect exposures. CONCLUSIONS: The pharmacodynamics of ceftaroline against the species within the Enterobacteriaceae group are different. K. pneumoniae requires higher drug exposures than E. coli, and P. mirabilis strains are highly variable, which may have important clinical correlates. Translational extrapolations from preclinical observations using E. coli to other Enterobacteriaceae species may not be optimal.


Assuntos
Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Cefalosporinas/farmacologia , Cefalosporinas/farmacocinética , Infecções por Enterobacteriaceae/tratamento farmacológico , Enterobacteriaceae/efeitos dos fármacos , Antibacterianos/administração & dosagem , Cefalosporinas/administração & dosagem , Contagem de Colônia Microbiana , Infecções por Enterobacteriaceae/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Modelos Biológicos , Modelos Teóricos , Ceftarolina
18.
Ann Clin Microbiol Antimicrob ; 15: 23, 2016 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-27071911

RESUMO

BACKGROUND: Early Warning Score (EWS) is a physiological composite score of six bedside vital parameters, routinely used in UK hospitals. We evaluated the prognostic ability of EWS in Gram-negative bacteraemia causing sepsis. METHODS: We prospectively evaluated EWS as a marker of severity and prognosis in adult patients with Gram-negative bacteraemia. All adult patients with Gram-negative bacteraemia admitted to our tertiary Teaching hospital of the National Health Service in England were enrolled over 1 year period. The highest daily EWS score was recorded from 7 days before to 14 days after the date of onset of bacteraemia. The primary outcome was 28-day mortality. MAIN RESULTS: A total of 245 consecutive adult patients with Gram-negative bacteraemia with sepsis were enrolled. On multivariate analysis, following variables were associated with death for every single unit change (odds ratio in the brackets): higher age (1.05), lower mean arterial pressure (1.03), lower serum bicarbonate (1.08), higher EWS (1.27), higher SOFA score (1.36), hospital-onset of infection (5.43) and need for vasopressor agents (16.4). EWS on day 0, 1, 2, and average 14-day score were significantly higher in patients who died by 28 days from the onset of bacteraemia [95 % CI 0.4-0.6] p < 0.001. A stepwise rise in EWS and failure of improvement in EWS by 2 points 48 h after the onset of bacteraemia were associated with poor outcome. CONCLUSION: EWS is a simple and cost-effective bedside tool for the assessment of severity and prognosis of sepsis caused by Gram-negative bacteraemia.


Assuntos
Bacteriemia/diagnóstico , Técnicas e Procedimentos Diagnósticos , Infecções por Bactérias Gram-Negativas/diagnóstico , Sepse/diagnóstico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
20.
Antimicrob Agents Chemother ; 57(6): 2451-6, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23459495

RESUMO

An in vitro single-compartment dilutional pharmacokinetic model was used to study the pharmacodynamics of ceftaroline against Staphylococcus aureus (both methicillin-susceptible S. aureus [MSSA] and methicillin-resistant S. aureus [MRSA]). Mean serum free concentrations of ceftaroline (the active metabolite of the prodrug ceftaroline fosamil) dosed in humans at 600 mg every 12 h (q12h) were simulated, and activities against 12 S. aureus strains (3 MSSA strains and 9 MRSA strains, 3 of which had a vancomycin-intermediate phenotype) were determined. Ceftaroline produced 2.5- to 4.0-log10-unit reductions in viable counts by 24 h with all strains and a 0.5- to 4.0-log-unit drop in counts at 96 h. The antibacterial effect could not be related to the strain MIC across the ceftaroline MIC range from 0.12 to 2.0 µg/ml. In dose-ranging studies, the cumulative percentage of a 24-h period that the free drug concentration exceeded the MIC under steady-state pharmacokinetic conditions (fT(MIC)) of 24.5% ± 8.9% was associated with a 24-h bacteriostatic effect, one of 27.8% ± 9.5% was associated with a -1-log-unit drop, and one of 32.1% ± 8.1% was associated with a -2-log-unit drop. The MSSA and MRSA strains had similar fT(MIC) values. fT(MIC) values increased with increasing duration of exposure up to 96 h. Changes in ceftaroline population analysis profiles were related to fT(MIC). fT(MIC)s of <50% were associated with growth on 4× MIC recovery plates at 96 h of drug exposure. These data support the use of ceftaroline fosamil at doses of 600 mg q12h to treat S. aureus strains with MICs of ≤ 2 µg/ml. An fT(MIC) of 25 to 30% would make a suitable pharmacodynamic index target, but fTMIC values of ≥ 50% are needed to suppress the emergence of resistance and require clinical evaluation.


Assuntos
Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefalosporinas/farmacologia , Cefalosporinas/uso terapêutico , Contagem de Colônia Microbiana , Humanos , Meticilina/farmacologia , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Modelos Biológicos , Staphylococcus aureus/crescimento & desenvolvimento , Ceftarolina
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