RESUMO
Minimal inhibitory concentrations (MICs) of ticarcillin/clavulanic acid (TLc), ceftolozane/tazobactam (C/T), and aztreonam (AT) were determined for 6 SPM-1-producing Pseudomonas aeruginosa (PSA) using Etest® strips and the synergistic effect of such antimicrobials against was evaluated by gradient diffusion strip crossing (GDSC) test. The fraction inhibitory concentration indexes (FICI) were calculated and showed a synergistic (nâ¯=â¯3) and additive (nâ¯=â¯2) effects of TLcâ¯+â¯AT against SPM-1 producers, while TLcâ¯+â¯C/T combination caused no effect. Average MIC reduction of TLc and AT by GDSC was 3-fold and 2-fold dilutions, respectively. Thus, TLcâ¯+â¯AT might be a candidate as a combination therapy to treat SPM-1-producing PSA infections.
Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , beta-Lactamases/metabolismo , Aztreonam/administração & dosagem , Aztreonam/farmacologia , Cefalosporinas/farmacologia , Ácidos Clavulânicos/administração & dosagem , Ácidos Clavulânicos/farmacologia , Sinergismo Farmacológico , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Tazobactam/farmacologia , Ticarcilina/administração & dosagem , Ticarcilina/farmacologia , beta-Lactamases/genéticaRESUMO
OBJECTIVES: Carbapenem-resistant Pseudomonas aeruginosa (CR-PSA) imposes great limitations on empirical therapeutic choices, which are further complicated by metallo-ß-lactamase production. This study evaluated in vitro antimicrobial synergy of ceftolozane/tazobactam in combination with aztreonam and fosfomycin against MDR PSA. METHODS: MICs were determined by broth microdilution and gradient strips. The effect of ceftolozane/tazobactam+aztreonam and ceftolozane/tazobactam+fosfomycin combinations were tested against 27 MDR PSA isolates carrying blaSPM-1 (n = 13), blaIMP (n = 4), blaVIM (n = 3), blaGES-1 (n = 2) and blaCTX-M-like (n = 2), and 3 isolates with no acquired ß-lactamase production detected by gradient diffusion strip crossing (GDSC). Six genetically unrelated SPM-1-producing isolates were also evaluated by time-kill analysis (TKA). RESULTS: All CR-PSA isolates harbouring blaSPM-1, blaGES-1 and blaIMP-1 were categorized as resistant to ceftolozane/tazobactam, meropenem and fosfomycin, with 70% being susceptible to aztreonam. Synergism for ceftolozane/tazobactam+fosfomycin and ceftolozane/tazobactam+aztreonam combinations was observed for 88.9% (24/27) and 18.5% (5/27) of the isolates by GDSC, respectively. A 3- to 9-fold reduction in ceftolozane/tazobactam MICs was observed, depending on the combination. Ceftolozane/tazobactam+fosfomycin was synergistic by TKA against one of six SPM-1-producing isolates, with additional non-synergistic bacterial density reduction for another isolate. Aztreonam peak concentrations alone demonstrated a ≥3 log10 cfu/mL reduction against all six isolates, but all strains were within the susceptible range for the drug. No antagonism was observed. CONCLUSIONS: In the context of increasing CR-PSA and the genetic diversity of resistance mechanisms, new combinations and stewardship strategies may need to be explored in the face of increasingly difficult to treat pathogens.
Assuntos
Fosfomicina , Infecções por Pseudomonas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Aztreonam/farmacologia , Cefalosporinas/farmacologia , Fosfomicina/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa , Tazobactam/farmacologiaRESUMO
The prevalence of carbapenem-resistant Pseudomonas aeruginosa is increasing. Identification of carbapenemase-producing P. aeruginosa will have therapeutic, epidemiological, and infection control implications. This study evaluated the performance of the EDTA-modified carbapenem inactivation method (eCIM) in tandem with the modified carbapenem inactivation method (mCIM) against a large collection of clinical P. aeruginosa isolates (n = 103) to provide clinicians a phenotypic test that not only identifies carbapenemase production but also distinguishes between metallo-ß-lactamase and serine-carbapenemase production in P. aeruginosa The mCIM test was performed according to Clinical and Laboratory Standards Institute guidelines, while the eCIM was conducted as previously described for Enterobacteriaceae Test performance was compared to the genotypic profile as the reference. mCIM testing successfully categorized 91% (112/123) of P. aeruginosa isolates as carbapenemases or non-carbapenemase producers, with discordant isolates being primarily Guiana extended-spectrum (GES)-type producers. To increase the sensitivity of the mCIM for GES-harboring isolates, a double inoculum, prolonged incubation, or both was evaluated, with each modification improving sensitivity to 100% (12/12). Upon eCIM testing, all Verona integrin-encoded metallo-ß-lactamases (VIM; n = 27) and New Delhi metallo-ß-lactamases (NDM; n = 13) tested had 100% concordance to their genotypic profiles, whereas all Klebsiella pneumoniae carbapenemase (KPC; n = 8) and GES (n = 12) isolates tested negative, as expected, in the presence of EDTA. The eCIM failed to identify all imipenemase (IMP)-producing (n = 22) and Sao Paulo metallo-ß-lactamase (SPM)-producing (n = 14) isolates. KPC-, VIM-, and NDM-producing P. aeruginosa were well defined by the conventional mCIM and eCIM testing methods; additional modifications appear required to differentiate GES-, IMP-, and SPM-producing isolates.
Assuntos
Pseudomonas aeruginosa , beta-Lactamases , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Brasil , Carbapenêmicos/farmacologia , Ácido Edético/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/genética , beta-Lactamases/genéticaRESUMO
BACKGROUND: Staphylococcus aureus is one of the major causes of bloodstream infections (BSI) worldwide, representing a major challenge for public health due to its resistance profile. Higher vancomycin minimum inhibitory concentrations (MIC) in S. aureus are associated with treatment failure and defining optimal empiric options for BSIs in settings where these isolates are prevalent is rather challenging. In silico pharmacodynamic models based on stochastic simulations (Monte Carlo) are important tools to estimate best antimicrobial regimens in different scenarios. We aimed to compare the pharmacodynamic profiles of different antimicrobials regimens for the treatment of S. aureus BSI in an environment with high vancomycin MIC. METHODS: Steady-state drug area under the curve ratio to MIC (AUC/MIC) or the percent time above MIC (fT > MIC) were modeled using a 5000-patient Monte Carlo simulation to achieve pharmacodynamic exposures against 110 consecutive S. aureus isolates associated with BSI. RESULTS: Cumulative fractions of response (CFRs) against all S. aureus isolates were 98% for ceftaroline; 79% and 92% for daptomycin 6 mg/kg q24h and for the high dose of 10 mg/kg q24h, respectively; 77% for linezolid 600 mg q12h when MIC was read according to CLSI M100-S26 instructions, and 64% when MIC was considered at the total growth inhibition; 65% and 86% for teicoplanin, three loading doses of 400 mg q12 h followed by 400 mg q24 h and for teicoplanin 400 mg q12 h, respectively; 61% and 76% for vancomycin 1000 mg q12 h and q8 h, respectively. CONCLUSIONS: Based on this model, ceftaroline and high-dose daptomycin regimens delivered best pharmacodynamic exposures against S. aureus BSIs. Teicoplanin higher dose regimen achieved the best CFR (86%) among glycopeptides, although optimal threshold was not achieved, and vancomycin performance was critically affected by the S. aureus vancomycin MIC ≥2 mg/L. Linezolid effectiveness (CFR of 73%) is also affected by high prevalence of isolates with linezolid MIC ≥2 mg/L. These data show the need to continually evaluate the pharmacodynamic profiles of antimicrobials for empiric treatment of these infections.
Assuntos
Antibacterianos/farmacologia , Bacteriemia/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Vancomicina/farmacologia , Antibacterianos/farmacocinética , Bacteriemia/microbiologia , Brasil , Cefalosporinas/farmacocinética , Cefalosporinas/farmacologia , Daptomicina/farmacocinética , Daptomicina/farmacologia , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Estudos Retrospectivos , Infecções Estafilocócicas/microbiologia , Vancomicina/farmacocinética , CeftarolinaRESUMO
PURPOSE: A case of vancomycin enzyme immunoassay (EIA) interference confirmed by high-performance liquid chromatography (HPLC) is described. SUMMARY: Therapeutic drug monitoring is standard of practice in vancomycin dosing and monitoring in order to maximize the pharmacodynamic effects and minimize toxicity. After a 52-year-old woman received 5 doses of vancomycin, serum concentrations continued to rise for several days in the absence of ongoing vancomycin administration. Despite persistently elevated vancomycin concentrations, the patient clinically deteriorated and required treatment with an alternative agent. Subsequently, serum concentrations were processed via HPLC and analyzed for percent protein binding. Confirmatory analysis revealed substantially lower concentrations by HPLC than were obtained by EIA and an abnormal elevation in protein binding. After discharge from the index admission, the patient returned 11 months later and had a dectectable vancomycin concentration by EIA prior to receipt of vancomycin. HPLC analysis confirmed the true concentration was undetectable. Though the exact interfering substance was not identified, the above discrepancy in concentrations between the two assay methods indicates the presence of assay interference, and adds to the available literature suggesting similar occurrences. This case is particularly troubling given that the level of interference was not such that it would lead a clinician to immediately suspect interference, and the patient experienced treatment failure. CONCLUSION: Falsely elevated values for serum vancomycin concentration, measured by EIA, contributed to treatment failure in a patient. The substance presumably responsible for EIA interferences was not identified.
Assuntos
Antibacterianos/sangue , Monitoramento de Medicamentos/métodos , Técnicas Imunoenzimáticas , Vancomicina/sangue , Cromatografia Líquida de Alta Pressão , Reações Falso-Positivas , Feminino , Humanos , Pessoa de Meia-Idade , Falha de TratamentoRESUMO
OBJECTIVES: This study was designed to simulate standard and optimized dosing regimens for intravenous antibiotics against contemporary populations of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa using MIC distribution data to determine which of the tested carbapenem regimens provided the greatest opportunity for obtaining maximal pharmacodynamic (PD) activity. METHODS: The isolates studied were obtained from the COMPACT-COLOMBIA surveillance program conducted between February and November 2009. Antimicrobial susceptibility testing was conducted by broth microdilution method according to the CLSI guidelines. Doripenem, imipenem-cilastatin, and meropenem, were the modeled antibiotics. A 5,000 patient Monte Carlo simulation was performed for each regimen and PD targets were defined as free drug concentrations above the MIC for at least 40 percent of the dosing interval. RESULTS: All carbapenem regimens obtained optimal exposures against E. coli, unlike the other Enterobacteriaceae tested. Against P. aeruginosa, only a prolonged infusion of doripenem exceeded the 90 percent cumulative fraction of response (CFR) threshold. Worrisomely, no regimens for any of the drugs tested obtained optimal CFR against A. baumannii. For P. aeruginosa intensive care unit (ICU) isolates, CFR was approximately 20 percent lower for isolates collected in the respiratory tract compared with bloodstream or intra-abdominal for imipenem and meropenem. Noteworthy, all doripenem and meropenem regimens achieved greater than 90 percent CFR against bloodstream and respiratory isolates of K. pneumoniae. CONCLUSIONS: Our data suggests that higher dosing and prolonged infusion of doripenem or meropenem may be suitable for empirically treating ICU P. aeruginosa, while none of the carbapenems achieved optimal cumulative fraction of response against A. baumannii. Standard dosing regimens of all the carbapenems tested achieved optimal CFR against E. coli isolates, but higher carbapenem dosages might be required for empiric treatment of K. pneumoniae, particularly from an intra-abdominal source. Non-standard dosage regimens studied in this modeling should be proven effective in prospective clinical trials.
Assuntos
Humanos , Antibacterianos/farmacologia , Carbapenêmicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Imipenem/farmacologia , Tienamicinas/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacocinética , Colômbia , Carbapenêmicos/farmacocinética , Escherichia coli/efeitos dos fármacos , Bactérias Gram-Negativas/metabolismo , Infecções por Bactérias Gram-Negativas/metabolismo , Infecções por Bactérias Gram-Negativas/microbiologia , Infusões Intravenosas , Unidades de Terapia Intensiva , Imipenem/farmacocinética , Klebsiella pneumoniae/efeitos dos fármacos , Método de Monte Carlo , Testes de Sensibilidade Microbiana/métodos , Pseudomonas aeruginosa/efeitos dos fármacos , Tienamicinas/farmacocinéticaRESUMO
OBJECTIVES: This study was designed to simulate standard and optimized dosing regimens for intravenous antibiotics against contemporary populations of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa using MIC distribution data to determine which of the tested carbapenem regimens provided the greatest opportunity for obtaining maximal pharmacodynamic (PD) activity. METHODS: The isolates studied were obtained from the COMPACT-COLOMBIA surveillance program conducted between February and November 2009. Antimicrobial susceptibility testing was conducted by broth microdilution method according to the CLSI guidelines. Doripenem, imipenem-cilastatin, and meropenem, were the modeled antibiotics. A 5,000 patient Monte Carlo simulation was performed for each regimen and PD targets were defined as free drug concentrations above the MIC for at least 40% of the dosing interval. RESULTS: All carbapenem regimens obtained optimal exposures against E. coli, unlike the other Enterobacteriaceae tested. Against P. aeruginosa, only a prolonged infusion of doripenem exceeded the 90% cumulative fraction of response (CFR) threshold. Worrisomely, no regimens for any of the drugs tested obtained optimal CFR against A. baumannii. For P. aeruginosa intensive care unit (ICU) isolates, CFR was approximately 20% lower for isolates collected in the respiratory tract compared with bloodstream or intra-abdominal for imipenem and meropenem. Noteworthy, all doripenem and meropenem regimens achieved greater than 90% CFR against bloodstream and respiratory isolates of K. pneumoniae. CONCLUSIONS: Our data suggests that higher dosing and prolonged infusion of doripenem or meropenem may be suitable for empirically treating ICU P. aeruginosa, while none of the carbapenems achieved optimal cumulative fraction of response against A. baumannii. Standard dosing regimens of all the carbapenems tested achieved optimal CFR against E. coli isolates, but higher carbapenem dosages might be required for empiric treatment of K. pneumoniae, particularly from an intra-abdominal source. Non-standard dosage regimens studied in this modeling should be proven effective in prospective clinical trials.
Assuntos
Antibacterianos/farmacologia , Carbapenêmicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Imipenem/farmacologia , Tienamicinas/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacocinética , Carbapenêmicos/farmacocinética , Colômbia , Doripenem , Escherichia coli/efeitos dos fármacos , Bactérias Gram-Negativas/metabolismo , Infecções por Bactérias Gram-Negativas/metabolismo , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Imipenem/farmacocinética , Infusões Intravenosas , Unidades de Terapia Intensiva , Klebsiella pneumoniae/efeitos dos fármacos , Meropeném , Testes de Sensibilidade Microbiana/métodos , Método de Monte Carlo , Pseudomonas aeruginosa/efeitos dos fármacos , Tienamicinas/farmacocinéticaRESUMO
The rapidly escalating prevalence of antimicrobial resistance is a global concern. This reduced susceptibility to currently available antimicrobial agents coupled with the progressive shortage of newly approved compounds is a worrisome situation. Major problems are encountered for a growing number of Gram-positive (i.e., Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus spp.) and Gram-negative pathogens (i.e., Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae). We provide an overview of bacterial resistance focusing on the most common pathogens responsible for infection in both the community and healthcare settings. In addition, several strategies to curb antimicrobial resistance are also discussed. It is increasingly evident that without the introduction of novel antimicrobial agents, a return to the clinical outcomes associated with the pre-antibiotic era are inevitable.