RESUMEN
Ceftazidime-avibactam was used to treat 77 patients with carbapenem-resistant Enterobacteriaceae (CRE) infections at our center. Thirty- and 90-day survival rates were 81% and 69%, respectively; these rates were higher than those predicted by SAPS II and SOFA scores at the onset of infection. Clinical success was achieved for 55% of patients but differed by the site of infection. Success rates were lowest for pneumonia (36%) and higher for bacteremia (75%) and urinary tract infections (88%). By multivariate analysis, pneumonia (P = 0.045) and receipt of renal replacement therapy (RRT) (P = 0.046) were associated with clinical failure. Microbiologic failures occurred in 32% of patients and occurred more commonly among patients infected with KPC-3-producing CRE than among those infected with KPC-2-producing CRE (P = 0.002). Pneumonia was an independent predictor of microbiologic failure (P = 0.007). Ceftazidime-avibactam resistance emerged in 10% of patients, including 14% of those infected with Klebsiella pneumoniae and 32% of those with microbiologic failure. RRT was an independent predictor of the development of resistance (P = 0.009). Resistance was identified exclusively among K. pneumoniae bacteria harboring variant KPC-3 enzymes. Upon phylogenetic analysis of whole-genome sequences, resistant isolates from 87.5% (7/8) of patients clustered within a previously defined sequence type 258 (ST258) clade II sublineage; resistant isolates from one patient clustered independently from other ST258 clade II isolates. In conclusion, our report offers new insights into the utility and limitations of ceftazidime-avibactam across CRE infection types. Immediate priorities are to identify ceftazidime-avibactam dosing and therapeutic regimens that improve on the poor outcomes among patients with pneumonia and those receiving RRT.
Asunto(s)
Compuestos de Azabiciclo/uso terapéutico , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Enterobacteriaceae Resistentes a los Carbapenémicos/patogenicidad , Ceftazidima/uso terapéutico , Neumonía/complicaciones , Terapia de Reemplazo Renal/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Combinación de Medicamentos , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Infecciones por Enterobacteriaceae/microbiología , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenRESUMEN
Ceftazidime-avibactam and ceftolozane-tazobactam are newly approved agents for the treatment of infections caused by multidrug-resistant Gram-negative bacteria. Resistance to both agents has been described clinically. Susceptibility testing on automated systems is unavailable for either agent. Our objective was to compare the disk diffusion and Etest methods to standard broth microdilution (BMD) methods for testing ceftazidime-avibactam and ceftolozane-tazobactam against a diverse collection of carbapenem-resistant Enterobacteriaceae (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRP) isolates, respectively. Among 74 ceftazidime-avibactam-susceptible and -resistant CRE isolates, BMD categorical agreement was higher with Etest (96%) than with disk diffusion (72%; P = 0.0003). Twenty-eight percent of ceftazidime-avibactam-susceptible CRE isolates were classified as resistant by disk diffusion. Results were comparable to those obtained with resistance defined genotypically. Among 72 ceftolozane-tazobactam-susceptible and -resistant CRP isolates, the levels of BMD categorical agreement with disk diffusion and Etest were 94% and 96%, respectively; the only errors identified were minor. Our findings demonstrate that Etest measurements of ceftazidime-avibactam and ceftolozane-tazobactam susceptibility correlate closely with standard BMD methods, suggesting a useful role clinically. On the other hand, disk diffusion measurements overcalled CRE resistance to ceftazidime-avibactam. A better understanding of ceftazidime-avibactam interpretive breakpoints is needed before disk diffusion is used routinely in the clinic. Until clinicians and microbiologists understand Etest and disk diffusion performance at their centers, test results should be interpreted cautiously.
Asunto(s)
Compuestos de Azabiciclo/farmacología , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Ceftazidima/farmacología , Cefalosporinas/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Tazobactam/farmacología , Antibacterianos/farmacología , Enterobacteriaceae Resistentes a los Carbapenémicos/aislamiento & purificación , Combinación de Medicamentos , Farmacorresistencia Bacteriana Múltiple/genética , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/aislamiento & purificaciónRESUMEN
Background: Data on the use of ceftolozane-tazobactam and emergence of ceftolozane-tazobactam resistance during multidrug resistant (MDR)-Pseudomonas aeruginosa infections are limited. Methods: We performed a retrospective study of 21 patients treated with ceftolozane-tazobactam for MDR-P. aeruginosa infections. Whole genome sequencing and quantitative real-time polymerase chain reaction were performed on longitudinal isolates. Results: Median age was 58 years; 9 patients (43%) were transplant recipients. Median simplified acute physiology score-II (SAPS-II) was 26. Eighteen (86%) patients were treated for respiratory tract infections; others were treated for bloodstream, complicated intraabdominal infections, or complicated urinary tract infections. Ceftolozane-tazobactam was discontinued in 1 patient (rash). Thirty-day all-cause and attributable mortality rates were 10% (2/21) and 5% (1/21), respectively; corresponding 90-day mortality rates were 48% (10/21) and 19% (4/21). The ceftolozane-tazobactam failure rate was 29% (6/21). SAPS-II score was the sole predictor of failure. Ceftolozane-tazobactam resistance emerged in 3 (14%) patients. Resistance was associated with de novo mutations, rather than acquisition of resistant nosocomial isolates. ampC overexpression and mutations were identified as potential resistance determinants. Conclusions: In this small study, ceftolozane-tazobactam was successful in treating 71% of patients with MDR-P. aeruginosa infections, most of whom had pneumonia. The emergence of ceftolozane-tazobactam resistance in 3 patients is worrisome and may be mediated in part by AmpC-related mechanisms. More research on treatment responses and resistance during various types of MDR-P. aeruginosa infections is needed to define ceftolozane-tazobactam's place in the armamentarium.
Asunto(s)
Antibacterianos , Cefalosporinas , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Ácido Penicilánico/análogos & derivados , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Cefalosporinas/farmacología , Cefalosporinas/uso terapéutico , Femenino , Genoma Bacteriano/genética , Humanos , Masculino , Persona de Mediana Edad , Ácido Penicilánico/farmacología , Ácido Penicilánico/uso terapéutico , Pennsylvania/epidemiología , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/epidemiología , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/genética , Estudios Retrospectivos , Tazobactam , Adulto JovenRESUMEN
We used meropenem to successfully treat a patient with bacteremia due to ceftazidime-avibactam-resistant, meropenem- susceptible Klebsiella pneumoniae that carried mutant blaKPC-3. Meropenem was bactericidal against ceftazidime-avibactam- resistant K pneumoniae isolates in vitro. Nevertheless, the role of carbapenems in treating such infections remains uncertain, because meropenem resistance is selected readily during passage experiments.
RESUMEN
There are no data comparing outcomes of patients treated with ceftazidime-avibactam versus comparators for carbapenem-resistant Enterobacteriaceae infections. At our center, ceftazidime-avibactam treatment of carbapenem-resistant Klebsiella pneumoniae bacteremia was associated with higher rates of clinical success (P = 0.006) and survival (P = 0.01) than other regimens. Across treatment groups, there were no differences in underlying diseases, severity of illness, source of bacteremia, or strain characteristics (97% produced K. pneumoniae carbapenemase). Aminoglycoside- and colistin-containing regimens were associated with increased rates of nephrotoxicity (P = 0.002).
Asunto(s)
Antibacterianos/uso terapéutico , Compuestos de Azabiciclo/uso terapéutico , Bacteriemia/tratamiento farmacológico , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Ceftazidima/uso terapéutico , Infecciones por Klebsiella/tratamiento farmacológico , Klebsiella pneumoniae/efectos de los fármacos , Inhibidores de beta-Lactamasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Bacterianas/metabolismo , Carbapenémicos/uso terapéutico , Combinación de Medicamentos , Farmacorresistencia Bacteriana Múltiple , Femenino , Humanos , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/aislamiento & purificación , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , beta-Lactamasas/metabolismoRESUMEN
Background: There is marked interest in using DNA-based methods to detect antimicrobial resistance (AMR), with targeted polymerase chain reaction (PCR) approaches increasingly being incorporated into clinical care. Whole-genome sequencing (WGS) could offer significant advantages over targeted PCR for AMR detection, particularly for species where mutations are major drivers of AMR. Methods: Illumina MiSeq WGS and broth microdilution (BMD) assays were performed on 90 bloodstream isolates of the 4 most common gram-negative bacteria causing bloodstream infections in neutropenic patients. The WGS data, including both gene presence/absence and detection of mutations in an array of AMR-relevant genes, were used to predict resistance to 4 ß-lactams commonly used in the empiric treatment of neutropenic fever. The genotypic predictions were then compared to phenotypic resistance as determined by BMD and by commercial methods during routine patient care. Results: Of 133 putative instances of resistance to the ß-lactams of interest identified by WGS, only 87 (65%) would have been detected by a typical PCR-based approach. The sensitivity, specificity, and positive and negative predictive values for WGS in predicting AMR were 0.87, 0.98, 0.97, and 0.91, respectively. Using BMD as the gold standard, our genotypic resistance prediction approach had a significantly higher positive predictive value compared to minimum inhibitory concentrations generated by commercial methods (0.97 vs 0.92; P = .025). Conclusions: These data demonstrate the potential feasibility of using WGS to guide antibiotic treatment decisions for patients with life-threatening infections for an array of medically important pathogens.
Asunto(s)
Genoma Bacteriano/genética , Bacterias Gramnegativas , Infecciones por Bacterias Gramnegativas/microbiología , Tipificación Molecular/métodos , Análisis de Secuencia de ADN/métodos , Resistencia betalactámica/genética , ADN Bacteriano/análisis , ADN Bacteriano/genética , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/genética , Humanos , Pruebas de Sensibilidad Microbiana , Sensibilidad y EspecificidadRESUMEN
Ceftazidime-avibactam resistance is mediated by blaKPC-3 mutations, which restore carbapenem susceptibility. We subjected Klebsiella pneumoniae isolates with different blaKPC-3 mutations (n = 5) or wild-type blaKPC-3 (n = 2) to serial passages with meropenem. The meropenem MIC against each isolate increased. Mutations in the ompK36 porin gene evolved in 5 isolates. Among isolates with D179Y substitutions in KPC-3, blaKPC-3 mutations reverted to wild type, were replaced by new mutations, or were retained. Carbapenem treatment of ceftazidime-avibactam-resistant K. pneumoniae infections may select for carbapenem resistance.
Asunto(s)
Antibacterianos/farmacología , Compuestos de Azabiciclo/farmacología , Proteínas Bacterianas/genética , Ceftazidima/farmacología , Farmacorresistencia Bacteriana Múltiple/genética , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/genética , Tienamicinas/farmacología , beta-Lactamasas/genética , Enterobacteriaceae Resistentes a los Carbapenémicos/genética , Combinación de Medicamentos , Humanos , Klebsiella pneumoniae/aislamiento & purificación , Meropenem , Pruebas de Sensibilidad Microbiana , Porinas/genética , Selección Genética/genéticaRESUMEN
Ceftazidime-avibactam is a novel ß-lactam/ß-lactamase inhibitor with activity against carbapenem-resistant Enterobacteriaceae (CRE) that produce Klebsiella pneumoniae carbapenemase (KPC). We report the first cases of ceftazidime-avibactam resistance to develop during treatment of CRE infections and identify resistance mechanisms. Ceftazidime-avibactam-resistant K. pneumoniae emerged in three patients after ceftazidime-avibactam treatment for 10 to 19 days. Whole-genome sequencing (WGS) of longitudinal ceftazidime-avibactam-susceptible and -resistant K. pneumoniae isolates was used to identify potential resistance mechanisms. WGS identified mutations in plasmid-borne blaKPC-3, which were not present in baseline isolates. blaKPC-3 mutations emerged independently in isolates of a novel sequence type 258 sublineage and resulted in variant KPC-3 enzymes. The mutations were validated as resistance determinants by measuring MICs of ceftazidime-avibactam and other agents following targeted gene disruption in K. pneumoniae, plasmid transfer, and blaKPC cloning into competent Escherichia coli In rank order, the impact of KPC-3 variants on ceftazidime-avibactam MICs was as follows: D179Y/T243M double substitution > D179Y > V240G. Remarkably, mutations reduced meropenem MICs ≥4-fold from baseline, restoring susceptibility in K. pneumoniae from two patients. Cefepime and ceftriaxone MICs were also reduced ≥4-fold against D179Y/T243M and D179Y variant isolates, but susceptibility was not restored. Reverse transcription-PCR revealed that expression of blaKPC-3 encoding D179Y/T243M and D179Y variants was diminished compared to blaKPC-3 expression in baseline isolates. In conclusion, the development of resistance-conferring blaKPC-3 mutations in K. pneumoniae within 10 to 19 days of ceftazidime-avibactam exposure is troubling, but clinical impact may be ameliorated if carbapenem susceptibility is restored in certain isolates.
Asunto(s)
Antibacterianos/farmacología , Compuestos de Azabiciclo/farmacología , Proteínas Bacterianas/genética , Ceftazidima/farmacología , Genoma Bacteriano , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/genética , Resistencia betalactámica/genética , beta-Lactamasas/genética , Anciano , Sustitución de Aminoácidos , Proteínas Bacterianas/metabolismo , Cefepima , Ceftriaxona/farmacología , Cefalosporinas/farmacología , Clonación Molecular , Combinación de Medicamentos , Escherichia coli/genética , Escherichia coli/metabolismo , Femenino , Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Infecciones por Klebsiella/tratamiento farmacológico , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/crecimiento & desarrollo , Klebsiella pneumoniae/aislamiento & purificación , Masculino , Meropenem , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Mutación , Plásmidos/química , Plásmidos/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Tienamicinas/farmacología , beta-Lactamasas/metabolismoRESUMEN
Thirty-seven carbapenem-resistant Enterobacteriaceae (CRE)-infected patients were treated with ceftazidime-avibactam. Clinical success and survival rates at 30 days were 59% (22/37) and 76% (28/37), respectively. In 23% (5/22) of clinical successes, CRE infections recurred within 90 days. Microbiologic failure rate was 27% (10/37). Ceftazidime-avibactam resistance was detected in 30% (3/10) of microbiologic failures.
Asunto(s)
Compuestos de Azabiciclo/uso terapéutico , Enterobacteriaceae Resistentes a los Carbapenémicos , Ceftazidima/uso terapéutico , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Inhibidores de beta-Lactamasas/uso terapéutico , Adulto , Anciano , Compuestos de Azabiciclo/efectos adversos , Ceftazidima/efectos adversos , Combinación de Medicamentos , Farmacorresistencia Bacteriana , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Inhibidores de beta-Lactamasas/efectos adversosRESUMEN
A novel and highly accurate diagnostic assay platform was established for rapid identification of FKS mutations associated with echinocandin resistance in Candida glabrata The assay platform uses allele-specific molecular beacon and DNA melt analysis following asymmetric PCR. A dual assay for FKS1 and FKS2 was developed to identify within 3 h the most common and clinically relevant resistance-associated mutations, including 8 FKS1 HS1 (wild type [WT], S629P, F625S, D632Y, D632E [T1896G], D632E [T1896A], I634V, and F625F) and 7 FKS2 HS1 (WT, F659del, F659S, F659V, F659L, S663P, and S663F) genotypes. A blinded panel of 188 C. glabrata clinical isolates was tested by both assays. The molecular diagnostic results from the dual assay were 100% concordant with data obtained from DNA sequencing. This platform has the potential to overcome the deficiencies of existing in vitro susceptibility-based assays to identify echinocandin-resistant C. glabrata and holds promise as a surrogate diagnostic method to better direct echinocandin therapy.
Asunto(s)
Candida glabrata/genética , ADN de Hongos/genética , Farmacorresistencia Fúngica/genética , Equinocandinas/farmacología , Proteínas Fúngicas/genética , Glucosiltransferasas/genética , Alelos , Antifúngicos/farmacología , Candida glabrata/efectos de los fármacos , Candida glabrata/enzimología , Candida glabrata/aislamiento & purificación , Candidiasis/microbiología , ADN de Hongos/química , Proteínas Fúngicas/metabolismo , Expresión Génica , Glucosiltransferasas/metabolismo , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Pruebas de Sensibilidad Microbiana , Sondas Moleculares/química , Mutación , Desnaturalización de Ácido Nucleico , Reacción en Cadena de la Polimerasa/métodos , Sensibilidad y EspecificidadRESUMEN
Aminoglycoside treatment of carbapenem-resistant (CR) Klebsiella pneumoniae bacteremia was associated with a 70% rate (23/33) of 30-day survival. Successful treatment was associated with sources of bacteremia amenable to reliable aminoglycoside pharmacokinetics (P = 0.037), acute physiology and chronic health evaluation II (APACHE II) scores of <20 (P = 0.16), and nonfatal underlying diseases (P = 0.015). Success rates were 78% and 100% if ≥2 and all 3 factors were present, respectively. Clinicians may consider the use of aminoglycosides against CR K. pneumoniae bacteremia if strains are susceptible and the sources of infection are amenable to reliable pharmacokinetics.
Asunto(s)
Aminoglicósidos/uso terapéutico , Antibacterianos/uso terapéutico , Bacteriemia/tratamiento farmacológico , Carbapenémicos/uso terapéutico , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/patogenicidad , Adulto , Anciano , Aminoglicósidos/farmacocinética , Antibacterianos/farmacocinética , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana EdadRESUMEN
We compared ceftazidime-avibactam, ceftolozane-tazobactam, ceftazidime, cefepime, and piperacillin-tazobactam MICs for 38 meropenem-resistant Pseudomonas aeruginosa isolates. No isolates harbored carbapenemases; 74% were oprD mutants. Ceftazidime-avibactam and ceftolozane-tazobactam were active against 92% of the isolates, including 80% that were resistant to all three ß-lactams. Forty-three percent of ceftazidime-avibactam-susceptible isolates and 6% of ceftolozane-tazobactam-susceptible isolates exhibited MICs at the respective breakpoints. Ceftolozane-tazobactam and ceftazidime-avibactam are therapeutic options for meropenem-resistant P. aeruginosa infections that should be used judiciously to preserve activity.
Asunto(s)
Compuestos de Azabiciclo/farmacología , Ceftazidima/farmacología , Cefalosporinas/farmacología , Ácido Penicilánico/análogos & derivados , Pseudomonas aeruginosa/efectos de los fármacos , Tienamicinas/farmacología , Combinación de Medicamentos , Farmacorresistencia Bacteriana/genética , Meropenem , Pruebas de Sensibilidad Microbiana , Ácido Penicilánico/farmacología , Pseudomonas aeruginosa/enzimología , TazobactamRESUMEN
Precise FKS mutation rates among Candida species are undefined because studies have not systematically screened consecutive, disease-causing isolates. The Sensititre YeastOne (SYO) assay measures echinocandin MICs against Candida with less variability than reference broth microdilution methods. However, clinical breakpoint MICs may overstate caspofungin nonsusceptibility compared to other agents. Our objectives were to determine Candida FKS mutation rates by studying consecutive bloodstream isolates and to determine if discrepant susceptibility results were associated with FKS mutations. FKS hot spots were sequenced in echinocandin-intermediate and -resistant isolates and those from patients with breakthrough candidemia or ≥ 3 days of prior echinocandin exposure. Overall, 453 isolates from 384 patients underwent susceptibility testing; 16% were echinocandin intermediate or resistant. Intermediate susceptibility rates were higher for Candida glabrata than for other species (P < 0.0001) and higher for caspofungin than for other agents (P < 0.0001). Resistance rates were similar between agents. FKS mutations were detected in 5% of sequenced isolates and 2% of isolates overall. Corresponding rates among C. glabrata isolates were 8% and 4%, respectively. Among Candida albicans isolates, rates were 5% and <1%, respectively. Mutations occurred exclusively with prior echinocandin exposure and were not detected in other species. Isolates with discrepant susceptibility results did not harbor FKS mutations. Mutation rates among isolates resistant to ≥ 2, 1, and 0 agents were 75%, 13%, and 0%, respectively. In conclusion, FKS mutations were uncommon among non-C. glabrata species, even with prior echinocandin exposure. Discrepancies in echinocandin susceptibility by SYO testing were not driven by mutations and likely reflect imprecise caspofungin clinical breakpoints.
Asunto(s)
Antifúngicos/farmacología , Candida/genética , Candida/patogenicidad , Proteínas Fúngicas/genética , Candida/efectos de los fármacos , Candida/aislamiento & purificación , Candida glabrata/efectos de los fármacos , Candida glabrata/genética , Candida glabrata/aislamiento & purificación , Candidiasis/sangre , Candidiasis/microbiología , Caspofungina , Farmacorresistencia Fúngica/genética , Equinocandinas/farmacología , Humanos , Lipopéptidos/farmacología , Micafungina , Pruebas de Sensibilidad Microbiana , Tasa de MutaciónRESUMEN
Avibactam is a novel ß-lactamase inhibitor with affinity for Klebsiella pneumoniae carbapenemases (KPCs). In combination with ceftazidime, the agent demonstrates activity against KPC-producing K. pneumoniae (KPC-Kp). KPC-Kp strains are genetically diverse and harbor multiple resistance determinants, including defects in outer membrane proteins and extended-spectrum ß-lactamases (ESBLs). Mutations in porin gene ompK36 confer high-level carbapenem resistance to KPC-Kp strains. Whether specific mechanisms of antimicrobial resistance also influence the activity of ceftazidime-avibactam is unknown. We defined the effects of ceftazidime-avibactam against 72 KPC-Kp strains with diverse mechanisms of resistance, including various combinations of KPC subtypes and ESBL and ompK36 mutations. Ceftazidime MICs ranged from 64 to 4,096 µg/ml and were lowered by a median of 512-fold with the addition of avibactam. All strains exhibited ceftazidime-avibactam MICs at or below the CLSI breakpoint for ceftazidime (≤4 µg/ml; range, 0.25 to 4). However, the MICs were within two 2-fold dilutions of the CLSI breakpoint against 24% of the strains, and those strains would be classified as nonsusceptible to ceftazidime by EUCAST criteria (MIC > 1 µg/ml). Median ceftazidime-avibactam MICs were higher against KPC-3 than KPC-2 variants (P = 0.02). Among KPC-2-Kp strains, the presence of both ESBL and porin mutations was associated with higher drug MICs compared to those seen with either factor alone (P = 0.003 and P = 0.02, respectively). In conclusion, ceftazidime-avibactam displays activity against genetically diverse KPC-Kp strains. Strains with higher-level drug MICs provide a reason for caution. Judicious use of ceftazidime-avibactam alone or in combination with other agents will be important to prevent the emergence of resistance.
Asunto(s)
Antibacterianos/farmacología , Compuestos de Azabiciclo/farmacología , Proteínas Bacterianas/metabolismo , Ceftazidima/farmacología , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/enzimología , Porinas/genética , Inhibidores de beta-Lactamasas/farmacología , beta-Lactamasas/metabolismo , Combinación de Medicamentos , Pruebas de Sensibilidad Microbiana , Mutación/genéticaRESUMEN
Treatment failures of a carbapenem-colistin regimen among patients with bacteremia due to sequence type 258 (ST258), KPC-2-producing Klebsiella pneumoniae were significantly more likely if both agents were inactive in vitro, as defined by a colistin MIC of >2 µg/ml and the presence of either a major ompK36 porin mutation (guanine and alanine insertions at amino acids 134 and 135 [ins aa 134-135 GD], IS5 promoter insertion [P = 0.007]) or a doripenem MIC of >8 µg/ml (P = 0.01). Major ompK36 mutations among KPC-K. pneumoniae strains are important determinants of carbapenem-colistin responses in vitro and in vivo.
Asunto(s)
Bacteriemia/tratamiento farmacológico , Proteínas Bacterianas/genética , Carbapenémicos/uso terapéutico , Colistina/uso terapéutico , Klebsiella pneumoniae/efectos de los fármacos , Porinas/genética , beta-Lactamasas/metabolismo , Adulto , Anciano , Antibacterianos/uso terapéutico , Bacteriemia/microbiología , Proteínas Bacterianas/metabolismo , Doripenem , Quimioterapia Combinada/métodos , Femenino , Genotipo , Humanos , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/metabolismo , Masculino , Pruebas de Sensibilidad Microbiana/métodos , Persona de Mediana Edad , Porinas/efectos de los fármacos , Porinas/metabolismo , Estudios RetrospectivosRESUMEN
FKS mutant Candida isolates were recovered from 24% (6/25) of abdominal candidiasis patients exposed to echinocandin. Candida glabrata (29%) and Candida albicans (14%) mutants were identified. Multidrug-resistant bacteria were recovered from 83% of FKS mutant infections. Mutations were associated with prolonged echinocandin exposure (P = 0.01), breakthrough infections (P = 0.03), and therapeutic failures despite source control interventions (100%). Abdominal candidiasis is a hidden reservoir for the emergence of echinocandin-resistant Candida.
Asunto(s)
Absceso Abdominal/microbiología , Antifúngicos/uso terapéutico , Candida albicans/efectos de los fármacos , Candida glabrata/efectos de los fármacos , Candidiasis/microbiología , Equinocandinas/uso terapéutico , Peritonitis/microbiología , Absceso Abdominal/tratamiento farmacológico , Absceso Abdominal/mortalidad , Absceso Abdominal/patología , Adulto , Anciano , Candida albicans/genética , Candida albicans/crecimiento & desarrollo , Candida glabrata/genética , Candida glabrata/crecimiento & desarrollo , Candidiasis/tratamiento farmacológico , Candidiasis/mortalidad , Candidiasis/patología , Farmacorresistencia Fúngica/genética , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Mutación , Peritonitis/tratamiento farmacológico , Peritonitis/mortalidad , Peritonitis/patología , Análisis de SupervivenciaRESUMEN
The aminoglycoside-modifying enzyme AAC(6')-Ib is common among carbapenem-resistant Klebsiella pneumoniae (CR-Kp) strains. We investigated amikacin (AMK) activity against 20 AAC(6')-Ib-producing CR-Kp strains. MICs clustered at 16 to 32 µg/ml. By the time-kill study, AMK (1× and 4× the MIC) was bactericidal against 30% and 85% of the strains, respectively. At achievable human serum concentrations, however, the majority of strains showed regrowth, suggesting that AAC(6')-Ib confers intermediate AMK resistance. AMK and trimethoprim-sulfamethoxazole (TMP-SMX) were synergistic against 90% of the strains, indicating that the combination may overcome resistance.
Asunto(s)
Acetiltransferasas/genética , Amicacina/farmacología , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Klebsiella pneumoniae/efectos de los fármacos , Combinación Trimetoprim y Sulfametoxazol/farmacología , Acetiltransferasas/metabolismo , Proteínas Bacterianas/metabolismo , Farmacorresistencia Bacteriana/efectos de los fármacos , Farmacorresistencia Bacteriana/genética , Sinergismo Farmacológico , Expresión Génica , Humanos , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/enzimología , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/crecimiento & desarrollo , Pruebas de Sensibilidad MicrobianaRESUMEN
We measured in vitro activity of plazomicin, a next-generation aminoglycoside, and other aminoglycosides against 50 carbapenem-resistant Klebsiella pneumoniae strains from two centers and correlated the results with the presence of various aminoglycoside-modifying enzymes (AMEs). Ninety-four percent of strains were sequence type 258 (ST258) clones, which exhibited 5 ompK36 genotypes; 80% and 10% of strains produced Klebsiella pneumoniae carbapenemase 2 (KPC-2) and KPC-3, respectively. Ninety-eight percent of strains possessed AMEs, including AAC(6')-Ib (98%), APH(3')-Ia (56%), AAC(3)-IV (38%), and ANT(2")-Ia (2%). Gentamicin, tobramycin, and amikacin nonsusceptibility rates were 40, 98, and 16%, respectively. Plazomicin MICs ranged from 0.25 to 1 µg/ml. Tobramycin and plazomicin MICs correlated with gentamicin MICs (r = 0.75 and 0.57, respectively). Plazomicin exerted bactericidal activity against 17% (1× MIC) and 94% (4× MIC) of strains. All strains with AAC(6')-Ib were tobramycin-resistant; 16% were nonsusceptible to amikacin. AAC(6')-Ib combined with another AME was associated with higher gentamicin, tobramycin, and plazomicin MICs than AAC(6')-Ib alone (P = 0.01, 0.0008, and 0.046, respectively). The presence of AAC(3)-IV in a strain was also associated with higher gentamicin, tobramycin, and plazomicin MICs (P = 0.0006, P < 0.0001, and P = 0.01, respectively). The combination of AAC(6')-Ib and another AME, the presence of AAC(3)-IV, and the presence of APH(3')-Ia were each associated with gentamicin resistance (P = 0.0002, 0.003, and 0.01, respectively). In conclusion, carbapenem-resistant K. pneumoniae strains (including ST258 clones) exhibit highly diverse antimicrobial resistance genotypes and phenotypes. Plazomicin may offer a treatment option against strains resistant to other aminoglycosides. The development of molecular assays that predict antimicrobial responses among carbapenem-resistant K. pneumoniae strains should be a research priority.
Asunto(s)
Antibacterianos/metabolismo , Farmacorresistencia Bacteriana Múltiple/genética , Klebsiella pneumoniae/enzimología , Sisomicina/análogos & derivados , Amicacina/metabolismo , Amicacina/farmacología , Aminoglicósidos/metabolismo , Aminoglicósidos/farmacología , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Combinación de Medicamentos , Pruebas de Enzimas , Expresión Génica , Gentamicinas/metabolismo , Gentamicinas/farmacología , Isoenzimas/genética , Isoenzimas/metabolismo , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/crecimiento & desarrollo , Pruebas de Sensibilidad Microbiana , Sisomicina/metabolismo , Sisomicina/farmacología , Resistencia betalactámica/genética , beta-Lactamasas/genética , beta-Lactamasas/metabolismo , beta-Lactamas/farmacologíaRESUMEN
We compared in vitro killing of colistin, doripenem, and sulbactam by time-kill methods against Acinetobacter baumannii isolates collected from patients before and after colistin-doripenem treatment (initial and recurrent isolates, respectively). Colistin-doripenem bactericidal activity against recurrent isolates was attenuated (mean log10 kill, -5.74 versus -2.88; P = 0.01) but was restored by adding sulbactam. Doripenem MICs rather than colistin MICs correlated with the activity of colistin-doripenem. Among colistin-resistant isolates, colistin-doripenem-sulbactam combinations achieved greater killing than colistin-doripenem alone (-5.65 versus -2.43; P = 0.04).