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BACKGROUND: Vancomycin (VAN)-associated acute kidney injury (AKI) is increased when VAN is combined with certain beta-lactams (BLs) such as piperacillin-tazobactam (TZP) but has not been evaluated with ceftolozane-tazobactam (C/T). Our aim was to investigate the AKI incidence of VAN in combination with C/T (VAN/C/T) compared with VAN in combination to TZP (VAN-TZP). METHODS: We conducted a multicenter, observational, comparative study across the United States. The primary analysis was a composite outcome of AKI and risk, injury, failure, loss, end stage renal disease; Acute Kidney Injury Network; or VAN-induced nephrotoxicity according to the consensus guidelines. Multivariable logistic regression analysis was conducted to adjust for confounding variables and stratified Kaplan-Meir analysis to assess the time to nephrotoxicity between the 2 groups. RESULTS: We included VAN/C/T (n = 90) and VAN-TZP (n = 284) at an enrollment ratio of 3:1. The primary outcome occurred in 12.2% vs 25.0% in the VAN-C/T and VAN-TZP groups, respectively (P = .011). After adjusting for confounding variables, VAN-TZP was associated with increased odds of AKI compared with VAN-C/T; with an adjusted odds ratio of 3.308 (95% confidence interval, 1.560-6.993). Results of the stratified Kaplan-Meir analysis with log-rank time-to-nephrotoxicity analysis indicate that time to AKI was significantly shorter among patients who received VAN-TZP (P = .004). Cox proportional hazards analysis demonstrated that TZP was consistent with the primary analysis (P = .001). CONCLUSIONS: Collectively, our results suggest that the AKI is not likely to be related to tazobactam but rather to piperacillin, which is a component in VAN-TZP but not in VAN-C/T.
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Lesión Renal Aguda , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Vancomicina/efectos adversos , Antibacterianos/efectos adversos , beta-Lactamas/efectos adversos , Estudios Retrospectivos , Combinación Piperacilina y Tazobactam/efectos adversos , Tazobactam/efectos adversos , Piperacilina/efectos adversos , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/tratamiento farmacológico , Quimioterapia CombinadaRESUMEN
Pseudomonas aeruginosa-associated infective endocarditis represents difficult-to-treat, deep-seated infections. Phage-antibiotic combinations have shown to eradicate multi-drug resistant (MDR) P. aeruginosa, limit the development of phage resistance, and restore antibiotic sensitivity. The objective of this study was to evaluate the activity of phage-ciprofloxacin (CIP) combinations in 4-day ex vivo simulated endocardial vegetation (SEV) models against drug-resistant P. aeruginosa isolates. Two P. aeruginosa isolates, extensively drug-resistant AR351 and MDR I0003-1, were selected for their drug resistance and sensitivity to phage. Three phages [LL-5504721-AH (LL), E2005-C (EC), and 109] and CIP were evaluated alone and in combination for their activity and influence on drug and phage resistance using 24-h time-kill analysis. The three-phage cocktail (q24h) in combination with CIP (400 mg q12h) was then tested in dynamic 4-day ex vivo SEV models, with reduction of log10 CFU/mL compared using ANOVA with Bonferroni analysis. Compared to other combinations, CIP-LL-EC-109 demonstrated synergistic and bactericidal activity from starting CFU/g against AR351 and I0003-1 (-Δ5.65 and 6.60 log10 CFU/g, respectively; P < 0.001). Additionally, CIP-LL-EC-109 mitigated phage resistance, while all other therapies had a high degree of resistance to >1 phages, and all phage-containing regimens prevented CIP mean inhibitory concentration increases compared to CIP alone for both AR351 and I0003-1 at 96 h.
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Bacteriófagos , Infecciones por Pseudomonas , Humanos , Ciprofloxacina/farmacología , Pseudomonas aeruginosa , Antibacterianos/farmacología , Infecciones por Pseudomonas/terapiaRESUMEN
Biofilm-associated infections lead to substantial morbidity. Omadacycline (OMC) is a novel aminomethylcycline with potent in vitro activity against Staphylococcus aureus and Staphylococcus epidermidis, but data surrounding its use in biofilm-associated infections are lacking. We investigated the activity of OMC alone and in combination with rifampin (RIF) against 20 clinical strains of staphylococci in multiple in vitro biofilm analyses, including an in vitro pharmacokinetic/pharmacodynamic (PK/PD) CDC biofilm reactor (CBR) model (simulating human exposures). The observed MICs for OMC demonstrated potent activity against the evaluated strains (0.125 to 1 mg/L), with an increase of MICs generally observed in the presence of biofilm (0.25 to >64 mg/L). Furthermore, RIF was shown to reduce OMC biofilm MICs (bMICs) in 90% of strains, and OMC plus RIF combination in biofilm time-kill analyses (TKAs) exhibited synergistic activity in most of the strains. Within the PK/PD CBR model, OMC monotherapy primarily displayed bacteriostatic activity, while RIF monotherapy generally exhibited initial bacterial eradication, followed by rapid regrowth likely due to the emergence of RIF resistance (RIF bMIC, >64 mg/L). However, the combination of OMC plus RIF produced rapid and sustained bactericidal activity in nearly all the strains (3.76 to 4.03 log10 CFU/cm2 reductions from starting inoculum in strains in which bactericidal activity was reached). Furthermore, OMC was shown to prevent the emergence of RIF resistance. Our data provide preliminary evidence that OMC in combination with RIF could be a viable option for biofilm-associated infections with S. aureus and S. epidermidis. Further research involving OMC in biofilm-associated infections is warranted.
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Rifampin , Infecciones Estafilocócicas , Humanos , Rifampin/farmacología , Staphylococcus aureus , Antibacterianos/farmacología , Staphylococcus epidermidis , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Biopelículas , Pruebas de Sensibilidad MicrobianaRESUMEN
Biofilm-producing Pseudomonas aeruginosa infections pose a severe threat to public health and are responsible for high morbidity and mortality. Phage-antibiotic combinations (PACs) are a promising strategy for combatting multidrug-resistant (MDR), extensively drug-resistant (XDR), and difficult-to-treat P. aeruginosa infections. Ten MDR/XDR P. aeruginosa strains and five P. aeruginosa-specific phages were genetically characterized and evaluated based upon their antibiotic susceptibilities and phage sensitivities. Two selected strains, AR351 (XDR) and I0003-1 (MDR), were treated singly and in combination with either a broad-spectrum or narrow-spectrum phage, phage EM-T3762627-2_AH (EM), or 14207, respectively, and bactericidal antibiotics of five classes in biofilm time-kill analyses. Synergy and/or bactericidal activity was demonstrated with all PACs against one or both drug-resistant P. aeruginosa strains (average reduction: -Δ3.32 log10 CFU/cm2). Slightly improved ciprofloxacin susceptibility was observed in both strains after exposure to phages (EM and 14207) in combination with ciprofloxacin and colistin. Based on phage cocktail optimization with four phages (EM, 14207, E20050-C (EC), and 109), we identified several effective phage-antibiotic cocktails for further analysis in a 4-day pharmacokinetic/pharmacodynamic in vitro biofilm model. Three-phage cocktail, EM + EC + 109, in combination with ciprofloxacin demonstrated the greatest biofilm reduction against AR351 (-Δ4.70 log10 CFU/cm2 from baseline). Of remarkable interest, the addition of phage 109 prevented phage resistance development to EM and EC in the biofilm model. PACs can demonstrate synergy and offer enhanced eradication of biofilm against drug-resistant P. aeruginosa while preventing the emergence of resistance.
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Bacteriófagos , Infecciones por Pseudomonas , Humanos , Pseudomonas aeruginosa , Antibacterianos/farmacología , Ciprofloxacina/farmacología , Infecciones por Pseudomonas/tratamiento farmacológico , BiopelículasRESUMEN
Infections due to nontuberculous mycobacteria (NTM) continue to increase in prevalence, leading to problematic clinical outcomes. Omadacycline (OMC) is an aminomethylcycline antibiotic with FDA orphan drug and fast-track designations for pulmonary NTM infections, including Mycobacteroides abscessus (MAB). This multicenter retrospective study across 16 U.S. medical institutions from January 2020 to March 2023 examined the long-term clinical success, safety, and tolerability of OMC for NTM infections. The cohort included patients aged ≥18 yr, who were clinically evaluable, and` had been treated with OMC for ≥3 mo without a previous diagnosis of cystic fibrosis. The primary outcome was 3 mo clinical success, with secondary outcomes including clinical improvement and mortality at 6- and 12 mo, persistence or reemergence of infection, adverse effects, and reasons for OMC utilization. Seventy-five patients were included in this analysis. Most patients were female (48/75, 64.0%) or Caucasian (58/75, 77.3%), with a median (IQR) age of 59 yr (49-67). Most had NTM pulmonary disease (33/75, 44.0%), skin and soft tissue disease (19/75, 25.3%), or osteomyelitis (10/75, 13.3%), and Mycobacterium abscessus (60/75, 80%) was the most commonly isolated NTM pathogen. The median (IQR) treatment duration was 6 mo (4 - 14), and the most commonly co-administered antibiotic was azithromycin (33/70, 47.1%). Three-month clinical success was observed in 80.0% (60/75) of patients, and AEs attributable to OMC occurred in 32.0% (24/75) of patients, leading to drug discontinuation in 9.3% (7/75).
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Fibrosis Quística , Infecciones por Mycobacterium no Tuberculosas , Mycobacterium abscessus , Humanos , Femenino , Masculino , Estudios Retrospectivos , Infecciones por Mycobacterium no Tuberculosas/microbiología , Micobacterias no Tuberculosas , Fibrosis Quística/microbiología , Antibacterianos/efectos adversos , Evaluación de Resultado en la Atención de SaludRESUMEN
Enterococcus faecium is a significant multidrug-resistant pathogen. Bacteriophage cocktails are being proposed to complement antibiotic therapy. After a screen of 8 E. faecium strains against 4 phages, 2 phages (113 and 9184) with the broadest host ranges were chosen for further experiments. Transmission electron microscopy, whole-genome sequencing, comparative genome analyses, and time-kill analyses were performed. Daptomycin (DAP) plus the phage cocktail (113 [myophage] and 9184 [siphopage]) showed bactericidal activity in most regimens, while DAP addition prevented phage 9184 resistance against daptomycin-nonsusceptible E. faecium.
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Bacteriófagos , Daptomicina , Enterococcus faecium , Antibacterianos/farmacología , Bacteriófagos/genética , Daptomicina/farmacología , Enterococcus faecium/genética , Pruebas de Sensibilidad MicrobianaRESUMEN
AIMS: Here, we investigate the impact of phage-antibiotic combinations (PAC) on bacterial killing, resistance development and outer membrane vesicle (OMV) production in multidrug-resistant (MDR) P. aeruginosa. METHODS AND RESULTS: After screening 10 well-characterized MDR P. aeruginosa strains against three P. aeruginosa phages, representative strains, R10266 and R9316, were selected for synergy testing based on high phage sensitivity and substantial antibiotic resistance patterns, while phage EM was chosen based on host range. To understand the impact of phage-antibiotic combinations (PAC) against MDR P. aeruginosa, time-kill analyses, OMV quantification and phage/antibiotic resistance testing were performed. Phage and meropenem demonstrated synergistic activity against both MDR strains. Triple combination regimens, phage-meropenem-colistin and phage-ciprofloxacin-colistin, resulted in the greatest CFU reduction for strains R9316 (3.50 log10 CFU ml-1 ) and R10266 (4.50 log10 CFU ml-1 ) respectively. PAC resulted in regained and improved antibiotic susceptibility to ciprofloxacin (MIC 2 to 0.0625) and meropenem (MIC 32 to 16), respectively, in R9316. Phage resistance was prevented or reduced in the presence of several classes of antibiotics and OMV production was reduced in the presence of phage for both strains, which was associated with significantly improved bacterial eradication. CONCLUSIONS: These findings support the potential of phage-antibiotic synergy (PAS) to augment killing of MDR P. aeruginosa. Systematic in vitro and in vivo studies are needed to better understand phage interactions with antipseudomonal antibiotics, to define the role of OMV production in P. aeruginosa PAC therapy and to outline pharmacokinetic and pharmacodynamic parameters conducive to PAS. SIGNIFICANCE AND IMPACT OF STUDY: This study identifies novel bactericidal phage-antibiotic combinations capable of thwarting resistance development in MDR and XDR P. aeruginosa strains. Furthermore, phage-mediated OMV reduction is identified as a potential mechanism through which PAC potentiates bacterial killing.
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Bacteriófagos , Infecciones por Pseudomonas , Antibacterianos/farmacología , Ciprofloxacina/farmacología , Colistina/farmacología , Farmacorresistencia Bacteriana Múltiple , Sinergismo Farmacológico , Humanos , Meropenem/farmacología , Pruebas de Sensibilidad Microbiana , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosaRESUMEN
Drug-resistant tuberculosis (TB) is a major public health concern and contributes to high morbidity and mortality. New evidence supports the use of shorter duration, all-oral regimens, which represent an encouraging treatment strategy for drug-resistant TB. As a result, the landscape of drug-resistant TB pharmacotherapy has drastically evolved regarding treatment principles and preferred agents. This narrative review focuses on the key updates of drug-resistant TB treatment, including the use of short-duration all-oral regimens, while calling attention to current gaps in knowledge that may be addressed in future observational studies.
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Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , PulmónRESUMEN
Antibiotics are amongst the most prescribed medications globally in both inpatient and outpatient settings. Antibiotic-induced neuropsychiatric toxicity is relatively uncommon; yet, when it occurs, it can lead to severe morbidity ranging from dizziness and confusion to seizure and psychosis. However, the actual incidence rate of these adverse events may be higher due to underdiagnosis or misdiagnosis as they are commonly confused with clinical manifestations of different neuropsychiatric conditions. The incidence and mechanism of antibiotic-induced neuropsychiatric toxicity vary between different antibiotic classes and clinical presentation (i.e. neurotoxicity versus psychiatric toxicity). However, the exact mechanism by which antibiotics can cause neuropsychiatric toxicity remains unclear. This article reviews the epidemiology of antibiotic-induced neuropsychiatric toxicity, explores potential mechanisms of this adverse event, investigates variations in frequency and clinical presentations between different antibiotic classes causing neuropsychiatric toxicity, and discusses management strategies.
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BACKGROUND: Dental appointments offer an opportunity to evaluate a documented penicillin (PCN) allergy and determine whether the patient might be a candidate for medical reassessment of their allergy. The authors gathered feedback on the Penicillin Allergy Reassessment for Treatment Improvement (PARTI) tool, designed to enhance dentist-patient communications regarding PCN allergies. METHODS: From January 2022 through May 2023, the authors conducted a mixed-methods study, collecting focus group data from patients with PCN allergies and surveying health care workers (HCWs) regarding the PARTI tool. Feedback focused on reassessment procedures, patient-centered allergy information, and medical records updates. Thematic analysis was used for focus group data. RESULTS: The study included 15 patients in focus groups and 50 HCW survey respondents representing diverse US regions. Patient demographic characteristics included varied races, the mean age was 52 years, and most of the patients were female (53.3%). Most patients had health care interactions within the preceding year, at which 86.6% of patients were asked about drug allergies. HCW respondents primarily consisted of pharmacists (30%) and dentists, dental hygienists, and dental assistants (28%). Feedback on the PARTI tool was constructive, with both patients and HCWs recognizing its potential benefits and providing insights for improvement. Many HCWs (68%) highlighted the importance of step 3 of the PARTI tool, that is, the section on PCN allergy testing. Feedback from participants was incorporated into the final PARTI tool. CONCLUSIONS: Patient and HCW feedback on the PARTI tool was used to finalize a tool for the dental office to provide to patients who are candidates for PCN allergy reassessment. The feedback will also be used to inform an upcoming pilot study in US dental offices, focused on the process for PCN allergy reassessment and health record documentation. PRACTICAL IMPLICATIONS: Deploying the PARTI tool in dental offices is pivotal, as mislabeling patients with PCN allergies could have severe consequences, such as hindering the prescription of lifesaving antibiotics for conditions like endocarditis, in the future. This implementation not only enhances communication between dentists and patients, but it is also crucial for ensuring improved patient safety and maintaining accurate medical records among health care settings.
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Hipersensibilidad a las Drogas , Penicilinas , Humanos , Femenino , Penicilinas/efectos adversos , Masculino , Persona de Mediana Edad , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Consultorios Odontológicos , Grupos Focales , Adulto , Etiquetado de MedicamentosRESUMEN
Multi-drug resistant gram-negative bacteria present a significant global health threat. Cefiderocol (CFDC), a siderophore cephalosporin, has shown potential in combating this threat, but with the currently available data, its role in therapy remains poorly defined. This multi-center, retrospective cohort study evaluated the real-world application of CFDC across six U.S. medical centers from January 2018 to May 2023. Patients aged ≥18 years and who had received ≥72 hours of CFDC were included. The primary outcome was a composite of clinical success: survival at 30 days, absence of symptomatic microbiologic recurrence at 30 days following CFDC treatment initiation, and resolution of signs and symptoms. Secondary outcomes included time to CFDC therapy and on-treatment non-susceptibility to CFDC. A total of 112 patients were included, with median (interquartile range [IQR]) APACHE II scores of 15 (19-18). Clinical success was observed in 68.8% of patients, with a mortality rate of 16.1% and comparable success rates across patients infected with carbapenem-resistant gram-negative infections. The most common isolated organisms were Pseudomonas aeruginosa (61/112, 54.5%, of which 55/61 were carbapenem-resistant) and carbapenem-resistant Acinetobacter baumannii (32/112, 28.6%). Median (IQR) time to CFDC therapy was 77 (14-141) hours. Two patients experienced a non-anaphylactic rash as an adverse drug reaction. On-treatment non-susceptibility to CFDC was found in six patients, notably due to P. aeruginosa and A. baumannii.IMPORTANCECFDC was safe and clinically effective as a monotherapy or in combination in treating a variety of carbapenem-resistant gram-negative infections. Further prospective studies are warranted to confirm these findings.
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Antibacterianos , Cefiderocol , Humanos , Adolescente , Adulto , Antibacterianos/farmacología , Estudios Retrospectivos , Cefalosporinas/farmacología , Carbapenémicos/farmacología , Bacterias Gramnegativas , Pruebas de Sensibilidad MicrobianaRESUMEN
OBJECTIVE: To assess the impact of a virtual medication adherence training (VMAT) program on students' perceived confidence and perceived competency in delivering medication adherence services via telehealth. METHODS: This pilot pre-/post-observational study consisted of 2 subsequent sections: (1) 4 asynchronous self-study modules via Canvas (Instructure, Inc.) learning management system, and (2) 2 live application-based sessions involving virtual and telephonic standardized patients. A pre-/post-survey was given to first-, second-, and third-year Doctor of Pharmacy students to assess perceived confidence and perceived competence. Participants completed a 5-question multiple-choice quiz before and after each module to assess knowledge. RESULTS: Students' overall perceived confidence and perceived competency significantly increased upon completing VMAT. Knowledge in each module assessment also significantly improved. During the assessment of performance throughout the live sessions, most participants lost points when resolving issues within the interaction, addressing the need for patient follow-up, and assessing patient knowledge of medication adherence. CONCLUSION: This novel VMAT suggests that this or similar programs would be beneficial to improve pharmacy students' perceived confidence, perceived competence, and knowledge in delivering virtual medication adherence services in the telehealth setting. The incorporation of such training within the didactic curriculum of doctoral pharmacy programs should be considered to improve patient care skills for future medication experts.
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Competencia Clínica , Educación en Farmacia , Cumplimiento de la Medicación , Estudiantes de Farmacia , Telemedicina , Humanos , Estudiantes de Farmacia/psicología , Educación en Farmacia/métodos , Proyectos Piloto , Evaluación Educacional , Femenino , Curriculum , Masculino , Encuestas y CuestionariosRESUMEN
Background: Limited data suggest that serious infections caused by Enterobacterales with a moderate to high risk of clinically significant AmpC production can be successfully treated with cefepime if the cefepime minimum inhibitory concentration (MIC) is ≤2â µg/mL. However, isolates with a cefepime-susceptible dose-dependent (SDD) MIC of 4-8â µg/mL should receive a carbapenem due to target attainment and extended-spectrum ß-lactamase (ESBL) concerns. Methods: This was a retrospective cohort study of hospitalized patients with E. cloacae, K. aerogenes, or C. freundii bacteremia from January 2015 to March 2022 receiving high-dose cefepime or a carbapenem. Cox regression models were used with incorporation of inverse probability of treatment weighting and time-varying covariates. Results: Of the 315 patients included, 169 received cefepime and 146 received a carbapenem (ertapenem n = 90, meropenem n = 56). Cefepime was not associated with an increased risk of 30-day mortality compared with carbapenem therapy (adjusted hazard ratio [aHR], 1.45; 95% CI, 0.79-2.14), which was consistent for patients with cefepime SDD isolates (aHR, 1.19; 95% CI, 0.52-1.77). Multivariable weighted Cox models identified Pitt bacteremia score >4 (aHR, 1.41; 95% CI, 1.04-1.92), deep infection (aHR, 2.27; 95% CI, 1.21-4.32), and ceftriaxone-resistant AmpC-E (aHR, 1.32; 95% CI, 1.03-1.59) to be independent predictors associated with increased mortality risk, while receipt of prolonged-infusion ß-lactam was protective (aHR, 0.67; 95% CI, 0.40-0.89). Conclusions: Among patients with bacteremia caused by Enterobacterales with moderate to high risk of clinically significant AmpC production, these data demonstrate similar risk of 30-day mortality for high-dose cefepime or a carbapenem as definitive ß-lactam therapy.
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Phage therapy has gained attention due to the spread of antibiotic-resistant bacteria and narrow pipeline of novel antibiotics. Phage cocktails are hypothesized to slow the overall development of resistance by challenging the bacteria with more than one phage. Here, we have used a combination of plate-, planktonic-, and biofilm-based screening assays to try to identify phage-antibiotic combinations that will eradicate preformed biofilms of Staphylococcus aureus strains that are otherwise difficult to kill. We have focused on methicillin-resistant S aureus (MRSA) strains and their daptomycin-nonsusceptible vancomycin-intermediate (DNS-VISA) derivatives to understand whether the phage-antibiotic interactions are altered by the changes associated with evolution from MRSA to DNS-VISA (which is known to occur in patients receiving antibiotic therapy). We evaluated the host range and cross-resistance patterns of five obligately lytic S. aureus myophages to select a three-phage cocktail. We screened these phages for their activity against 24-h bead biofilms and found that biofilms of two strains, D712 (DNS-VISA) and 8014 (MRSA), were the most resistant to killing by single phages. Specifically, even initial phage concentrations of 107 PFU per well could not prevent visible regrowth of bacteria from the treated biofilms. However, when we treated biofilms of the same two strains with phage-antibiotic combinations, we prevented bacterial regrowth when using up to 4 orders of magnitude less phage and antibiotic concentrations that were lower than our measured minimum biofilm inhibitory concentration. We did not see a consistent association between phage activity and the evolution of DNS-VISA genotypes in this small number of bacterial strains. IMPORTANCE The extracellular polymeric matrix of biofilms presents an impediment to antibiotic diffusion, facilitating the emergence of multidrug-resistant populations. While most phage cocktails are designed for the planktonic state of bacteria, it is important to take the biofilm mode of growth (the predominant mode of bacterial growth in nature) into consideration, as it is unclear how interactions between any specific phage and its bacterial hosts will depend on the physical properties of the growth environment. In addition, the extent of bacterial sensitivity to any given phage may vary from the planktonic to the biofilm state. Therefore, phage-containing treatments targeting biofilm infections such as catheters and prosthetic joint material may not be merely based on host range characteristics. Our results open avenues to new questions regarding phage-antibiotic treatment efficiency in the eradication of topologically structured biofilm settings and the extent of eradication efficacy relative to the single agents in biofilm populations.
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Bacteriófagos , Daptomicina , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Humanos , Staphylococcus aureus , Bacteriófagos/genética , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Biopelículas , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Vancomicina , Pruebas de Sensibilidad MicrobianaRESUMEN
The Centers for Disease Control and Prevention (CDC) categorized carbapenem-resistant Enterobacterales (CRE) infections as an "urgent" health care threat requiring public attention and research. Certain patients with CRE infections may be at higher risk for poor clinical outcomes than others. Evidence on risk or protective factors for CRE infections are warranted in order to determine the most at-risk populations, especially with newer beta-lactam/beta-lactamase inhibitor (BL/BLI) antibiotics available to treat CRE. We aimed to identify specific variables involved in CRE treatment that are associated with clinical failure (either 30-day mortality, 30-day microbiologic recurrence, or clinical worsening/failure to improve throughout antibiotic treatment). We conducted a retrospective, observational cohort study of hospitalized patients with CRE infection sampled from 2010 to 2020 at two medical systems in Detroit, Michigan. Patients were included if they were ≥18 years old and culture positive for an organism in the Enterobacterales order causing clinical infection with in vitro resistance by Clinical and Laboratory Standards Institute (CLSI) breakpoints to at least one carbapenem. Overall, there were 140 confirmed CRE infections of which 39% had clinical failure. The most common infection sources were respiratory (38%), urinary (20%), intra-abdominal (16%), and primary bacteremia (14%). A multivariable logistic regression model was developed to identify statistically significant associated predictors with clinical failure, and they included Sequential Organ Failure Assessment (SOFA) score (adjusted odds ratio [aOR], 1.18; 95% confidence interval [CI], 1.06 to 1.32), chronic dialysis (aOR, 5.86; 95% CI, 1.51-22.7), and Klebsiella pneumoniae in index culture (aOR, 3.09; 95% CI, 1.28 to 7.47). Further research on CRE infections is needed to identify best practices to promote treatment success. IMPORTANCE This work compares carbapenem-resistant Enterobacterales (CRE) infections using patient, clinical, and treatment variables to understand which characteristics are associated with the highest risk of clinical failure. Knowing which risk factors are associated with CRE infection failure can provide clinicians better prognostic and targeted interventions. Research can also further investigate why certain risk factors cause more clinical failure and can help develop treatment strategies to mitigate associated risk factors.
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Carbapenémicos , Infecciones por Enterobacteriaceae , Humanos , Adolescente , Carbapenémicos/farmacología , Carbapenémicos/uso terapéutico , Estudios Retrospectivos , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Infecciones por Enterobacteriaceae/microbiología , Antibacterianos/efectos adversos , Inhibidores de beta-Lactamasas , Insuficiencia del Tratamiento , Factores de Riesgo , Pruebas de Sensibilidad MicrobianaRESUMEN
Multidrug-resistant (MDR) and extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates are frequent causes of serious nosocomial infections that may compromise the selection of antimicrobial therapy. The goal of this review is to summarize recent epidemiologic, microbiologic, and clinical data pertinent to the therapeutic management of patients with infections caused by MDR/XDR-P. aeruginosa. Historically, conventional antipseudomonal ß-lactam antibiotics have been used for the empiric treatment of MDR/XDR-P. aeruginosa. Owing to the remarkable capacity of P. aeruginosa to confer resistance via multiple mechanisms, these traditional therapies are often rendered ineffective. To increase the likelihood of administering empiric antipseudomonal therapy with in vitro activity, a second agent from a different antibiotic class is often administered concomitantly with a traditional antipseudomonal ß-lactam. However, combination therapy may pose an increased risk of antibiotic toxicity and secondary infection, notably, Clostridioides difficile. Multiple novel agents that demonstrate in vitro activity against MDR-P. aeruginosa (e.g., ß-lactam/ß-lactamase inhibitor combinations and cefiderocol) have been recently granted US Food and Drug Administration (FDA) approval and are promising additions to the antipseudomonal armamentarium. Even so, comparative clinical data pertaining to these novel agents is sparse, and concerns surrounding the scarcity of antibiotics active against refractory MDR/XDR-P. aeruginosa necessitates continued assessment of alternative therapies. This is particularly important in patients with cystic fibrosis (CF) who may be chronically colonized and suffer from recurrent infections and disease exacerbations due in part to limited efficacious antipseudomonal agents. Bacteriophages represent a promising candidate for combatting recurrent and refractory infections with their ability to target specific host bacteria and circumvent traditional mechanisms of antibiotic resistance seen in MDR/XDR-P. aeruginosa. Future goals for the management of these infections include increased comparator clinical data of novel agents to determine in what scenario certain agents may be preferred over others. Until then, appropriate treatment of these infections requires a thorough evaluation of patient- and infection-specific factors to guide empiric and definitive therapeutic decisions.
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We report our clinical and laboratory experience treating a 50-year-old patient who was critically ill with extensively drug-resistant Acinetobacter baumannii necrotizing pneumonia complicated by empyema in Detroit, Michigan. A precision medicine approach using whole-genome sequencing, susceptibility testing, and synergy analysis guided the selection of rational combination antimicrobial therapy.
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Multidrug-resistant (MDR) Enterococcus faecium is a challenging nosocomial pathogen known to colonize medical device surfaces and form biofilms. Bacterio (phages) may constitute an emerging anti-infective option for refractory, biofilm-mediated infections. This study evaluates eight MDR E. faecium strains for biofilm production and phage susceptibility against nine phages. Two E. faecium strains isolated from patients with bacteremia and identified to be biofilm producers, R497 (daptomycin (DAP)-resistant) and HOU503 (DAP-susceptible dose-dependent (SDD), in addition to four phages with the broadest host ranges (ATCC 113, NV-497, NV-503-01, NV-503-02) were selected for further experiments. Preliminary phage-antibiotic screening was performed with modified checkerboard minimum biofilm inhibitory concentration (MBIC) assays to efficiently screen for bacterial killing and phage-antibiotic synergy (PAS). Data were compared by one-way ANOVA and Tukey (HSD) tests. Time kill analyses (TKA) were performed against R497 and HOU503 with DAP at 0.5× MBIC, ampicillin (AMP) at free peak = 72 µg/mL, and phage at a multiplicity of infection (MOI) of 0.01. In 24 h TKA against R497, phage-antibiotic combinations (PAC) with DAP, AMP, or DAP + AMP combined with 3- or 4-phage cocktails demonstrated significant killing compared to the most effective double combination (ANOVA range of mean differences 2.998 to 3.102 log10 colony forming units (CFU)/mL; p = 0.011, 2.548 to 2.868 log10 colony forming units (CFU)/mL; p = 0.023, and 2.006 to 2.329 log10 colony forming units (CFU)/mL; p = 0.039, respectively), with preserved phage susceptibility identified in regimens with 3-phage cocktails containing NV-497 and the 4-phage cocktail. Against HOU503, AMP combined with any 3- or 4-phage cocktail and DAP + AMP combined with the 3-phage cocktail ATCC 113 + NV-497 + NV-503-01 demonstrated significant PAS and bactericidal activity (ANOVA range of mean differences 2.251 to 2.466 log10 colony forming units (CFU)/mL; p = 0.044 and 2.119 to 2.350 log10 colony forming units (CFU)/mL; p = 0.028, respectively), however, only PAC with DAP + AMP maintained phage susceptibility at the end of 24 h TKA. R497 and HOU503 exposure to DAP, AMP, or DAP + AMP in the presence of single phage or phage cocktail resulted in antibiotic resistance stabilization (i.e., no antibiotic MBIC elevation compared to baseline) without identified antibiotic MBIC reversion (i.e., lowering of antibiotic MBIC compared to baseline in DAP-resistant and DAP-SDD isolates) at the end of 24 h TKA. In conclusion, against DAP-resistant R497 and DAP-SDD HOU503 E. faecium clinical blood isolates, the use of DAP + AMP combined with 3- and 4-phage cocktails effectively eradicated biofilm-embedded MDR E. faecium without altering antibiotic MBIC or phage susceptibility compared to baseline.
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INTRODUCTION: Infections caused by multidrug-resistant (MDR), extensively drug-resistant (XDR), and difficult-to-treat (DTR) Pseudomonas aeruginosa are increasingly challenging to combat. Ceftolozane-tazobactam (C/T) is a novel ß-lactam-ß-lactamase inhibitor combination now commonly used to treat MDR and XDR P. aeruginosa. Lower respiratory tract infections (LRTIs) remain the most common source of infection caused by MDR/XDR P. aeruginosa. Comparative effectiveness studies to date have been limited by the type of comparator agents (i.e., aminoglycosides and polymyxins) and the inclusion of multiple infection sources (i.e., urinary tract, abdominal, skin and soft tissue, etc.). METHODS: We performed a multicenter, retrospective analysis of adults with LRTI caused by MDR or XDR P. aeruginosa admitted from January 2014 to December 2019. We aimed to compare clinical outcomes between patients who received C/T (n = 118) versus best alternative therapy (n = 88). The primary outcome was clinical failure, defined as 30-day mortality and/or an adverse drug reaction on antibiotic therapy. RESULTS: Two hundred and six patients met inclusion criteria. The C/T group had a significantly higher proportion of XDR P. aeruginosa and ventilator-associated bacterial pneumonia (VABP). After multivariable logistic regression, C/T treatment was independently associated with a 73.3% reduction in clinical failure compared to those who received best alternative therapy (P < 0.001). The number needed to harm with best alternative therapy was 3. CONCLUSION: Our results suggest that C/T is a safe and effective therapeutic regimen for patients with MDR and XDR P. aeruginosa LRTI.
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Multidrug-resistant (MDR) Enterococcus faecium is a challenging pathogen known to cause biofilm-mediated infections with limited effective therapeutic options. Lytic bacteriophages target, infect, and lyse specific bacterial cells and have anti-biofilm activity, making them a possible treatment option. Here, we examine two biofilm-producing clinical E. faecium strains, daptomycin (DAP)-resistant R497 and DAP-susceptible dose-dependent (SDD) HOU503, with initial susceptibility to E. faecium bacteriophage 113 (ATCC 19950-B1). An initial synergy screening was performed with modified checkerboard MIC assays developed by our laboratory to efficiently screen for antibiotic and phage synergy, including at very low phage multiplicity of infection (MOI). The data were compared by one-way ANOVA and Tukey (HSD) tests. In 24 h time kill analyses (TKA), combinations with phage-DAP-ampicillin (AMP), phage-DAP-ceftaroline (CPT), and phage-DAP-ertapenem (ERT) were synergistic and bactericidal compared to any single agent (ANOVA range of mean differences 3.34 to 3.84 log10 CFU/mL; p < 0.001). Furthermore, phage-DAP-AMP and phage-DAP-CPT prevented the emergence of DAP and phage resistance. With HOU503, the combination of phage-DAP-AMP showed the best killing effect, followed closely by phage-DAP-CPT; both showed bactericidal and synergistic effects compared to any single agent (ANOVA range of mean differences 3.99 to 4.08 log10 CFU/mL; p < 0.001).