ABSTRACT
OBJECTIVES: Gram-positive cocci is the main pathogen responsible for early infection after liver transplantation (LT), posing a huge threat to the prognosis of liver transplant recipients. This study aims to analyze the distribution and drug resistance of Gram-positive cocci, the risk factors for infections and efficacy of antibiotics within 2 months after LT, and to guide the prevention and treatment of these infections. METHODS: In this study, data of pathogenic bacteria distribution, drug resistance and therapeutic efficacy were collected from 39 Gram-positive cocci infections among 256 patients who received liver transplantation from donation after citizens' death in the Third Xiangya Hospital of Central South University from January 2019 to July 2022, and risk factors for Gram-positive cocci infection were analyzed. RESULTS: Enterococcus faecium was the dominant pathogenic bacteria (33/51, 64.7%), followed by Enterococcus faecalis (11/51, 21.6%). The most common sites of infection were abdominal cavity/biliary tract (13/256, 5.1%) and urinary tract (10/256, 3.9%). Fifty (98%) of the 51 Gram-positive cocci infections occurred within 1 month after LT. The most sensitive drugs to Gram-positive cocci were teicoplanin, tigecycline, linezolid and vancomycin. Vancomycin was not used in all patients, considering its nephrotoxicity. Vancomycin was not administered to all patients in view of its nephrotoxicity.There was no significant difference between the efficacy of daptomycin and teicoplanin in the prevention of cocci infection (P>0.05). Univariate analysis indicated that preoperative Model for End-Stage Liver Disease (MELD) score >25 (P=0.005), intraoperative red blood cell infusion ≥12 U (P=0.013) and exposure to more than 2 intravenous antibiotics post-LT (P=0.003) were related to Gram-positive cocci infections. Multivariate logistic regression analysis revealed that preoperative MELD score >25 (OR=2.378, 95% CI 1.124 to 5.032, P=0.024) and intraoperative red blood cell transfusion ≥ 12 U (OR=2.757, 95% CI 1.227 to 6.195, P=0.014) were independent risk factors for Gram-positive cocci infections after LT. Postoperative Gram-positive cocci infections were reduced in LT recipients exposing to more than two intravenous antibiotics post-LT (OR=0.269, 95% CI 0.121 to 0.598, P=0.001). CONCLUSIONS: Gram-positive cocci infections occurring early after liver transplantation were dominated by Enterococcus faecalis infections at the abdominal/biliary tract and urinary tract. Teicoplanin, tigecycline and linezolid were anti-cocci sensitive drugs. Daptomycin and teicoplanin were equally effective in preventing cocci infections due to Gram-positive cocci. Patients with high preoperative MELD score and massive intraoperative red blood cell transfusion were more likely to suffer Gram-positive cocci infection after surgery. Postoperative Gram-positive cocci infections were reduced in recipients exposing to more than two intravenous antibiotics post-LT.
Subject(s)
Daptomycin , End Stage Liver Disease , Gram-Positive Bacterial Infections , Gram-Positive Cocci , Liver Transplantation , Humans , Daptomycin/pharmacology , Daptomycin/therapeutic use , Linezolid/pharmacology , Linezolid/therapeutic use , Teicoplanin/pharmacology , Teicoplanin/therapeutic use , Liver Transplantation/adverse effects , Tigecycline/pharmacology , Tigecycline/therapeutic use , End Stage Liver Disease/complications , End Stage Liver Disease/drug therapy , Gram-Positive Bacterial Infections/etiology , Gram-Positive Bacterial Infections/microbiology , Severity of Illness Index , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/pharmacology , Vancomycin/pharmacology , Vancomycin/therapeutic use , Microbial Sensitivity TestsABSTRACT
OBJECTIVES: Because of a steady increase in the detection of daptomycin-resistant (DAP-R) Staphylococcus aureus at three medical centres in Cologne, Germany, molecular surveillance was established from June 2016 to June 2018 to investigate the causes of the emergence and spread of respective isolates. Seventy-five S. aureus isolates, both DAP-R and DAP-susceptible, were collected from 42 patients for further analysis. METHODS: Broth microdilution was used to determine the MICs for DAP and polyhexamethylene biguanide/polyhexanide (PHMB). To investigate the effect of PHMB on the development of DAP resistance, we performed selection experiments with PHMB. All isolates studied were subjected to whole-genome sequencing. Epidemiological, clinical, microbiological and molecular data were analysed comparatively. RESULTS: Acquisition of DAP resistance was mainly observed in patients with acute and chronic wounds (40/42, 96.2%) treated with antiseptic (32/42, 76.2%) rather than systemic antibiotic therapy using DAP or vancomycin (7/42, 16.7%). DAP-R S. aureus had a diverse genetic background; however, within individual patients, isolates were closely related. At least three potential transmission events were detected. Most DAP-R isolates had concomitant elevated MICs for PHMB (50/54, 92.6%), and in vitro selection experiments confirmed that PHMB treatment is capable of generating DAP resistance. DAP resistance could be linked to 12 different polymorphisms in the mprF gene in the majority of clinical isolates (52/54, 96.3%) as well as in all in vitro selected strains. DISCUSSION: DAP resistance in S. aureus can occur independently of prior antibiotic therapy and can be selected by PHMB. Therefore, wound treatment with PHMB may trigger individual resistance development associated with gain-of-function mutations in the mprF gene.
Subject(s)
Anti-Infective Agents, Local , Daptomycin , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Humans , Daptomycin/pharmacology , Daptomycin/therapeutic use , Staphylococcus aureus/genetics , Anti-Infective Agents, Local/pharmacology , Anti-Infective Agents, Local/therapeutic use , Polymorphism, Single Nucleotide , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Staphylococcal Infections/drug therapy , Staphylococcal Infections/epidemiology , Staphylococcal Infections/microbiology , Microbial Sensitivity Tests , Bacterial Proteins/geneticsABSTRACT
Daptomycin is a last-resort antibiotic used for the treatment of infections caused by Gram-positive antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). Treatment failure is commonly linked to accumulation of point mutations; however, the contribution of single mutations to resistance and the mechanisms underlying resistance remain incompletely understood. Here, we show that a single nucleotide polymorphism (SNP) selected during daptomycin therapy inactivates the highly conserved ClpP protease and is causing reduced susceptibility of MRSA to daptomycin, vancomycin, and ß-lactam antibiotics as well as decreased expression of virulence factors. Super-resolution microscopy demonstrated that inactivation of ClpP reduced binding of daptomycin to the septal site and diminished membrane damage. In both the parental strain and the clpP strain, daptomycin inhibited the inward progression of septum synthesis, eventually leading to lysis and death of the parental strain while surviving clpP cells were able to continue synthesis of the peripheral cell wall in the presence of 10× MIC daptomycin, resulting in a rod-shaped morphology. To our knowledge, this is the first demonstration that synthesis of the outer cell wall continues in the presence of daptomycin. Collectively, our data provide novel insight into the mechanisms behind bacterial killing and resistance to this important antibiotic. Also, the study emphasizes that treatment with last-line antibiotics is selective for mutations that, like the SNP in clpP, favor antibiotic resistance over virulence gene expression.
Subject(s)
Daptomycin , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Humans , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Daptomycin/pharmacology , Staphylococcus aureus/genetics , Vancomycin/pharmacology , Staphylococcal Infections/drug therapy , Microbial Sensitivity TestsABSTRACT
INTRODUCTION: Methicillin-resistant and -susceptible Staphylococcus aureus (MRSA/MSSA) infections are a major global health-care problem. Bacteremia with S. aureus exhibits high rates of morbidity and mortality and can cause complicated infections such as infective endocarditis (IE). The emerging resistance profile of S. aureus is worrisome, and several international agencies have appealed for new treatment approaches to be developed. AREAS COVERED: Daptomycin presents a rapid bactericidal effect against MRSA and has been considered at least as effective as vancomycin in treating MRSA bacteremia. However, therapy failure is often related to deep-seated infections, e.g. endocarditis, with high bacterial inocula and daptomycin regimens <10 mg/kg/day. Current antibiotic options for treating invasive S. aureus infections have limitations in monotherapy. Daptomycin in combination with other antibiotics, e.g. fosfomycin, may be effective in improving clinical outcomes in patients with MRSA IE. EXPERT OPINION: Exploring therapeutic combinations has shown fosfomycin to have a unique mechanism of action and to be the most effective option in preventing the onset of resistance to and optimizing the efficacy of daptomycin, suggesting the synergistic combination of fosfomycin with daptomycin is a useful alternative treatment option for MSSA or MRSA IE.
Subject(s)
Bacteremia , Daptomycin , Endocarditis, Bacterial , Endocarditis , Fosfomycin , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Humans , Daptomycin/pharmacology , Daptomycin/therapeutic use , Fosfomycin/adverse effects , Staphylococcus aureus , Anti-Bacterial Agents/therapeutic use , Endocarditis, Bacterial/drug therapy , Endocarditis, Bacterial/microbiology , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Endocarditis/drug therapy , Endocarditis/microbiology , Bacteremia/microbiology , Microbial Sensitivity TestsABSTRACT
OBJECTIVES: We analyzed the risk factors affecting linezolid treatment outcome in vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI). METHODS: We conducted a multicenter observational study of patients who received linezolid 600 mg every 12 hours for VRE BSI. The primary outcome was 28-day mortality. The estimated area under the concentration-time curve and trough concentration were calculated. Multivariable logistic regression was used for the outcome analysis. RESULTS: A total of 170 patients were included: 114 (67.1%) survived and 56 (32.9%) did not. A total of 26 (18.2%) isolates showed a linezolid minimum inhibitory concentration (MIC) of ≤1 mg/l, 113 (79.0%) of 2 mg/l, and 4 (2.8%) of 4 mg/l. The univariable analysis showed that the linezolid MIC and concentration-time curve/MIC were not associated with mortality (P = 0.95 and P = 0.42, respectively). After adjusting for underlying comorbidity and disease severity, the linezolid dose per body weight (LDBW), body height, and interaction between them were independent risks for mortality. Marginal analysis showed that increasing the LDBW was protective in patients with a body height <160 cm. A trough concentration of >12.2 mg/l was a risk factor for thrombocytopenia. CONCLUSION: The LDBW and body height were interactively associated with clinical outcomes of linezolid treatment for VRE BSI.
Subject(s)
Bacteremia , Daptomycin , Gram-Positive Bacterial Infections , Vancomycin-Resistant Enterococci , Humans , Linezolid/therapeutic use , Anti-Bacterial Agents/adverse effects , Vancomycin/therapeutic use , Daptomycin/therapeutic use , Bacteremia/drug therapy , Gram-Positive Bacterial Infections/drug therapy , Risk Factors , Microbial Sensitivity TestsABSTRACT
Methicillin-resistant Staphylococcus epidermidis (MRSE) endocarditis failing conventional therapy has been successfully treated with nafcillin plus daptomycin in the clinic. In vitro studies showed that nafcillin enhanced daptomycin killing of MRSE in both planktonic cells and biofilm. Nafcillin exposure also sensitized MRSE to killing by human neutrophils and cathelicidin antimicrobial peptide LL-37. Fluorescent microscopy showed increased daptomycin and LL-37 binding to the MRSE bacterial surface upon nafcillin treatment. Ceftaroline also increased MRSE killing by daptomycin in planktonic cultures and biofilms, as well as daptomycin and LL-37 binding on the bacterial surface. Nafcillin, ceftaroline, and possibly other ß-lactams, may serve an important role in the therapy of MRSE endocarditis through augmentation of cationic peptide, the innate immune system, and daptomycin killing. Clinical studies will be needed to determine how early these regimens should be deployed to optimize clinical outcome.
Subject(s)
Daptomycin , Endocarditis , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Humans , Daptomycin/pharmacology , Daptomycin/therapeutic use , Nafcillin/therapeutic use , Cathelicidins , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Staphylococcus epidermidis , Methicillin Resistance , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Endocarditis/drug therapy , Microbial Sensitivity Tests , CeftarolineABSTRACT
OBJECTIVES: This study aimed to evaluate both efficacy and safety of combination therapy with daptomycin plus ceftaroline (DAP/CPT) versus alternative therapy in the treatment of persistent methicillin-resistant Staphylococcus aureus bacteraemia (MRSAB). METHODS: This retrospective, single-centre study investigated adult patients who underwent a change in antibiotic therapy for persistent MRSAB. Daptomycin plus ceftaroline was compared with alternative therapy after initial treatment with vancomycin or DAP monotherapy was modified. The primary outcome was in-hospital mortality, and several secondary efficacy and safety outcomes were evaluated. RESULTS: A total of 68 patients with persistent MRSAB had initial therapy switched to DAP/CPT (n = 43) or alternative therapy (n = 25). In-hospital mortality was similar with DAP/CPT versus alternative therapy (16.3% vs. 16%; P = 1.0). On average, the total duration of bacteraemia was numerically 1 day less in patients switched to DAP/CPT (11.4 days vs. 12.5 days; P = 0.5). Daptomycin plus ceftaroline was de-escalated in 81% of patients after receiving combination therapy for an average of 12.5 days. Secondary outcomes, including rates of adverse events and emergence of antimicrobial resistance, were similar between the two groups. CONCLUSIONS: Switching to DAP/CPT after approximately 1 week of persistent MRSA bacteraemia may result in similar clinical outcomes when compared with alternative therapy. Rates of adverse events and emergence of antimicrobial resistance were low without a statistically significant difference observed between DAP/CPT and alternative therapy. These findings, as well as the impact of earlier switch or prolonged treatment with the combination, require further investigation.
Subject(s)
Bacteremia , Daptomycin , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Adult , Humans , Daptomycin/therapeutic use , Bacteremia/drug therapy , Retrospective Studies , Staphylococcal Infections/drug therapy , Staphylococcus aureus , Anti-Bacterial Agents/therapeutic use , Microbial Sensitivity Tests , CeftarolineABSTRACT
OBJECTIVES@#Gram-positive cocci is the main pathogen responsible for early infection after liver transplantation (LT), posing a huge threat to the prognosis of liver transplant recipients. This study aims to analyze the distribution and drug resistance of Gram-positive cocci, the risk factors for infections and efficacy of antibiotics within 2 months after LT, and to guide the prevention and treatment of these infections.@*METHODS@#In this study, data of pathogenic bacteria distribution, drug resistance and therapeutic efficacy were collected from 39 Gram-positive cocci infections among 256 patients who received liver transplantation from donation after citizens' death in the Third Xiangya Hospital of Central South University from January 2019 to July 2022, and risk factors for Gram-positive cocci infection were analyzed.@*RESULTS@#Enterococcus faecium was the dominant pathogenic bacteria (33/51, 64.7%), followed by Enterococcus faecalis (11/51, 21.6%). The most common sites of infection were abdominal cavity/biliary tract (13/256, 5.1%) and urinary tract (10/256, 3.9%). Fifty (98%) of the 51 Gram-positive cocci infections occurred within 1 month after LT. The most sensitive drugs to Gram-positive cocci were teicoplanin, tigecycline, linezolid and vancomycin. Vancomycin was not used in all patients, considering its nephrotoxicity. Vancomycin was not administered to all patients in view of its nephrotoxicity.There was no significant difference between the efficacy of daptomycin and teicoplanin in the prevention of cocci infection (P>0.05). Univariate analysis indicated that preoperative Model for End-Stage Liver Disease (MELD) score >25 (P=0.005), intraoperative red blood cell infusion ≥12 U (P=0.013) and exposure to more than 2 intravenous antibiotics post-LT (P=0.003) were related to Gram-positive cocci infections. Multivariate logistic regression analysis revealed that preoperative MELD score >25 (OR=2.378, 95% CI 1.124 to 5.032, P=0.024) and intraoperative red blood cell transfusion ≥ 12 U (OR=2.757, 95% CI 1.227 to 6.195, P=0.014) were independent risk factors for Gram-positive cocci infections after LT. Postoperative Gram-positive cocci infections were reduced in LT recipients exposing to more than two intravenous antibiotics post-LT (OR=0.269, 95% CI 0.121 to 0.598, P=0.001).@*CONCLUSIONS@#Gram-positive cocci infections occurring early after liver transplantation were dominated by Enterococcus faecalis infections at the abdominal/biliary tract and urinary tract. Teicoplanin, tigecycline and linezolid were anti-cocci sensitive drugs. Daptomycin and teicoplanin were equally effective in preventing cocci infections due to Gram-positive cocci. Patients with high preoperative MELD score and massive intraoperative red blood cell transfusion were more likely to suffer Gram-positive cocci infection after surgery. Postoperative Gram-positive cocci infections were reduced in recipients exposing to more than two intravenous antibiotics post-LT.
Subject(s)
Humans , Daptomycin/therapeutic use , Linezolid/therapeutic use , Teicoplanin/therapeutic use , Gram-Positive Cocci , Liver Transplantation/adverse effects , Tigecycline/therapeutic use , End Stage Liver Disease/drug therapy , Gram-Positive Bacterial Infections/microbiology , Severity of Illness Index , Anti-Bacterial Agents/pharmacology , Vancomycin/therapeutic use , Microbial Sensitivity TestsABSTRACT
BACKGROUND: There is in vitro and clinical evidence to suggest daptomycin has good activity against Enterococcus. In 2019, CLSI produced clinical breakpoints for Enterococcus spp. OBJECTIVES: To describe the distribution of MICs of daptomycin for enterococcal bloodstream infection (EBSI) isolates in a large Scottish health board, the indications for local daptomycin susceptibility testing and daptomycin doses used in vancomycin-resistant Enterococcus faecium (VREfm) infection. METHODS: We investigated all EBSIs over a 21â month period and identified isolates tested against daptomycin. We recorded the distribution of MICs, as well as indications for daptomycin susceptibility testing and information on daptomycin dosing, where it was used. RESULTS: There were 293 blood culture isolates of Enterococcus spp., of which 37 had daptomycin susceptibility testing performed, from 31 individual patients. Of the 293 isolates, 103 were E. faecium, of which 63 were VREfm. Daptomycin testing was indicated by vancomycin resistance in 24/37 isolates. All E. faecium isolates tested were in the CLSI 'susceptible dose-dependent (SDD)' range of MICs. All other Enterococcus spp. tested were in the 'susceptible' range. Twelve patients received daptomycin, and dosing information was recovered for 10. Nine of these patients received 8-12â mg/kg/day dosing. There were no recorded adverse drug reactions. Ten of 12 patients were alive at the time of data collection. CONCLUSIONS: Daptomycin MIC distribution for EBSI isolates suggests a high local rate of susceptibility, according to CLSI breakpoints, in a population with high rates of VREfm. CLSI-recommended doses of daptomycin were used, with encouraging survival outcomes.
Subject(s)
Daptomycin , Enterococcus faecium , Gram-Positive Bacterial Infections , Sepsis , Vancomycin-Resistant Enterococci , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Daptomycin/pharmacology , Daptomycin/therapeutic use , Gram-Positive Bacterial Infections/drug therapy , Humans , Microbial Sensitivity Tests , Sepsis/drug therapy , Vancomycin/pharmacology , Vancomycin/therapeutic useABSTRACT
OBJECTIVES: The aim of this study was to investigate the effect of daptomycin against methicillin-resistant staphylococci (MRSA and MRSE) bacteremia using computer modeling. METHODS: A pharmacokinetic/pharmacodynamic (PK/PD) modeling strategy to explain the data from an in vitro dynamic model employing time-kill curves for MRSA and MRSE was proposed. Bacterial killing was followed over time by determining viable counts and the resulting time-kill data was analyzed. Monte Carlo simulations were performed using pharmacokinetic parameters and pharmacodynamic data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration (MIC) targets of daptomycin. Simulations were conducted to assess the reduction in the number of colony-forming units (CFU)/mL for 18 days of treatment with daptomycin at doses of 6, 8, and 10 mg/kg/24 h or 48 h with variations in creatinine clearance (CLCR): 15-29 mL/min/1.73 m2, 30-49 mL/min/1.73 m2, 50-100 mL/min/1.73 m2, as well as for defining the probability of reaching the target fAUC/MIC = 80 in the same dose and clearance range. A PK/PD model with saturation in the number of bacteria in vitro, growth delay, and bacterial death, as well as Hill's factor, was used to describe the data for both MRSA and MRSE. RESULTS: Monte Carlo simulations showed that for MRSA there was a reduction > 2 log CFU/mL with doses ≥ 6 mg/kg/day in 75th percentile of the simulated population after 18 days of treatment with daptomycin, whereas for MRSE this reduction was observed in 95th percentile of the population. CONCLUSIONS: The presented in vitro PK/PD model and associated modeling approach were able to characterize the time-kill kinetics of MRSA and MRSE. Our study based on PTAs suggests that doses ≥ 6 mg/kg/day of daptomycin should be used to treat bacteremia caused by MRSA and MRSE in patients with CLCR of 15-29 mL/min/1.73 m2. For patients with CLCR ≥ 50 mL/min/1.73 m2, it would be necessary to employ a dose of 10 mg/kg/day to treat complicated bacteremias.
Subject(s)
Bacteremia , Daptomycin , Methicillin-Resistant Staphylococcus aureus , Monte Carlo Method , Staphylococcal Infections , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Bacteremia/drug therapy , Daptomycin/pharmacokinetics , Daptomycin/pharmacology , Daptomycin/therapeutic use , Humans , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Staphylococcal Infections/drug therapyABSTRACT
BACKGROUND AND OBJECTIVE: When administered for severe infections in intravenous drug users (IDUs) at a daily dose of 6 mg/kg, daptomycin displayed abnormal pharmacokinetic parameters compared with those seen in healthy volunteers; specifically, decreased trough and maximum concentrations (Ctrough; Cmax) and increased clearance (CL). The objective of this study was to evaluate the pharmacokinetics and pharmacodynamics of daptomycin administered at a daily dosage of 12 mg/kg for Staphylococcus aureus infective endocarditis (IE) in patients concomitantly treated with methadone, and to compare the results with those published in the literature for healthy controls treated with the same daily dose. METHODS: Antibiotic treatment included daptomycin (12 mg/kg daily) in combination with an antistaphylococcal ß-lactam (cefazolin 2 g three times a day). The minimum inhibitory concentration (MIC) of Staphylococcus aureus isolated through blood cultures was used to calculate pharmacokinetic and pharmacodynamic parameters such as the ratio of the area under the concentration-time curve over 24 h to the MIC (AUC0-24/MIC) and Cmax/MIC. RESULTS: Five IDUs hospitalized for IE were enrolled. The mean measured daptomycin Cmax and Ctrough were 54.1 µg/mL (CV: 0.32) and 8.7 µg/mL (CV: 0.59), respectively; the mean calculated AUC0-24 was 742.7 µg × h/mL (CV: 0.31). The estimated average volume of distribution at the steady state (Vd,ss) and the half-life (t1/2) were 316.5 mL/kg (CV: 0.53) and 14.4 h (CV: 0.30), respectively. The mean daptomycin clearance from plasma normalized for body weight (CLwp) was 17.3 mL/(h × kg) (CV: 0.33). The calculated average Cmax and AUC0-24 (183.7 µg/mL and 1277.4 µg × h/mL, respectively) were lower than and statistically significantly different from (p < 0.001 and p = 0.001, respectively) those expected for healthy volunteers. CONCLUSIONS: Treatment of Staphylococcus aureus IE in IDUs on methadone treatment requires the use of high daptomycin daily doses in order to achieve satisfactory pharmacodynamic parameters. Close monitoring of the daptomycin plasma concentration is suggested.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Daptomycin/administration & dosage , Endocarditis, Bacterial/drug therapy , Methadone/administration & dosage , Adult , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Area Under Curve , Daptomycin/pharmacokinetics , Daptomycin/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Endocarditis, Bacterial/microbiology , Female , Half-Life , Humans , Male , Methadone/pharmacology , Microbial Sensitivity Tests , Middle Aged , Opiate Substitution Treatment , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Staphylococcus aureus/isolation & purification , Tissue DistributionABSTRACT
The objective of this study was to evaluate the efficacy of various dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin against methicillin-resistant Staphylococcus aureus (MRSA) in neutropenic patients with cancer. Monte Carlo simulations were conducted using pharmacokinetic parameters and pharmacodynamic data to determine cumulative fraction of response (CFRs) in terms of area under the concentration-time curve/minimum inhibition concentration target. Currently clinical standard dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin were insufficient to provide expected CFRs against MRSA for neutropenic patients with cancer. The high dosing regimens of vancomycin (3500 mg/d), teicoplanin (800 mg/d) and daptomycin (8 mg/kg/d) could provide CFRs of ≥ 80%, showing a higher treatment success. However, the majority of CFRs with linezolid simulated dosing regimens reached < 80% against MRSA. Therefore, a strategy of high dosages of vancomycin, teicoplanin and daptomycin may be needed to attain optimal therapeutic efficacy against MRSA in neutropenic patients with cancer.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Chemotherapy-Induced Febrile Neutropenia/epidemiology , Methicillin-Resistant Staphylococcus aureus/drug effects , Staphylococcal Infections/drug therapy , Staphylococcal Infections/epidemiology , Adult , Age Factors , Aged , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/pharmacokinetics , Body Weight , Creatinine/blood , Daptomycin/administration & dosage , Daptomycin/pharmacokinetics , Dose-Response Relationship, Drug , Female , Humans , Linezolid/administration & dosage , Linezolid/pharmacokinetics , Male , Microbial Sensitivity Tests , Middle Aged , Monte Carlo Method , Teicoplanin/administration & dosage , Teicoplanin/pharmacokinetics , Vancomycin/administration & dosage , Vancomycin/pharmacokineticsABSTRACT
OBJECTIVES: To investigate if the addition of cloxacillin to vancomycin enhances the activity of both monotherapies for treating MSSA and MRSA experimental endocarditis (EE) in rabbits. METHODS: Vancomycin plus cloxacillin was compared with the respective monotherapies and daptomycin. In vitro time-kill studies were performed using standard (105 cfu) and high (108 cfu) inocula of five MRSA, one glycopeptide-intermediate (GISA) and five MSSA strains. One MSSA (MSSA-678) and one MRSA (MRSA-277) strain were selected to be used in the in vivo model. A human-like pharmacokinetics model was applied and the equivalents of cloxacillin 2 g/4 h IV and daptomycin 6 mg/kg/day IV were administered. To optimize vancomycin activity, dosage was adjusted to achieve an AUC/MIC ≥400. RESULTS: Daptomycin sterilized significantly more vegetations than cloxacillin (13/13, 100% versus 9/15, 60%; Pâ=â0.02) and showed a trend of better activity than vancomycin (10/14, 71%; Pâ=â0.09) and vancomycin plus cloxacillin (10/14, 71%; Pâ=â0.09) against MSSA-678. Addition of cloxacillin to vancomycin (13/15, 87%) was significantly more effective than vancomycin (8/16, 50%; Pâ=â0.05) and showed similar activity to daptomycin (13/18, 72%; Pâ=â0.6) against MRSA-277. In all treatment arms, the bacterial isolates recovered from vegetations were re-tested and showed the same daptomycin susceptibility as the original strains. CONCLUSIONS: Vancomycin plus cloxacillin proved synergistic and bactericidal activity against MRSA. Daptomycin was the most efficacious option against MSSA and similar to vancomycin plus cloxacillin against MRSA. In settings with high MRSA prevalence, vancomycin plus cloxacillin might be a good alternative for empirical therapy of S. aureus IE.
Subject(s)
Daptomycin , Endocarditis, Bacterial , Endocarditis , Methicillin-Resistant Staphylococcus aureus , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Cloxacillin , Endocarditis/drug therapy , Endocarditis, Bacterial/drug therapy , Methicillin/pharmacology , Methicillin Resistance , Microbial Sensitivity Tests , Rabbits , Staphylococcus aureus , VancomycinABSTRACT
The rise of multidrug resistant bacteria has significantly compromised our supply of antibiotics and poses an alarming medical and economic threat to society. To combat this problem, it is imperative that new antibiotics and treatment modalities be developed, especially those toward which bacteria are less capable of developing resistance. Peptide natural products stand as promising candidates to meet this need as bacterial resistance is typically slow in response to their unique modes of action. They also have additional benefits including favorable modulation of host immune responses and often possess broad-spectrum activity against notoriously treatment resistant bacterial biofilms. Moreover, nature has provided a wealth of peptide-based natural products from a range of sources, including bacteria and fungi, which can be hijacked in order to combat more dangerous clinically relevant infections.This Account highlights recent advances in the total synthesis and development of a range of peptide-based natural product antibiotics and details the medicinal chemistry approaches used to optimize their activity.In the context of antibiotics with potential to treat Gram-positive bacterial infections, this Account covers the synthesis and optimization of the natural products daptomycin, glycocin F, and alamethicin. In particular, the reported synthesis of daptomycin highlights the utility of on-resin ozonolysis for accessing a key kynurenine residue from the canonical amino acid tryptophan. Furthermore, the investigation into glycocin F analogues uncovered a potent lead compound against Lactobacillus plantarum that bears a non-native thioacetal linkage to a N-acetyl-d-glucosamine (GlcNAc) sugar, which is otherwise O-linked in its native form.For mycobacterial infections, this Account covers the synthesis and optimization of teixobactin, callyaerin A, lassomycin, and trichoderin A. The synthesis of callyaerin A, in particular, highlighted the importance of a (Z)-2,3-diaminoacrylamide motif for antimicrobial activity against Mycobacterium tuberculosis, while the synthesis of trichoderin A highlighted the importance of (R)-stereoconfiguration in a key 2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid (AHMOD) residue.Lastly, this Account covers lipopeptide antibiotics bearing activity toward Gram-negative bacterial infections, namely, battacin and paenipeptin C. In both cases, optimization of the N-terminal lipid tails led to the identification of analogues with potent activity toward Escherichia coli and Pseudomonas aeruginosa.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Peptides/chemical synthesis , Alamethicin/chemical synthesis , Alamethicin/pharmacology , Amino Acid Sequence , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacteriocins/chemical synthesis , Bacteriocins/pharmacology , Daptomycin/chemical synthesis , Daptomycin/pharmacology , Drug Evaluation, Preclinical , Drug Resistance, Multiple, Bacterial/drug effects , Gram-Positive Bacteria/drug effects , Lipopeptides/chemical synthesis , Lipopeptides/pharmacology , Microbial Sensitivity Tests , Ozone/chemistry , Peptides/chemistry , Peptides/pharmacology , Structure-Activity RelationshipABSTRACT
Complicated methicillin-resistant Staphylococcus aureus bloodstream infections (MRSA-BSIs), particularly those with delayed culture clearance, are associated with high mortality. Combination therapy with daptomycin and ceftaroline (DAP+CPT) represents a novel therapeutic approach to MRSA-BSI owing to synergistic bactericidal activity. This study aimed to compare DAP+CPT with historical standard of care (SoC) for treatment of complicated MRSA-BSI. This single-centre retrospective cohort study included patients with complicated MRSA-BSI at University of Colorado Hospital. Patients receiving DAP+CPT for ≥48 h between November 2013 and March 2020 or SoC with vancomycin or DAP ± gentamicin and/or rifampicin from November 2011 to December 2013 were compared. The primary outcome was clinical failure defined as a composite of MRSA-related mortality and recurrent infection at 60 days. A total of 60 patients received DAP+CPT (n = 30) or SoC (n = 30). Median age was 56 years and median Pitt bacteremia score was 3. Common infectious sites were endovascular (63%) and musculoskeletal (40%). DAP+CPT was associated with a numerically lower incidence of clinical failure compared with SoC (20% vs. 43%; P = 0.052). Multivariable analysis controlling for immunocompromised status (OR, 6.90, 95% CI 1.08-44.15), Charlson comorbidity index (OR, 1.12, 95% CI 0.90-1.39) and source control (OR, 0.35, 95% CI 0.08-1.46) associated DAP+CPT with 77% lower odds of clinical failure (OR, 0.23, 95% CI 0.06-0.89). In patients with complicated MRSA-BSI with delayed clearance, DAP+CPT trended towards lower rates of clinical failure than SoC and was significantly associated with decreased clinical failure after adjustment for baseline differences.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Cephalosporins/therapeutic use , Daptomycin/therapeutic use , Methicillin-Resistant Staphylococcus aureus/drug effects , Salvage Therapy , Staphylococcal Infections/drug therapy , Adult , Aged , Bacteremia/drug therapy , Drug Synergism , Drug Therapy, Combination , Female , Gentamicins/therapeutic use , Humans , Male , Microbial Sensitivity Tests , Middle Aged , Retrospective Studies , Rifampin/therapeutic use , Standard of Care , Staphylococcal Infections/mortality , Treatment Outcome , Vancomycin/therapeutic use , CeftarolineABSTRACT
BACKGROUND: Use of daptomycin at doses ≥ 6 mg/kg for treatment of osteomyelitis is increasing in clinical practice; unfortunately, limited data are available to guide optimal dosing and duration. The objective of this study was to assess daptomycin dosing and duration regimens for osteomyelitis treatment. METHODS: This was a retrospective, multi-site, cohort study conducted in an integrated healthcare delivery system. Nonpregnant patients ≥ 18 years of age with osteomyelitis diagnosed between November 1, 2003 and June 30, 2011, ≥ 2 weeks outpatient daptomycin therapy, and ≥ 1 month of follow-up were included. Daptomycin doses < 6 mg/kg and ≥ 6 mg/kg at durations of < 6 weeks and ≥ 6 weeks were examined with univariate and multivariate analyses to assess treatment success and all-cause mortality. RESULTS: A total of 247 patients were included, with 39 (15.8%), 37 (15.0%), 107 (43.3%), and 64 (25.9%) receiving < 6 mg/kg and ≥ 6 weeks, < 6 mg/kg and < 6 weeks, ≥ 6 mg/kg and ≥ 6 weeks, and ≥ 6 mg/kg and < 6 weeks of daptomycin therapy, respectively. Patients had a mean age of 58 years and had received prior vancomycin therapy (65.6%). Patients receiving < 6 weeks of therapy were less likely to experience treatment success compared with ≥ 6 weeks (41.5% vs 25.3%, adjusted odds ratio = 0.55; 95% confidence interval = 0.31-0.98) independent of duration. There were no differences across groups in mortality after adjustment. CONCLUSION: In a diverse clinical population, daptomycin for treatment of osteomyelitis of 6 weeks or longer duration was associated with success independent of dose. This finding supports longer treatment with daptomycin as a first-line agent in antimicrobial stewardship initiatives.
Subject(s)
Daptomycin , Osteomyelitis , Anti-Bacterial Agents/adverse effects , Cohort Studies , Daptomycin/adverse effects , Daptomycin/therapeutic use , Humans , Middle Aged , Osteomyelitis/chemically induced , Osteomyelitis/drug therapy , Outpatients , Retrospective Studies , Treatment OutcomeABSTRACT
The antimicrobial resistance crisis has persisted despite broad attempts at intervention. It has been proposed that an important driver of resistance is selection imposed on bacterial populations that are not the intended target of antimicrobial therapy. But to date, there has been limited quantitative measure of the mean and variance of resistance following antibiotic exposure. Here we focus on the important nosocomial pathogen Enterococcus faecium in a hospital system where resistance to daptomycin is evolving despite standard interventions. We hypothesized that the intravenous use of daptomycin generates off-target selection for resistance in transmissible gastrointestinal (carriage) populations of E. faecium. We performed a cohort study in which the daptomycin resistance of E. faecium isolated from rectal swabs from daptomycin-exposed patients was compared to a control group of patients exposed to linezolid, a drug with similar indications. In the daptomycin-exposed group, daptomycin resistance of E. faecium from the off-target population was on average 50% higher than resistance in the control group (n = 428 clones from 22 patients). There was also greater phenotypic diversity in daptomycin resistance within daptomycin-exposed patients. In patients where multiple samples over time were available, a wide variability in temporal dynamics were observed, from long-term maintenance of resistance to rapid return to sensitivity after daptomycin treatment stopped. Sequencing of isolates from a subset of patients supports the argument that selection occurs within patients. Our results demonstrate that off-target gastrointestinal populations rapidly respond to intravenous antibiotic exposure. Focusing on the off-target evolutionary dynamics may offer novel avenues to slow the spread of antibiotic resistance.
Subject(s)
Daptomycin/pharmacology , Drug Resistance, Bacterial/drug effects , Vancomycin-Resistant Enterococci/drug effects , Adaptation, Physiological/drug effects , Adaptation, Physiological/physiology , Adult , Anti-Bacterial Agents/therapeutic use , Cohort Studies , Enterococcus faecium/drug effects , Enterococcus faecium/metabolism , Female , Humans , Male , Microbial Sensitivity Tests , Phylogeny , Vancomycin/pharmacology , Vancomycin-Resistant Enterococci/metabolismABSTRACT
Vancomycin and daptomycin are options for the initial treatment of patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Treatment options for persistent MRSA bacteremia or bacteremia due to vancomycin-intermediate or vancomycin-resistant strains include daptomycin, ceftaroline, and combination therapies. There is a critical need for high-level evidence from clinical trials to allow optimally informed decisions in the treatment of MRSA bacteremia.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Bacteremia/microbiology , Methicillin-Resistant Staphylococcus aureus/drug effects , Staphylococcal Infections/drug therapy , Anti-Bacterial Agents/pharmacology , Bacteremia/drug therapy , Cephalosporins/pharmacology , Cephalosporins/therapeutic use , Clinical Trials as Topic , Daptomycin/pharmacology , Daptomycin/therapeutic use , Humans , Microbial Sensitivity Tests , Staphylococcal Infections/microbiology , Vancomycin/pharmacology , Vancomycin/therapeutic use , CeftarolineABSTRACT
Enterococcus faecalis is a Gram-positive bacterium that normally exists as an intestinal commensal in humans but is also a leading cause of nosocomial infections. Previous work noted that growth supplementation with serum induced tolerance to membrane-damaging agents, including the antibiotic daptomycin. Specific fatty acids found within serum could independently provide tolerance to daptomycin (protective fatty acids), yet some fatty acids found in serum did not and had negative effects on enterococcal physiology (nonprotective fatty acids). Here, we measured a wide array of physiological responses after supplementation with combinations of protective and nonprotective fatty acids to better understand how serum induces daptomycin tolerance. When cells were supplemented with either nonprotective fatty acid, palmitic acid, or stearic acid, there were marked defects in growth and morphology, but these defects were rescued upon supplementation with either protective fatty acid, oleic acid, or linoleic acid. Membrane fluidity decreased with growth in either palmitic or stearic acid alone but returned to basal levels when a protective fatty acid was supplied. Daptomycin tolerance could be induced if a protective fatty acid was provided with a nonprotective fatty acid, and some specific combinations protected as well as serum supplementation. While cell envelope charge has been associated with tolerance to daptomycin in other Gram-positive bacteria, we concluded that it does not correlate with the fatty acid-induced protection we observed. Based on these observations, we conclude that daptomycin tolerance by serum is driven by specific, protective fatty acids found within the fluid.IMPORTANCE With an increasing prevalence of antibiotic resistance in the clinic, we strive to understand more about microbial defensive mechanisms. A nongenetic tolerance to the antibiotic daptomycin was discovered in Enterococcus faecalis that results in the increased survival of bacterial populations after treatment with the drug. This tolerance mechanism likely synergizes with antibiotic resistance in the clinic. Given that this tolerance phenotype is induced by incorporation of fatty acids present in the host, it can be assumed that infections by this organism require a higher dose of antibiotic for successful eradication. The mixture of fatty acids in human fluids is quite diverse, with little understanding between the interplay of fatty acid combinations and the tolerance phenotype we observe. It is crucial to understand the effects of fatty acid combinations on E. faecalis physiology if we are to suppress the tolerance physiology in the clinic.
Subject(s)
Anti-Bacterial Agents/pharmacology , Daptomycin/pharmacology , Drug Resistance, Bacterial , Enterococcus faecalis/physiology , Linoleic Acid/metabolism , Oleic Acid/metabolism , Cell Membrane/physiology , Enterococcus faecalis/drug effectsABSTRACT
BACKGROUND: We prospectively evaluated efficacy and safety of daptomycin versus active comparator in children with acute hematogenous osteomyelitis (AHO). METHODS: Randomized, controlled, double-blind, global, multicenter, phase 3 trial. Patients 1-17 years of age with suspected/confirmed AHO requiring hospitalization and intravenous therapy were randomized 1:1 to intravenous daptomycin (once-daily, age-adjusted doses) or comparator (vancomycin, nafcillin or equivalent) ≥4 days, followed by oral therapy (14-42 days total). Primary endpoint: protocol-defined clinical improvement by Day 5 in the modified intention-to-treat (MITT) population (confirmed AHO, ≥1 dose of study treatment); differences between study arms were evaluated using a prespecified 15% noninferiority margin for daptomycin. RESULTS: Seventy-three patients per arm received treatment. Pathogens were isolated from 62% of patients (83% methicillin-susceptible Staphylococcus aureus, 9% methicillin-resistant S. aureus [MRSA]). Clinical improvement by Day 5 was observed in 55/71 (78%) daptomycin- and 58/70 (83%) comparator-treated MITT patients (95% confidence interval [CI]: -19.4, 7.4). This difference was not statistically significant; however, daptomycin did not meet the prespecified 15% noninferiority margin, since the lower bound of the 95% CI extended below 15%. Overall, 82% of daptomycin and 87% of comparator patients achieved clinical cure at the test-of-cure visit (secondary endpoint). More comparator patients had treatment-emergent (63% vs. 46%) and treatment-related (18% vs. 7%) adverse events. CONCLUSIONS: Differences between daptomycin and comparator for the primary endpoint were not statistically significant; however, prespecified noninferiority criteria for daptomycin were not met. With insufficient cases of confirmed MRSA, we could not evaluate daptomycin for MRSA AHO. Our nonvalidated protocol design yields valuable information for implementing future trials in AHO (ClinicalTrials.gov NCT01922011).