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Microbiology Spectrum Aug 2023Enterococcus faecium is a difficult-to-treat pathogen with emerging resistance to most clinically available antibiotics. Daptomycin (DAP) is the standard of care, but...
Enterococcus faecium is a difficult-to-treat pathogen with emerging resistance to most clinically available antibiotics. Daptomycin (DAP) is the standard of care, but even high DAP doses (12 mg/kg body weight/day) failed to eradicate some vancomycin-resistant strains. Combination DAP-ceftaroline (CPT) may increase β-lactam affinity for target penicillin binding proteins (PBP); however, in a simulated endocardial vegetation (SEV) pharmacokinetic/pharmacodynamic (PK/PD) model, DAP-CPT did not achieve therapeutic efficacy against a DAP-nonsusceptible (DNS) vancomycin-resistant E. faecium (VRE) isolate. Phage-antibiotic combinations (PAC) have been proposed for resistant high-inoculum infections. We aimed to identify PAC with maximum bactericidal activity and prevention/reversal of phage and antibiotic resistance in an SEV PK/PD model against DNS isolate R497. Phage-antibiotic synergy (PAS) was evaluated with modified checkerboard MIC and 24-h time-kill analyses (TKA). Human-simulated antibiotic doses of DAP and CPT with phages NV-497 and NV-503-01 were then evaluated in 96-h SEV PK/PD models against R497. Synergistic and bactericidal activity was identified with the PAC of DAP-CPT combined with phage cocktail NV-497-NV-503-01, demonstrating a significant reduction in viability down to 3-log CFU/g (-Δ, 5.77-log CFU/g; 0.001). This combination also demonstrated isolate resensitization to DAP. Evaluation of phage resistance post-SEV demonstrated prevention of phage resistance for PACs containing DAP-CPT. Our results provide novel data highlighting bactericidal and synergistic activity of PAC against a DNS E. faecium isolate in a high-inoculum SEV PK/PD model with subsequent DAP resensitization and prevention of phage resistance. Our study supports the additional benefit of standard-of-care antibiotics combined with a phage cocktail compared to antibiotic alone against a daptomycin-nonsusceptible (DNS) E. faecium isolate in a high-inoculum simulated endocardial vegetation PK/PD model. E. faecium is a leading cause of hospital-acquired infections and is associated with significant morbidity and mortality. Daptomycin is considered the first-line therapy for vancomycin-resistant E. faecium (VRE), but the highest published doses have failed to eradicate some VRE isolates. The addition of a β-lactam to daptomycin may result in synergistic activity, but previous data demonstrate that daptomycin plus ceftaroline failed to eradicate a VRE isolate. Phage therapy as an adjunct to antibiotic therapy has been proposed as a salvage therapy for high-inoculum infections; however, pragmatic clinical comparison trials for endocarditis are lacking and difficult to design, reinforcing the timeliness of such analysis.
Topics: Humans; Anti-Bacterial Agents; Daptomycin; Enterococcus faecium; Vancomycin; beta-Lactams; Microbial Sensitivity Tests; Ceftaroline
PubMed: 37338375
DOI: 10.1128/spectrum.00340-23 -
Therapeutic Drug Monitoring Aug 2023Conventionally, vancomycin trough levels have been used for therapeutic drug monitoring (TDM). Owing to the increasing evidence of trough levels being poor surrogates of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Conventionally, vancomycin trough levels have been used for therapeutic drug monitoring (TDM). Owing to the increasing evidence of trough levels being poor surrogates of area under the curve (AUC) and the advent of advanced pharmacokinetics software, a paradigm shift has been made toward AUC-guided dosing. This study aims to evaluate the impact of AUC-guided versus trough-guided TDM on vancomycin-associated nephrotoxicity.
METHODS
A systematic review was conducted using PubMed, Embase, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Google scholar, and Cochrane library databases; articles published from January 01, 2009, to January 01, 2021, were retrieved and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Studies that evaluated trough-guided or AUC-guided vancomycin TDM and vancomycin-associated nephrotoxicity were included. Random-effects models were used to compare the differences in nephrotoxicity.
RESULTS
Of the 1191 retrieved studies, 57 were included. Most studies included adults and older adults (n = 47, 82.45%). The pooled prevalence of nephrotoxicity was lower in AUC-guided TDM [6.2%; 95% confidence interval (CI): 2.9%-9.5%] than in trough-guided TDM (17.0%; 95% CI: 14.7%-19.2%). Compared with the trough-guided approach, the AUC-guided approach had a lower risk of nephrotoxicity (odds ratio: 0.53; 95% CI: 0.32-0.89). The risk of nephrotoxicity was unaffected by the AUC derivation method. AUC thresholds correlated with nephrotoxicity only within the first 96 hours of therapy.
CONCLUSIONS
The AUC-guided approach had a lower risk of nephrotoxicity, supporting the updated American Society of Health-System Pharmacists guidelines. Further studies are needed to evaluate the optimal AUC-derivation methods and clinical utility of repeated measurements of the AUC and trough levels of vancomycin.
Topics: Humans; Aged; Vancomycin; Anti-Bacterial Agents; Area Under Curve; Drug Monitoring; Retrospective Studies; Microbial Sensitivity Tests
PubMed: 36728329
DOI: 10.1097/FTD.0000000000001075 -
Clinical Pharmacokinetics Jan 2024The latest vancomycin guideline recommends area under the curve (AUC)-targeted dosing and monitoring for efficacy and safety. However, guidelines for AUC-targeted... (Clinical Trial)
Clinical Trial
BACKGROUND AND OBJECTIVE
The latest vancomycin guideline recommends area under the curve (AUC)-targeted dosing and monitoring for efficacy and safety. However, guidelines for AUC-targeted starting dosing in patients with obesity and/or renal insufficiency are currently lacking. This study quantifies the pharmacokinetics (PK) of vancomycin in this population and provides AUC-targeted dosing recommendations.
METHODS
Vancomycin concentrations (n = 1188) from therapeutic drug monitoring of 210 overweight and obese patients with varying degrees of renal (dys)function from the ward (74.8%) and intensive care unit (ICU, 25.2%) were pooled with published rich concentration-time data (n = 207) from 20 (morbidly) obese subjects undergoing bariatric surgery. A population model was developed using NONMEM 7.4. Stochastic simulations were performed to design dosing guidelines targeting an AUC between 400-600 mg·h/L.
RESULTS
Vancomycin clearance (CL) was found to increase linearly with total bodyweight and with renal function (CKD-EPI) in a power relation. Additionally, CL proved 15.5% lower in ICU patients. Our model shows that, to reach the target AUC between 400 and 600 mg·h/L in the first 48 h, two loading doses are required for both continuous infusion and intermittent dosing regimens. Maintenance doses were found to require adjustment for total bodyweight, renal function, and ICU admission status. With this guideline, the median AUC is well within the target from the start of the treatment onwards.
CONCLUSIONS
To achieve safe and effective vancomycin exposure for maintenance doses in overweight and obese patients, renal function, total bodyweight, and ICU admission status should be taken into account.
TRIAL REGISTRATION
The AMIGO trial was registered in the Dutch Trial Registry [NTR6058].
Topics: Humans; Anti-Bacterial Agents; Area Under Curve; Kidney; Obesity; Overweight; Vancomycin
PubMed: 37971650
DOI: 10.1007/s40262-023-01324-5 -
The International Journal of Lower... Oct 2023Diabetic foot infections (DFIs) are a common and costly complication of diabetes. Soft tissue and bone infections in DFIs frequently lead to amputation and/or sepsis... (Review)
Review
Diabetic foot infections (DFIs) are a common and costly complication of diabetes. Soft tissue and bone infections in DFIs frequently lead to amputation and/or sepsis which can be costly for both the patient and the healthcare system. is the most commonly identified causative agent in DFIs, and people with diabetes may have an increased risk of infection with methicillin-resistant (MRSA). In addition to increased susceptibility to severe infection, MRSA in DFIs is associated with high rates of treatment failure, morbidity, and hospitalization costs meaning appropriate treatment is a high priority. While hospitalized patients are usually treated with intravenous (IV) vancomycin, this can be costly in terms of inpatient stays, staffing costs, and adverse events. For example, vancomycin-associated acute kidney injury not only delays hospital discharge and increases costs but is also a particular concern for patients with diabetes who already have an increased risk of kidney problems. Vancomycin-resistant strains of have also been identified, which means that alternative treatment options may need to be explored. Treatment alternatives to IV vancomycin, including oral antibiotics, have been shown to provide similar efficacy, with reduced costs, outpatient or home-based administration, and with fewer serious adverse effects. Although infectious disease specialists often use IV vancomycin alone, or in combination, as a first-line therapeutic option, they are increasingly seeing the value of outpatient or at-home oral antibiotics as an alternative. This manuscript reviews the evidence for true costs of vancomycin therapy for MRSA-associated DFIs and examines the alternatives.
PubMed: 37886812
DOI: 10.1177/15347346231207553 -
The Journal of Infectious Diseases Jan 2024Clostridioides difficile infection (CDI) is a common healthcare-associated infection with limited treatment options. Omadacycline, an aminomethylcycline tetracycline,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Clostridioides difficile infection (CDI) is a common healthcare-associated infection with limited treatment options. Omadacycline, an aminomethylcycline tetracycline, has potent in vitro activity against C difficile and a low propensity to cause CDI in clinical trials. We aimed to assess fecal pharmacokinetics and gut microbiome effects of oral omadacycline compared to oral vancomycin in healthy adults.
METHODS
This was a phase 1, nonblinded, randomized clinical trial conducted in healthy volunteers aged 18-40 years. Subjects received a 10-day course of omadacycline or vancomycin. Stool samples were collected at baseline, daily during therapy, and at follow-up visits. Omadacycline and vancomycin stool concentrations were assessed, and microbiome changes were compared.
RESULTS
Sixteen healthy volunteers with a mean age of 26 (standard deviation [SD], 5) years were enrolled; 62.5% were male, and participants' mean body mass index was 23.5 (SD, 4.0) kg/m2. Omadacycline was well tolerated with no safety signal differences between the 2 antibiotics. A rapid initial increase in fecal concentrations of omadacycline was observed compared to vancomycin, with maximum concentrations achieved within 48 hours. A significant difference in alpha diversity was observed following therapy in both the omadacycline and vancomycin groups (P < .05). Bacterial abundance and beta diversity analysis showed differing microbiome changes in subjects who received omadacycline versus vancomycin.
CONCLUSIONS
Subjects given omadacycline had high fecal concentrations with a distinct microbiome profile compared to vancomycin.
CLINICAL TRIALS REGISTRATION
NCT06030219.
Topics: Adult; Humans; Male; Female; Vancomycin; Gastrointestinal Microbiome; Healthy Volunteers; Anti-Bacterial Agents; Tetracyclines; Clostridium Infections
PubMed: 38051631
DOI: 10.1093/infdis/jiad537 -
Acta Ortopedica Mexicana 2024intravenous antibiotic prophylaxis has significantly reduced the incidence of periprosthetic joint infection (PJI) in knee surgeries. However, for patients colonized...
INTRODUCTION
intravenous antibiotic prophylaxis has significantly reduced the incidence of periprosthetic joint infection (PJI) in knee surgeries. However, for patients colonized with methicillin-resistant Staphylococcus aureus (MRSA) or those at risk of colonization, prophylaxis should include vancomycin. Intraosseous (IO) administration of vancomycin could enhance its effectiveness in total knee arthroplasty (TKA).
MATERIAL AND METHODS
a retrospective review was conducted, including 143 patients at risk of PJI scheduled for TKA who received IO vancomycin along with intravenous (IV) cefazolin, referred to as group I (GI), between May 2021 and December 2022. The occurrence of complications in the first three postoperative months was evaluated. Results were compared with 140 patients without risk factors who received standard IV prophylaxis, designated as group II (GII).
RESULTS
in GI, 500 mg of IO vancomycin was administered, injected into the proximal tibia, in addition to standard IV prophylaxis. In GII, patients received only IV cefazolin. The incidence of complications was 1.64% in GI and 1.4% in GII. The PJI rate at 90 postoperative days was 0.69% in GI and 0.71% in GII.
CONCLUSIONS
IO vancomycin administration, along with standard IV prophylaxis, provides a safe and effective alternative for patients at risk of MRSA colonization. This approach minimizes complications associated with IV vancomycin use and addresses logistical challenges of timely administration.
Topics: Humans; Vancomycin; Retrospective Studies; Arthroplasty, Replacement, Knee; Male; Female; Aged; Anti-Bacterial Agents; Antibiotic Prophylaxis; Middle Aged; Prosthesis-Related Infections; Cefazolin; Methicillin-Resistant Staphylococcus aureus; Infusions, Intraosseous; Aged, 80 and over; Staphylococcal Infections
PubMed: 38862147
DOI: 10.35366/115812 -
International Microbiology : the... Nov 2023The pathogenic potential of vancomycin and methicillin-resistant coagulase-negative Staphylococci (VMRCoNS) on Egyptian poultry farms has received little attention....
The pathogenic potential of vancomycin and methicillin-resistant coagulase-negative Staphylococci (VMRCoNS) on Egyptian poultry farms has received little attention. Therefore, this study aims to study the prevalence of CoNS in imported poultry flocks and commercial poultry farms, evaluate the presence of virulence and antibiotic resistance genes (sea, seb, sec, sed, see, and mecA), and assess their pathogenicity in broiler chicks. Seven species were identified among 25 isolates, such as 8 S. gallinarum, 5 S. saprophyticus, 5 S. chromogens, 3 S. warneri, 2 S. hominis, 1 S. caprae, and 1 S. epidermidis. All isolates were resistant to clindamycin, doxycycline, vancomycin, methicillin, rifampicin, and penicillin. The mecA gene was confirmed in 14 isolates, while the sed gene was revealed in seven isolates. Commercial 1-day-old Ross broiler chicks were divided into eight groups of three replicates (10 birds/group): group Ӏ was negative control; groups (П, Ш, IV, V, VI, VII, and VIII) were subcutaneously inoculated with 10 CFUml of S. hominis, S. caprae, S. epidermidis, S. gallinarum, S. chromogens, S. warneri, and S. saprophyticus, respectively. Groups VIII and V had mortality rates of 100% and 20%, respectively, with no evidence of mortalities in the other groups. The highest re-isolation of CoNS species was recorded in groups VII, VIII, and V. Postmortem and histopathological examination revealed the common presence of polyserositis in the internal organs, and hepatic and myocardial necrosis in groups IV, V, and VI. These findings revealed the pathogenic potential of CoNS, so special attention must be directed toward their public health impact.
Topics: Animals; Chickens; Coagulase; Virulence; Vancomycin; Staphylococcal Infections; Staphylococcus; Anti-Bacterial Agents; Microbial Sensitivity Tests
PubMed: 37055707
DOI: 10.1007/s10123-023-00354-0 -
Germs Dec 2023is a rare pathogen in human infections, despite being widely distributed in natural environments. This systematic review aims to evaluate the evidence related to... (Review)
Review
INTRODUCTION
is a rare pathogen in human infections, despite being widely distributed in natural environments. This systematic review aims to evaluate the evidence related to endophthalmitis caused by .
METHODS
A thorough search of PubMed, PubMed Central, and Scopus databases was conducted, covering the period up to October 2022.
RESULTS
A total of 53 records were identified, with 8 studies reporting a total of 21 cases meeting the inclusion criteria. Among these studies, 7 described isolated case reports, while 1 study described 14 cases. The overall quality of the reports was good, as all articles were determined to have low risk of bias. Vancomycin susceptibility was reported in only one case of isolated case reports, while the remaining cases were all vancomycin resistant. With regard to management, in most cases intravenous ampicillin and linezolid were administered, while only one study reported administration of vancomycin.
CONCLUSIONS
Ophthalmologists should be aware of the potential for to cause endophthalmitis infections and the challenges associated with its intrinsic resistance to vancomycin.
PubMed: 38361537
DOI: 10.18683/germs.2023.1404 -
PloS One 2023We developed a rat model of prosthetic vascular graft infection to assess, whether the fibrinolytic tissue plasminogen activator (tPA) could increase the efficacy of...
OBJECTIVES
We developed a rat model of prosthetic vascular graft infection to assess, whether the fibrinolytic tissue plasminogen activator (tPA) could increase the efficacy of antibiotic therapy.
MATERIALS AND METHODS
Rats were implanted a polyethylene graft in the common carotid artery, pre-inoculated with approx. 6 log10 colony forming units (CFU) of methicillin resistant Staphylococcus aureus. Ten days after surgery, rats were randomized to either: 0.9% NaCl (n = 8), vancomycin (n = 8), vancomycin + tPA (n = 8), vancomycin + rifampicin (n = 18) or vancomycin + rifampicin + tPA (n = 18). Treatment duration was seven days. Approximately 36 hours after the end of treatment, the rats were euthanized, and grafts and organs were harvested for CFU enumeration.
RESULTS
All animals in the control group had significantly higher CFU at the time of euthanization compared to bacterial load found on the grafts prior to inoculation (6.45 vs. 4.36 mean log10 CFU/mL, p = 0.0011), and both the procedure and infection were well tolerated. Vancomycin and rifampicin treatment were superior to monotherapy with vancomycin, as it lead to a marked decrease in median bacterial load on the grafts (3.50 vs. 6.56 log10 CFU/mL, p = 0.0016). The addition of tPA to vancomycin and rifampicin combination treatment did not show a further decrease in bacterial load (4.078 vs. 3.50 log10 CFU/mL, p = 0.26). The cure rate was 16% in the vancomycin + rifampicin group vs. 37.5% cure rate in the vancomycin + rifampicin + tPA group. Whilst interesting, this trend was not significant at our sample size (p = 0.24).
CONCLUSION
We developed the first functional model of an arterial prosthetic vascular graft infection in rats. Antibiotic combination therapy with vancomycin and rifampicin was superior to vancomycin monotherapy, and the addition of tPA did not significantly reduce bacterial load, nor significantly increase cure rate.
Topics: Animals; Rats; Anti-Bacterial Agents; Methicillin-Resistant Staphylococcus aureus; Prosthesis-Related Infections; Rifampin; Staphylococcal Infections; Tissue Plasminogen Activator; Vancomycin
PubMed: 37463137
DOI: 10.1371/journal.pone.0287671 -
Antimicrobial Resistance and Infection... Aug 2023The rising prevalence of vancomycin-resistant enterococci (VRE) is a matter of concern in hospital settings across Europe without a distinct geographical pattern. In... (Review)
Review
The rising prevalence of vancomycin-resistant enterococci (VRE) is a matter of concern in hospital settings across Europe without a distinct geographical pattern. In this scoping review, we compared the epidemiology of vancomycin-resistant Enterococcus spp. in hospitals in the Netherlands and Germany, between 1991 and 2022. We searched PubMed and summarized the national antibiotic resistance surveillance data of the two countries. We included 46 studies and summarized national surveillance data from the NethMap in the Netherlands, the National Antimicrobial Resistance Surveillance database in Germany, and the EARS-Net data. In total, 12 studies were conducted in hospitals in the Netherlands, 32 were conducted in German hospitals, and an additional two studies were conducted in a cross-border setting. The most significant difference between the two countries was that studies in Germany showed an increasing trend in the prevalence of VRE in hospitals, and no such trend was observed in studies in the Netherlands. Furthermore, in both Dutch and German hospitals, it has been revealed that the molecular epidemiology of VREfm has shifted from a predominance of vanA towards vanB over the years. According to national surveillance reports, vancomycin resistance in Enterococcus faecium clinical isolates fluctuates below 1% in Dutch hospitals, whereas it follows an increasing trend in German hospitals (above 20%), as supported by individual studies. This review demonstrates that VRE is more frequently encountered in German than in Dutch hospitals and discusses the underlying factors for the difference in VRE occurrence in these two neighboring countries by comparing differences in healthcare systems, infection prevention control (IPC) guidelines, and antibiotic use in the Netherlands and Germany.
Topics: Humans; Vancomycin-Resistant Enterococci; Netherlands; Gram-Positive Bacterial Infections; Germany; Hospitals
PubMed: 37568229
DOI: 10.1186/s13756-023-01278-0