Eosinophilic Pneumonia Induced by Daptomycin.

Daptomycin-induced eosinophilic pneumonia (DIEP) is a rare but serious complication associated with the use of this broad-spectrum antibiotic. We present the case of a teenager with a history of nasopharyngeal cancer who developed DIEP while receiving daptomycin to treat an infection associated with an implanted chamber catheter. Symptoms included recurrent dyspnea and peripheral eosinophilia, with radiological findings consistent with DIEP. The pathophysiology involves an immune response triggered by daptomycin, resulting in eosinophilic pulmonary inflammation. Diagnosis requires a thorough evaluation of medical history, clinical laboratory tests, and radiological findings. The main treatment involves discontinuation of daptomycin and, in severe cases, the use of steroids. It is essential to consider DIEP in patients with respiratory failure and bilateral pulmonary opacities who have used daptomycin and to suspect it in those with blood eosinophilia or in bronchoalveolar lavage.

Daptomycin-Induced Eosinophilic Pneumonia: Can an Antibiotic Cause Pneumonia?

We present an interesting case of a patient who was discharged from the hospital on daptomycin and ertapenem in the setting of osteomyelitis. The patient did not have any respiratory symptoms during that hospital stay. A few weeks after discharge, the patient came back to the hospital with complaints of fever and shortness of breath. Chest X-ray showed pulmonary infiltrates. Initially, the patient was treated for acute respiratory distress syndrome (ARDS) vs pneumonia, but she did not improve. When labs showed significant eosinophilia, daptomycin-induced eosinophilic pneumonia became the working diagnosis, and the patient improved significantly when daptomycin was discontinued and steroids were started.

Early Initiation of Ceftaroline-Based Combination Therapy for Methicillin-resistant Staphylococcus aureus Bacteremia.

Purpose: Monotherapy with vancomycin or daptomycin remains guideline-based care for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B) despite concerns regarding efficacy. Limited data support potential benefit of combination therapy with ceftaroline as initial therapy. We present an assessment of outcomes of patients initiated on early combination therapy for MRSA-B. Methods: This was a single-center, retrospective study of adult patients admitted with MRSA-B between July 1, 2017 and April 31, 2023. During this period, there was a change in institutional practice from routine administration of monotherapy to initial combination therapy for most patients with MRSA-B. Combination therapy included vancomycin or daptomycin plus ceftaroline within 72 hours of index blood culture and monotherapy was vancomycin or daptomycin alone. The primary outcome was a composite of persistent bacteremia, 30-day all-cause mortality, and 30-day bacteremia recurrence. Time to microbiological cure and safety outcomes were assessed. All outcomes were assessed using propensity score-weighted logistic regression. Results: Of 213 patients included, 118 received monotherapy (115 vancomycin, 3 daptomycin) and 95 received combination therapy with ceftaroline (76 vancomycin, 19 daptomycin). The mean time from MRSA-positive molecular diagnostic blood culture result to combination therapy was 12.1 hours. There was no difference between groups for the primary composite outcome (OR 1.58, 95% CI 0.60, 4.18). Time to microbiological cure was longer with combination therapy (mean difference 1.50 days, 95% CI 0.60, 2.41). Adverse event rates were similar in both groups. Conclusions: Early initiation of ceftaroline-based combination therapy did not improve outcomes for patients with MRSA-B in comparison to monotherapy therapy.

Rare Lung Malignancy Mimic: A Case of Daptomycin-Induced Acute Eosinophilic Pneumonia.

Daptomycin is an antibiotic used for resistant Gram-positive organisms and has the rare side effect of inducing acute eosinophilic pneumonia (AEP). This condition can be fatal due to respiratory failure if not treated, as eosinophils migrate to the lungs and inflammatory cascades cause epithelial injury. Daptomycin-induced AEP can be misdiagnosed as bacterial pneumonia or malignancy, which may lead to unnecessary testing or treatments. Diagnostic criteria include dyspnea, fever, recent daptomycin exposure, infiltrates on imaging, eosinophils on bronchoalveolar lavage or peripheral eosinophilia, and clinical improvement with medication discontinuation. We present a unique case of daptomycin-induced eosinophilic pneumonia in a 72-year-old male with the chief complaint of dyspnea and initial concerns for lung cancer after a spiculated nodule was seen on imaging. Prior to undergoing a lung biopsy, repeat imaging showed a decrease in the suspicious nodule, reducing the likelihood of malignancy and prompting a re-evaluation of the history of the present illness and medication list. Daptomycin was stopped, and the patient's symptoms and imaging improved. This case illustrates the importance of early recognition and appropriate treatment of AEP, which allows for complete clinical recovery.

Antibiotics daptomycin interacts with S protein of SARS-CoV-2 to promote cell invasion of Omicron (B1.1.529) pseudovirus.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has posed enormous challenges to global public health. The use of antibiotics has greatly increased during the SARS-CoV-2 epidemic owing to the presence of bacterial co-infection and secondary bacterial infections. The antibiotics daptomycin (DAP) is widely used in the treatment of infectious diseases caused by gram-positive bacteria owing to its highly efficient antibacterial activity. It is pivotal to study the antibiotics usage options for patients of coronavirus infectious disease (COVID-19) with pneumonia those need admission to receive antibiotics treatment for bacterial co-infection in managing COVID-19 disease. Herein, we have revealed the interactions of DAP with the S protein of SARS-CoV-2 and the variant Omicron (B1.1.529) using the molecular docking approach and Omicron (B1.1.529) pseudovirus (PsV) mimic invasion. Molecular docking analysis shows that DAP has a certain degree of binding ability to the S protein of SARS-CoV-2 and several derived virus variants, and co-incubation of 1-100 µM DAP with cells promotes the entry of the PsV into human angiotensin-converting enzyme 2 (hACE2)-expressing HEK-293T cells (HEK-293T-hACE2), and this effect is related to the concentration of extracellular calcium ions (Ca2+). The PsV invasion rate in the HEK-293T-hACE2 cells concurrently with DAP incubation was 1.7 times of PsV infection alone. In general, our findings demonstrate that DAP promotes the infection of PsV into cells, which provides certain reference of antibiotics selection and usage optimization for clinicians to treat bacterial coinfection or secondary infection during SARS-CoV-2 infection.

Membrane Lipids Augment Cell Envelope Stress Signaling via the MadRS System to Defend Against Antimicrobial Peptides and Antibiotics in Enterococcus faecalis.

Enterococci have evolved resistance mechanisms to protect their cell envelopes against bacteriocins and host cationic antimicrobial peptides (CAMPs) produced in the gastrointestinal environment. Activation of the membrane stress response has also been tied to resistance to the lipopeptide antibiotic daptomycin. However, the actual effectors mediating resistance have not been elucidated. Here, we show that the MadRS (formerly YxdJK) membrane antimicrobial peptide defense system controls a network of genes, including a previously uncharacterized three gene operon (madEFG) that protects the E. faecalis cell envelope from antimicrobial peptides. Constitutive activation of the system confers protection against CAMPs and daptomycin in the absence of a functional LiaFSR system and leads to persistence of cardiac microlesions in vivo. Moreover, changes in the lipid cell membrane environment alter CAMP susceptibility and expression of the MadRS system. Thus, we provide a framework supporting a multilayered envelope defense mechanism for resistance and survival coupled to virulence.

Daptomycin and ceftaroline combination for the treatment of persistent methicillin-resistant Staphylococcus aureus bloodstream infections: a case series and literature review.

Methicillin-resistant Staphylococcus aureus (MRSA) is challenging to treat due to a lack of guidance for clinicians. The daptomycin and ceftaroline combination is promising for treating persistent MRSA bloodstream infections (BSIs). In this report, we present a case series of 7 patients who failed vancomycin and then were treated with daptomycin and ceftaroline for persistent MRSA BSIs. The median age (IQR) of the included patients was 59 (48-67), with 5 male and 2 female patients. Six patients (85.7%) had a clinical cure for their persistent BSIs. The median time (IQR) for sterilization of MRSA BSIs after initiation of daptomycin and ceftaroline combination was 2 days (1-3). Among the patients who had clinical cures, the median time for clinical cures (IQR) was 6 weeks (4.5-6 weeks). The combination of daptomycin and ceftaroline could be an excellent treatment option for persistent MRSA BSIs.

Rapid Aggravation of Rhabdomyolysis Caused by Daptomycin After Aortic Arch Replacement: A Case Report.

Although rare, rhabdomyolysis is a serious complication of cardiothoracic surgery. Daptomycin is a polypeptide antimicrobial agent used to treat methicillin-resistant Staphylococcus aureus (MRSA) infections of the soft tissues. Daptomycin is associated with elevations in serum creatine kinase (CK). A 50-year-old man with acute Stanford A-type aortic dissection was performed Bentall procedure and total arch replacement with frozen elephant trunk. The CK level was 6,573 U/L on the first postoperative day (POD), suggesting rhabdomyolysis associated with lower limb ischemia. The CK level increased to 11,934 U/L on POD 2 and started to decrease thereafter. On POD 5, the patient had a suspected surgical site infection. Antibiotics were changed to empiric therapy of daptomycin and meropenem to address soft tissue MRSA infection. The CK level at the start of daptomycin administration was 4,122 U/L. However, the CK level rose to 21,813 U/L on POD 6. None of the findings suggested new-onset lower limb ischemia. Assuming that the rhabdomyolysis was induced by daptomycin, it was discontinued. The CK level peaked at 26,123 U/L on POD 8, after which it started to decrease and normalized on POD 16. Daptomycin should be used with extreme caution in patients recovering from rhabdomyolysis.

Daptomycin Inhibits Multiple Myeloma Progression through Downregulating the Expression of RPS19.

OBJECTIVES: This study aimed to explore new therapeutic drugs for multiple myeloma (MM). MM is a common plasma cell malignant proliferative disease, accounting for 15% of hematological malignancies. The role of daptomycin (DAP), a potential anti-tumor drug, remains unclear in MM. In the present research, we investigated the anticancer effect of DAP in MM cell line RPMI 8226. METHODS: RPMI 8226 cells were treated with DAP (20 µM, 40 µM, and 80 µM) with 20 nM bortezomib (BZ) as a positive control. Cell function was detected using CCK8, flow cytometry, and transwell assay. RESULTS: In MM cells, DAP inhibited proliferation and induced apoptosis. The cell cycle was arrested at the G1 phase after the treatment of DAP. The migration and invasion abilities were also inhibited by DAP treatment in RPMI 8226 cells. Importantly, the mRNA and protein levels of RPS19 were downregulated in DAP-treated RPMI 8226 cells. CONCLUSION: DAP inhibited the proliferation, migration, and invasion and promoted the apoptosis of MM cells. Mechanistically, the RPS19 expression was significantly decreased in DAPtreated cells. This research provides a potential therapeutic drug for MM therapy.

Whole genome sequencing identifies MprF mutations in a genetically diverse population of daptomycin non-susceptible Staphylococcus aureus in Australia.

OBJECTIVES: Daptomycin is one of the few last-line antimicrobials available for the treatment of multidrug-resistant Staphylococcus aureus infections. An increasing number of daptomycin non-susceptible S. aureus infections has been reported worldwide, including Australia. Resistance to daptomycin is multifactorial and involves chromosomal mutations in genes encoding proteins involved in cell membrane and cell wall synthesis. METHODS: In this study, we performed broth microdilution (BMD) to determine the daptomycin minimum inhibitory concentration (MIC) of 66 clinical isolates of S. aureus previously reported as daptomycin non-susceptible by the VITEKⓇ 2. We used whole genome sequencing to characterise the isolates and screened the genomes for mutations associated with daptomycin non-susceptibility. RESULTS: Only 56 of the 66 isolates had a daptomycin MIC >1 mg/L by BMD. Although the 66 isolates were polyclonal, ST22 was the predominant sequence type and one-third of the isolates were multidrug resistant. Daptomycin non-susceptibility was primarily associated with MprF mutations-at least one MprF mutation was identified in the 66 isolates. Twelve previously reported MprF mutations associated with daptomycin non-susceptibility were identified in 83% of the isolates. Novel MprF mutations identified included P314A, P314F, P314T, S337T, L341V, F349del, and T423R. CONCLUSIONS: Daptomycin non-susceptible S. aureus causing infections in Australia are polyclonal and harbour MprF mutation(s). The identification of multidrug-resistant daptomycin non-susceptible S. aureus is a public health concern.

Genomic Insights into Staphylococcus aureus Isolates Exhibiting Diminished Daptomycin Susceptibility.

Daptomycin is one of the last therapeutic resources for multidrug-resistant gram-positive bacteria. Despite its structural similarities with glycopeptides, its mechanisms of action and resistance are different and in some respects are not completely understood. Mutations in several genes have been associated with daptomycin resistance, especially in mprF, walkR, rpoB and rpoC, but their role and importance remain to be elucidated. We have studied mutations in 11 genes, which have been previously associated with daptomycin non-susceptibility, in nine daptomycin-non-susceptible Staphylococcus aureus clinical isolates (daptomycin MIC: >1 mg/L). Susceptibility to daptomycin, vancomycin, linezolid, oxacillin, telavancin and dalbavancin was studied. walkR, agrA, cls1, cls2, fakA, pnpA, clpP, prs, rpoB, rpoC and mprF were amplified by PCR and sequenced. The sequences were compared with the S. aureus ATCC 25923 complete genome (GenBank gi: 685631213) by using BLAST® software. We did not find any changes in walkR, pnpA, prs and clpP. All isolates excepting isolate MSa5 showed a high number of significant mutations (between 13 and 25 amino acid changes) in mprF. Most isolates also showed mutations in the rpo genes, the cls genes and fakA. Daptomycin non-susceptibility in S. aureus clinical isolates seems to be reached through different mutation combinations when compared to S. aureus ATCC 25293. Especially mprF and cls1 showed very high polymorphism in most isolates. Meanwhile, one isolate, MSa5, showed only single mutation in mprF (P314T).

Safety and Treatment Outcomes of Infants and Children Treated With Daptomycin: Six-Year Experience From a Pediatric Academic Medical Center.

Daptomycin is a common treatment for serious infections caused by gram-positive bacteria in adult patients; however, data regarding its safety and efficacy in the pediatric population are limited. This was a retrospective chart review of adverse reactions and treatment outcomes associated with daptomycin use in children <13 years old who received at least 1 dose of daptomycin. At least 1 dose of daptomycin was received by 147 patients. Seventy-two patients received daptomycin for 5 or more days. New-onset loose stools on daptomycin initiation were reported for 14 (9.5%) patients, elevations in creatine kinase in 3 (2%) patients, and elevated aspartate transaminase and alanine transaminase in 13 (8.8%) and 9 (6.1%) patients, respectively. Two patients (1.4%) had daptomycin discontinued due to specific concerns for adverse drug reactions. Daptomycin was found to be safe and effective in this pediatric cohort that included young children and infants with a variety of types and severities of infections.

Daptomycin Use for Persistent Coagulase-Negative Staphylococcal Bacteremia in a Neonatal Intensive Care Unit.

During the last two decades, the incidence of late-onset sepsis (LOS) has increased due to improved survival of premature neonates. Persistent bacteremia (PB) in LOS is defined as more than two positive blood cultures obtained on different calendar days during the same infectious episode. Although rare, PB should be treated aggressively to prevent adverse outcomes. Daptomycin, a lipopeptide antibiotic, has been used in neonates with persistent coagulase-negative staphylococci (CoNS) bacteremia with promising results, but studies reporting on the efficacy and safety of the agent are scarce. The purpose of this study was to evaluate the efficacy and safety of daptomycin use for persistent CoNS bacteremia in a neonatal cohort. This is a retrospective, observational, single-center study of neonates treated with daptomycin during 2011-2022 in the Tertiary Neonatal Intensive Care Unit (NICU) of the University General Hospital of Patras, Greece. For the years 2011-2022, there were 3.413 admissions to the NICU. During the last 3 years (2020-2022)-the active epidemiological surveillance period-123 infants (out of 851 admissions, 14.4%) developed CoNS bacteremia (LOS). During the study period, twelve infants with PB were treated with daptomycin. They had a median gestational age of 32 weeks (IQR 31-34) and mean (SD) birth weight of 1.840 (867) grams. CoNS bacteremia isolates were s. epidermidis (50%), s. haemolyticus (20%), s. hominis (20%) and s. warneri (10%). The decision to start daptomycin (6 mg/kg/dose twice daily) was taken on median day 10 (ΙQR 7-15) of infection. None of the infants had focal complications or meningitis. Daptomycin therapy caused no renal, hepatic, muscular or gastrointestinal adverse events. One neonate developed seizures, and one death occurred due to multiple complications of prematurity. Most infants (11/12) were successfully treated and eventually had negative blood culture. Daptomycin monotherapy showed an adequate cure rate in premature neonates with persistent CoNS bacteremia in a tertiary NICU. In our study, daptomycin was effective and well tolerated; the safety profile, however, needs to be confirmed in larger studies and randomized controlled trials.

A machine learning approach to predict daptomycin exposure from two concentrations based on Monte Carlo simulations.

Daptomycin is a concentration-dependent lipopeptide antibiotic for which exposure/effect relationships have been shown. Machine learning (ML) algorithms, developed to predict the individual exposure to drugs, have shown very good performances in comparison to maximum a posteriori Bayesian estimation (MAP-BE). The aim of this work was to predict the area under the blood concentration curve (AUC) of daptomycin from two samples and a few covariates using XGBoost ML algorithm trained on Monte Carlo simulations. Five thousand one hundred fifty patients were simulated from two literature population pharmacokinetics models. Data from the first model were split into a training set (75%) and a testing set (25%). Four ML algorithms were built to learn AUC based on daptomycin blood concentration samples at pre-dose and 1 h post-dose. The XGBoost model (best ML algorithm) with the lowest root mean square error (RMSE) in a 10-fold cross-validation experiment was evaluated in both the test set and the simulations from the second population pharmacokinetic model (validation). The ML model based on the two concentrations, the differences between these concentrations, and five other covariates (sex, weight, daptomycin dose, creatinine clearance, and body temperature) yielded very good AUC estimation in the test (relative bias/RMSE = 0.43/7.69%) and validation sets (relative bias/RMSE = 4.61/6.63%). The XGBoost ML model developed allowed accurate estimation of daptomycin AUC using C0, C1h, and a few covariates and could be used for exposure estimation and dose adjustment. This ML approach can facilitate the conduct of future therapeutic drug monitoring (TDM) studies.

Daptomycin and Ceftaroline Combination Therapy in Complicated Endovascular Infections Caused by Methicillin-Resistant Staphylococcus epidermidis.

Background In complicated endovascular infections by methicillin-resistant Staphylococcus aureus (MRSA) or Staphylococcus epidermidis (MRSE), when first-line therapy with vancomycin (VAN) or daptomycin (DAP) fails, combination therapy with ceftaroline (CFT) and DAP has been shown to be a useful approach as salvage therapy for persistent MRSA bacteremia. Objectives This study aimed to describe experience with daptomycin and ceftaroline combination therapy in MRSE-complicated endovascular infections. Methods A single-center retrospective review of consecutive patients with MRSE-complicated endovascular infections treated with ≥72 hours of DAP+CFT at any time during the course of treatment, from January 1, 2016 to December 31, 2020, at Centro Hospitalar Universitário São João (CHUSJ), Porto, Portugal, was conducted. The exclusion criteria were known resistance to daptomycin or ceftaroline, total time of combination therapy <72 hours and loss to follow-up. Results We identified seven cases that matched our criteria: five endocarditis and two central venous catheter infections. Six patients switched to combination therapy due to treatment failure with first-line agents - three due to persistent bacteremia and three due to progression of infection despite negative blood cultures. Effective surgical source control took one to four weeks to occur. Three patients died during the treatment, one from progression of the disease and two due to another infection. Conclusions We consider the DAP+CFT combination therapy to be a valid and safe therapeutic choice in complicated patients, such as those with severe infection, poor functional status, and impossibility or delay of surgical source control. However, conclusions on the role of combination therapy should be careful due to the low number of patients and the several confounding factors.

An essential protease, FtsH, influences daptomycin resistance acquisition in Enterococcus faecalis.

Daptomycin is a last-line antibiotic commonly used to treat vancomycin-resistant Enterococci, but resistance evolves rapidly and further restricts already limited treatment options. While genetic determinants associated with clinical daptomycin resistance (DAPR) have been described, information on factors affecting the speed of DAPR acquisition is limited. The multiple peptide resistance factor (MprF), a phosphatidylglycerol-modifying enzyme involved in cationic antimicrobial resistance, is linked to DAPR in pathogens such as methicillin-resistant Staphylococcus aureus. Since Enterococcus faecalis encodes two paralogs of mprF and clinical DAPR mutations do not map to mprF, we hypothesized that functional redundancy between the paralogs prevents mprF-mediated resistance and masks other evolutionary pathways to DAPR. Here, we performed in vitro evolution to DAPR in mprF mutant background. We discovered that the absence of mprF results in slowed DAPR evolution and is associated with inactivating mutations in ftsH, resulting in the depletion of the chaperone repressor HrcA. We also report that ftsH is essential in the parental, but not in the ΔmprF, strain where FtsH depletion results in growth impairment in the parental strain, a phenotype associated with reduced extracellular acidification and reduced ability for metabolic reduction. This presents FtsH and HrcA as enticing targets for developing anti-resistance strategies.

Daptomycin Dose Optimization in Pediatric Staphylococcus aureus Bacteremia: A Pharmacokinetic/Pharmacodynamic Investigation.

Daptomycin is an antibiotic with Gram-positive activity, including methicillin-resistant Staphylococcus aureus, for which optimal pediatric dosing is unknown. This study aimed to evaluate daptomycin exposures achieved with package label dosing and to identify dosing regimens necessary to enhance efficacy and minimize toxicity in children with S. aureus bacteremia. Monte Carlo simulations were performed to determine probability of target attainment (PTA) for six pediatric age cohorts. Area under the curve to minimum inhibitory concentration ratio (AUC0-24 :MIC) ≥666 was used to determine the PTA for efficacy (PTAE ). Minimum concentration (Cmin ) ≥24.3 mg/L determined the PTA for toxicity (PTAT ). Acceptable dosing regimens were those which achieved the combined target of ≥90% PTAE and ≤5% PTAT . Package label dosing of daptomycin yielded insufficient efficacy with only 26.3% PTAE in children 13-24 months, 39.5% PTAE in children 2-6 years, 30.1% PTAE in children 7-11 years, and 50.1% PTAE in adolescents ≥12 years. To achieve the combined efficacy and safety target, doses of 18-24 mg/kg in children 3-12 months, 20-24 mg/kg in children 13-24 months, 19-24 mg/kg in children 2-6 years, 17-19 mg/kg in children 7-11 years, and 10-14 mg/kg in adolescents ≥12 years are necessary. Package label dosing resulted in suboptimal exposure for the majority of pediatric patients in all age groups evaluated. If targeting validated efficacy and safety endpoints, daily daptomycin doses of at least 20 mg/kg in children ≤6 years, 17 mg/kg in children 7-11 years, and 10 mg/kg in adolescents ≥12 years are necessary. Clinical studies evaluating these higher doses are needed.

Phage-antibiotic synergy against daptomycin-nonsusceptible MRSA in an ex vivo simulated endocardial pharmacokinetic/pharmacodynamic model.

Phage-antibiotic combinations (PAC) offer a potential solution for treating refractory daptomycin-nonsusceptible (DNS) methicillin-resistant Staphylococcus aureus (MRSA) infections. We examined PAC activity against two well-characterized DNS MRSA strains (C4 and C37) in vitro and ex vivo. PACs comprising daptomycin (DAP) ± ceftaroline (CPT) and a two-phage cocktail (Intesti13 + Sb-1) were evaluated for phage-antibiotic synergy (PAS) against high MRSA inoculum (109 CFU/mL) using (i) modified checkerboards (CB), (ii) 24-h time-kill assays (TKA), and (iii) 168-h ex vivo simulated endocardial vegetation (SEV) models. PAS was defined as a fractional inhibitory concentration ≤0.5 in CB minimum inhibitory concentration (MIC) or a ≥2 log10 CFU/mL reduction compared to the next best regimen in time-kill assays and SEV models. Significant differences between regimens were assessed by analysis of variance with Tukey's post hoc modification (α = 0.05). CB assays revealed PAS with Intesti13 + Sb-1 + DAP ± CPT. In 24-h time-kill assays against C4, Intesti13 + Sb-1 + DAP ± CPT demonstrated synergistic activity (-Δ7.21 and -Δ7.39 log10 CFU/mL, respectively) (P < 0.05 each). Against C37, Intesti13 + Sb-1 + CPT ± DAP was equally effective (-Δ7.14 log10 CFU/mL each) and not significantly different from DAP + Intesti13 + Sb-1 (-Δ6.65 log10 CFU/mL). In 168-h SEV models against C4 and C37, DAP ± CPT + the phage cocktail exerted synergistic activities, significantly reducing bio-burdens to the detection limit [2 log10 CFU/g (-Δ7.07 and -Δ7.11 log10 CFU/g, respectively)] (P < 0.001). At 168 h, both models maintained stable MICs, and no treatment-emergent phage resistance occurred with DAP or DAP + CPT regimens. The two-phage cocktail demonstrated synergistic activity against two DNS MRSA isolates in combination with DAP + CPT in vitro and ex vivo. Further in vivo PAC investigations are needed.

Synergistic bactericidal effects of phage-enhanced antibiotic therapy against MRSA biofilms.

Methicillin-resistant Staphylococcus aureus (MRSA) causes biofilm-related medical device infections. Phage-antibiotic combinations offer potential therapy due to proven in vitro antibiofilm efficacy. We evaluated phage-antibiotic synergy against biofilms using modified checkerboard and 24-h time-kill assays. Humanized-simulated daptomycin (DAP) (10, 8, and 6 mg/kg q24h) and ceftaroline (CPT) (600 mg q12h) were combined with Intesti13, Sb-1, and Romulus phages (tMOI 1, q12h). Assays were conducted in 168-h biofilm reactor models against DAP non-susceptible (DNS) vancomycin intermediate S. aureus (VISA) MRSA D712 and DAP-susceptible MRSA 8014. Synergistic activity and bactericidal activity were defined as ≥2log10 CFU/mL reduction from antibiotic-only regimens and ≥3log10 CFU/mL decrease from baseline at 24 h. Differences were analyzed by one-way analysis of variance with Tukey's post hoc test (P ≤ 0.05 is considered significant). Surviving bacteria were examined for antibiotic minimum biofilm inhibitory concentration (MBIC) changes and phage susceptibility. In 168-h biofilm models, humanized DAP 10 mg/kg + CPT, combined with a 2-phage cocktail (Intesti13 + Sb-1) against D712, and a 3-phage cocktail (Intesti13 + Sb-1 + Romulus) against 8014, demonstrated synergistic bactericidal activity. At 168 h, bacteria were minimally detectable [2log10 CFU/cm2 (-Δ4.23 and -Δ4.42 log10 CFU/cm2; both P < 0.001)]. Antibiotic MBIC remained unchanged compared to baseline across various time points. None of the tested bacteria at 168 h exhibited complete phage resistance. This study reveals bactericidal efficacy of DAP + CPT with 2-phage and 3-phage cocktails against DNS VISA and MRSA isolates (D712 and 8014) in biofilm models, maintaining susceptibility. Further research is needed for diverse strains and durations, aligning with infection care. IMPORTANCE: The prevalence of biofilm-associated medical device infections caused by methicillin-resistant Staphylococcus aureus (MRSA) presents a pressing medical challenge. The latest research demonstrates the potential of phage-antibiotic combinations (PACs) as a promising solution, notably in vitro antibiofilm efficacy. By adopting modified checkerboard and 24-h time-kill assays, the study investigated the synergistic action of phages combined with humanized-simulated doses of daptomycin (DAP) and ceftaroline (CPT). The results were promising: a combination of DAP, CPT, and either a 2-phage or 3-phage cocktail effectively exhibited bactericidal activity against both DAP non-susceptible vancomycin intermediate S. aureus MRSA and DAP-susceptible MRSA strains within 168-h biofilm models. Moreover, post-treatment evaluations revealed no discernible rise in antibiotic resistance or complete phage resistance. This pioneering work suggests the potential of PACs in addressing MRSA biofilm infections, setting the stage for further expansive research tailored to diverse bacterial strains and treatment durations.

Oritavancin Versus Daptomycin for Osteomyelitis Treatment After Surgical Debridement.

INTRODUCTION: Weekly intravenous (IV) oritavancin and daily daptomycin were compared in an outpatient setting following extensive surgical debridement for treating patients with osteomyelitis. METHODS: This was a retrospective, observational study of patients diagnosed with acute osteomyelitis. Exclusion criteria were the use of Gram-negative antibiotic therapy, use of antibiotics for more than 48 h prior to oritavancin or daptomycin or prior use of > 2 doses of oritavancin or more than 4 weeks of daptomycin. Clinical success was resolution or improvement of symptoms and no further treatment. Data were analyzed with Chi-square test or Fisher's exact test. RESULTS: Consecutive outpatients (n = 150) with acute osteomyelitis who were treated with oritavancin or daptomycin (1:1) following extensive surgical debridement were identified. Staphylococcus aureus was the most common pathogen (n = 117). No patient in either group received prior antibiotic therapy (previous 30 days) or was hospitalized within 90 days prior to surgical debridement. Twenty-one (28%) patients prescribed oritavancin had chronic kidney disease, seven of whom were receiving hemodialysis or peritoneal dialysis. Compared to oritavancin, patients prescribed daptomycin had higher rates of all-cause readmission [odds ratio (OR) 2.89; p < 0.001], more infection-related readmission (OR 3.19; p < 0.001), and greater likelihood of receiving antibiotics post-discontinuation of initial therapy (OR 2.13; p < 0.001). Repeat surgical debridement was required for 68.0% with daptomycin vs. 23.1% with oritavancin (p < 0.001). CONCLUSIONS: Oritavancin demonstrated a significantly higher rate of clinical success compared to daptomycin, with lower all-cause and infection-related readmissions, reduced need for repeat surgical debridement, and fewer additional antibiotic requirements.