Combination Of Vancomycin Research Articles

Clinical outcome of combination of vancomycin and ceftaroline versus vancomycin monotherapy for treatment of methicillin resistant Staphylococcus aureus bloodstream infection

BackgroundThe role of combination therapies for serious methicillin-resistant Staphylococcus aureus (MRSA) infections is widely debated.MethodsThis retrospective cohort study included adults with MRSA bacteraemia treated between January 1, 2013, to December 31, 2022. Patients receiving combination therapy with vancomycin and ceftaroline were matched in a 2:1 ratio with those on vancomycin monotherapy based on bacteraemia source and illness severity. The primary outcome was frequency of bacteraemia recurrence. Secondary outcomes were all cause 30/90-day mortality, recurrence or mortality at 30/90 days and in hospital length of stay.ResultsOf 57 patients included, 37 (65%) were in the combination group. The overall intensive care unit admission rate was 63.2% (36/57) and the Pitt Bacteraemia Score was 1 [0–4] at the time of diagnosis. The most common source of infection was endovascular/endocarditis (n = 36, 63.2%). Demographic and clinical characteristics were similar between the monotherapy and combination group of patients, except for higher body mass index (32.5 [25.5–36.4] vs. 24.4 [20.9–29], p = 0.004) and a greater immunosuppression prevalence (3 (15%) vs. 0 (0%), p = 0.039) in monotherapy group. There was no significant difference in bacteraemia recurrence (3 (15%) vs. 4 (10.8%), p = 0.7) or all-cause 30-day mortality (3 (15%) vs. 4 (10.8%), p = 0.7) between the two groups.ConclusionThe results of this study are limited by a retrospective observational design; however, combination of vancomycin and ceftaroline for MRSA bacteraemia was not associated with lower bacteraemia recurrence or mortality compared to vancomycin monotherapy.

Bone allograft impregnated with tobramycin and vancomycin delivers antibiotics in high concentrations for prophylaxis against bacteria commonly associated with prosthetic joint infections.

Local delivery of antibiotics as prophylaxis for prosthetic joint infections (PJIs) is frequently used during total hip replacement surgery. Morselized bone allograft impregnated with vancomycin and tobramycin (TobraVanc) could provide effective prophylaxis against bacteria commonly associated with PJIs. In this study, the concentrations of antibiotics released by bone allograft impregnated with TobraVanc were determined by using an in vitro bioassay system entailing measuring inhibition zone diameters caused by antibiotic-impregnated bone chips cast in agar against standard curves. The concentrations were determined in samples of TobraVanc-impregnated bone graft taken before and after the application of the bone graft in the patients undergoing acetabular revision surgery. Antibiotic-impregnated bone grafts, sampled prior to application in the patient, delivered antibiotics in the concentration ranges of 730-9,800 mg/L for tobramycin and 1,300-11,000 mg/L for vancomycin. Samples taken after application in the patient released lower concentrations of tobramycin (490-1,900 mg/L; P < 0.01) and vancomycin (3,000-5,100 mg/L; P < 0.05); however, these concentrations remained well above the tobramycin minimum inhibitory concentrations (MICs) for investigated, highly tobramycin-resistant Staphylococcus epidermidis strains (MICs > 256 mg/L). At the tested concentrations, bone graft material mixed with TobraVanc delivered antibiotics in potent concentrations above the MICs for bacteria causing PJIs. Clinical trials are needed to evaluate the efficacy and risk of TobraVanc-impregnated bone graft as a prophylactic agent for patients undergoing hip replacement surgery.IMPORTANCEAntibiotic prophylaxis is the cornerstone of successful joint replacement surgery, reducing the risk for the dreaded complication of prosthetic joint infection (PJI) to roughly 0.5%-2% in standard total hip replacement (THR). In addition to systemic antibiotics, antibiotics added locally have the potential to reduce the PJI risk even further, because of the high concentrations that can be achieved in the joint with limited risk for systemic toxicity. The results in the current study show that bone chips impregnated with a combination of tobramycin and vancomycin (TobraVanc) release antibiotics in concentrations that are potent against common bacteria causing PJIs. Especially in high-risk patients, our results support the prophylactic use of TobraVanc in hip replacement surgery requiring the use of a bone graft. A clinical study testing the efficacy of TobraVanc-impregnated bone graft in reducing the incidence of PJI in hip replacement surgery is currently ongoing (EudraCT: 2021-001708-14).

Combined nephrotoxicity of Polymyxins and Vancomycin: a study on adverse event reporting for monotherapy versus combinations using the FDA adverse event reporting system (FAERS)

ABSTRACT Background Multidrug-resistant (MDR) infections pose a global public health crisis with significant mortality and economic burdens. Combination of polymyxins and vancomycin has shown effectiveness against MDR infections. However, their combined nephrotoxicity complicates clinical use. Given these concerns, we conducted a pharmacovigilance analysis using the FDA Adverse Event Reporting System (FAERS) to assess the nephrotoxicity of combinations of polymyxins and vancomycin compared to monotherapy. Research design and methods In this retrospective study, data from FAERS reports (2012 Q4 to 2023 Q2) were deduplicated and analyzed for adverse events (AEs) related to vancomycin, polymyxin B, and colistin. Disproportionality analyses were performed to evaluate the association between drugs and nephrotoxicity. Results A total of 9,796,784 adverse event reports, including 73,009 reports associated with nephrotoxicity, were included. All three drugs showed significant associations with nephrotoxicity. In combination therapy, polymyxin B-vancomycin exhibited a stronger association with nephrotoxicity compared to monotherapy, whereas colistin-vancomycin demonstrated a lower association with nephrotoxicity than colistin monotherapy. Conclusions This study found that combining vancomycin with colistin alleviated colistin-induced nephrotoxicity, while combining vancomycin with polymyxin B worsened polymyxin B-induced nephrotoxicity.

7964 Manipulation of the Gut Microbiome Using Antibiotics Is Associated With Sex-Specific Reductions in Systemic Testosterone Levels in Rats

Abstract Disclosure: G. Parodi: None. G. Leite: None. W. Morales: None. S.R. Weitsman: None. G.M. Barlow: None. M. Sanchez: None. M. Pimentel: None. M. Villanueva-Millan: None. M. Pimentel: None. R. Mathur: None. The gut microbiome has impacts on metabolic endocrine and reproductive functions. It is known that specific bacteria can impact host metabolism by synthesizing, secreting, and/or metabolizing sex-related hormones. However, the impacts of gut bacterial biosynthesis and/or metabolism of steroids on host metabolism and reproduction have not been fully addressed. In this study we challenged the gut microbiome of wild-type male and female rats with broad-spectrum antibiotics and examined the effects on circulating testosterone levels. Methods: Male (M) and female (F) Sprague-Dawley rats (8 weeks old) were housed with phytoestrogen-free bedding and received a phytoestrogen-free diet with water from glass bottles. Rats were given a combination of vancomycin (0.5g/L), ampicillin (1g/L), neomycin (1g/L), and metronidazole (1g/L) in their water for 8 days, and then returned to normal drinking water for another 13 days. Control rats were given normal water throughout the study. Serum and stool samples were collected before the start of antibiotics (baseline), on day 8 of antibiotics (AbxD8), and at 13 days post-removal of antibiotics (PAbxD13). Stool total DNA was extracted with the MagAttract PowerSoil DNA KF kit and quantified on a Qubit. Circulating testosterone levels were analyzed on a Luminex platform. Paired-ANOVA test was used to determine changes in testosterone levels in each group over time. Results: A total of 31 rats (M=16, F=15) received antibiotics, and 28 (M=14, F=14) were controls. Antibiotic exposure resulted in significant decreases in total stool DNA quantity in both male and female exposed rats relative to controls on AbxD8 (P&amp;lt;0.0001), which returned to baseline levels by PAbxD13. Antibiotic exposed male rats had a continuous decrease in testosterone levels throughout the timepoints collected (baseline: 5.78±2.74 ng/mL, AbxD8: 3.11±2.46 ng/mL, PAbxD13: 2.55±1.80 ng/mL, P=0.0027), however, in control male rats, circulating testosterone levels remained stable throughout the timepoints analyzed (baseline: 3.81±1.73 ng/mL, AbxD8: 3.72±1.12 ng/mL, PAbxD13: 3.92±3.38 ng/mL, P=0.49). There was no effect on circulating testosterone levels in female rats, with both groups, control and exposed, following the same cyclical pattern throughout the timepoints analyzed. Conclusions: Antibiotic depletion of the gut microbiome is associated with changes in systemic levels of testosterone in rats. These changes are sex-specific, and only detected in males. These results suggest a potential involvement of the gut microbiome in testosterone metabolism that is sex-specific. Presentation: 6/1/2024

7964 Manipulation of the Gut Microbiome Using Antibiotics Is Associated With Sex-Specific Reductions in Systemic Testosterone Levels in Rats

Abstract Disclosure: G. Parodi: None. G. Leite: None. W. Morales: None. S.R. Weitsman: None. G.M. Barlow: None. M. Sanchez: None. M. Pimentel: None. M. Villanueva-Millan: None. M. Pimentel: None. R. Mathur: None. The gut microbiome has impacts on metabolic endocrine and reproductive functions. It is known that specific bacteria can impact host metabolism by synthesizing, secreting, and/or metabolizing sex-related hormones. However, the impacts of gut bacterial biosynthesis and/or metabolism of steroids on host metabolism and reproduction have not been fully addressed. In this study we challenged the gut microbiome of wild-type male and female rats with broad-spectrum antibiotics and examined the effects on circulating testosterone levels. Methods: Male (M) and female (F) Sprague-Dawley rats (8 weeks old) were housed with phytoestrogen-free bedding and received a phytoestrogen-free diet with water from glass bottles. Rats were given a combination of vancomycin (0.5g/L), ampicillin (1g/L), neomycin (1g/L), and metronidazole (1g/L) in their water for 8 days, and then returned to normal drinking water for another 13 days. Control rats were given normal water throughout the study. Serum and stool samples were collected before the start of antibiotics (baseline), on day 8 of antibiotics (AbxD8), and at 13 days post-removal of antibiotics (PAbxD13). Stool total DNA was extracted with the MagAttract PowerSoil DNA KF kit and quantified on a Qubit. Circulating testosterone levels were analyzed on a Luminex platform. Paired-ANOVA test was used to determine changes in testosterone levels in each group over time. Results: A total of 31 rats (M=16, F=15) received antibiotics, and 28 (M=14, F=14) were controls. Antibiotic exposure resulted in significant decreases in total stool DNA quantity in both male and female exposed rats relative to controls on AbxD8 (P&amp;lt;0.0001), which returned to baseline levels by PAbxD13. Antibiotic exposed male rats had a continuous decrease in testosterone levels throughout the timepoints collected (baseline: 5.78±2.74 ng/mL, AbxD8: 3.11±2.46 ng/mL, PAbxD13: 2.55±1.80 ng/mL, P=0.0027), however, in control male rats, circulating testosterone levels remained stable throughout the timepoints analyzed (baseline: 3.81±1.73 ng/mL, AbxD8: 3.72±1.12 ng/mL, PAbxD13: 3.92±3.38 ng/mL, P=0.49). There was no effect on circulating testosterone levels in female rats, with both groups, control and exposed, following the same cyclical pattern throughout the timepoints analyzed. Conclusions: Antibiotic depletion of the gut microbiome is associated with changes in systemic levels of testosterone in rats. These changes are sex-specific, and only detected in males. These results suggest a potential involvement of the gut microbiome in testosterone metabolism that is sex-specific. Presentation: 6/1/2024

Infective endocarditis caused by penicillin-resistant viridans group streptococci: a series of nine cases from a Spanish cohort.

Infective endocarditis (IE) caused by viridans and gallolyticus group streptococci (VGS-GGS) resistant to penicillin (PEN-R; minimum inhibitory concentration ≥4 mg/L) is rare but poses therapeutic challenges. To describe the characteristics of patients with IE caused by PEN-R VGS-GGS, focusing on antimicrobial management. Retrospective analysis of a prospective cohort of definite IE caused by PEN-R VGS-GGS between 2008 and 2023 in 40 Spanish hospitals. We describe clinical characteristics, management and outcome of the cases, and compare them to IE caused by VGS-GGS with susceptibility or susceptibility with increased exposure to penicillin (PEN-I). We identified nine cases of PEN-R VGS-GGS IE in a cohort of 1563 streptococcal IE (0.58%). All isolates belonged to S. mitis group. Three cases died during hospitalization and no relapse occurred at 3 months of follow-up. Compared to cases with susceptibility or PEN-I, PEN-R showed a higher rate of mitral location (78% versus 51%), surgical indication (67% versus 51%), and in-hospital mortality (33% versus 12%). Most cases (86%) showed resistance to third-generation cephalosporins. The preferred antibiotic regimen was beta-lactam-based: ceftriaxone plus gentamicin, penicillin plus gentamicin, ceftriaxone plus levofloxacin, and ceftaroline plus daptomycin. Two cases received a combination of vancomycin plus gentamicin. Levofloxacin was used in two cases in combination with ceftriaxone or daptomycin. All patients that received cardiac surgery were cured at the end of follow-up. IE caused by PEN-R VGS-GGS was rare and only affected mitis group streptococci. Antibiotic combination including a beta-lactam seems to be effective in its management.

Efficacy and Safety of Antibiotics in the Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) Infections: A Systematic Review and Network Meta-Analysis.

Vancomycin is a first-line drug for the treatment of MRSA infection. However, overuse of vancomycin can cause bacteria to become resistant, forming resistant strains and making infections more difficult to treat. This study aimed to evaluate the efficacy and safety of different antibiotics in the treatment of MRSA infections and to compare them, mainly with vancomycin, to find better vancomycin alternatives. All studies were obtained from the PubMed and Embase databases from inception to 13 April 2023. The three comprehensive indicators of clinical cure success rate, clinical microbiological success rate, and adverse reactions were evaluated, and the clinical cure success rates of three disease types, complex skin and skin structure infections (cSSSIs), complex skin and soft tissue infections (cSSTIs), and pneumonia, were analyzed in subgroups. All statistical analyses were performed using R and STATA 14.0 software for network meta-analysis. A total of 38 trials with 6281 patients were included, and 13 drug treatments were evaluated. For MRSA infections, the results of network meta-analysis showed that the clinical success rates of linezolid, the combination of vancomycin and rifampin, and the combination of minocycline and rifampin were better than that of vancomycin (RR 1.71; 95%-CI 1.45-2.02), (RR 2.46; 95%-CI 1.10-5.49) (RR, 2.77; 95%-CI 1.06-7.21). The success rate of clinical microbiological treatment with vancomycin was inferior to that with telavancin (RR 0.74; 95%-CI 0.55-0.99). Linezolid had a higher rate of adverse reactions than teicoplanin (RR 5.35; 95%-CI 1.10-25.98). Subgroup analysis showed that vancomycin had a lower clinical success rate than linezolid in the treatment of MRSA-induced cSSSIs, cSSTIs, and pneumonia (RR 0.59; 95%-CI 0.44-0.80) (RR 0.55; 95%-CI 0.35-0.89) (RR 0.55; 95%-CI 0.32-0.93). This systematic review and NMA provide a new comparison framework for the clinical treatment of MRSA infection. The NMA suggests that linezolid may be the antibiotic of choice for the treatment of MRSA infections, with the ability to improve clinical and microbiological success rates despite its disadvantage in terms of adverse effects. At the same time, the combination of minocycline and rifampicin may be the most effective drug to treat MRSA-induced cSSSIs, tedizolid may be the best drug to treat MRSA-induced cSSTIs, and the combination of vancomycin and rifampicin may be the most effective treatment for MRSA-induced pneumonia. More high-quality studies are still needed in the future to further identify alternatives to vancomycin. PROSPERO registration number CRD42023416788.

WITHDRAWN: A successful management of concurrent infection with cranial Nocardia gipuzkoensis and pulmonary Klebsiella pneumoniae: A case report

BackgroundSuccessful management of concurrent infection with cranial N. gipuzkoensis and pulmonary Klebsiella pneumoniae has never been described. Case presentationA 71-year-old female was given referral to our hospital due to intracal space occupying lesion for over 20 days. Initial chief complaints implied cranial and pulmonary inflammation. Subsequently, drainage of brain lesion was obtained and identified as Nocardia gipuzkoensis infection through microbial culture and metagenomic next-generation sequencing (mNGS). Sputum culture determined as Klebsiella pneumoniae infection. Combined with results of antimicrobial susceptibility tests and allergic history, the patient was improved after being treated with two-week Meropenem (2g/8h iv) combined Vancomycin (1g/12h iv), and reached neurological recovery followed with oral administration of Linezolid (0.6g/12h po) and Levofloxacin (0.5g/24h po) for over 6 weeks. ConclusionA successful administration of concurrent infections was reported. It might provide supporting evidence for shortening the intravenous administration of nocardiosis.

Combination of bacteriophages and vancomycin in a co-delivery hydrogel for localized treatment of fracture-related infections

Fracture-related infections (FRIs), particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA), are challenging to treat. This study designed and evaluated a hydrogel loaded with a cocktail of bacteriophages and vancomycin (1.2 mg/mL). The co-delivery hydrogel showed 99.72% reduction in MRSA biofilm in vitro. The hydrogel released 54% of phages and 82% of vancomycin within 72 h and maintained activity for eight days, in vivo the co-delivery hydrogel with systemic antibiotic significantly reduced bacterial load by 0.99 log10 CFU compared to controls, with active phages detected in tissues at euthanasia (2 × 103 PFU/mL). No phage resistance was detected in the phage treatment groups, and serum neutralization resulted in only a 20% reduction in phage count. In this work, we show that a phage-antibiotic co-delivery system via CMC hydrogel is a promising adjunct to systemic antibiotic therapy for MRSA-induced FRI, highlighting its potential for localized, sustained delivery and improved treatment outcomes.

Protective Effects of Huo Xiang Zheng Qi Liquid on Clostridioides difficile Infection on C57BL/6 Mice.

Clostridioides difficile-associated disease (CDAD) is a major healthcare-associated infection. New treatment options for CDAD are needed. A traditional Chinese medicinal formula, Huo Xiang Zheng Qi (HXZQ), was chosen to test against CDAD in a mouse model. C57BL/6 mice were challenged with C difficile (ATCC 43255) orally; then received saline; vancomycin 25 mg/kg; or HXZQ in two different concentrations twice daily for 5 days. The animals' body weight; clinical signs; and survival rates were registered daily. Fecal pellets from each animal were taken for PCR analysis as a control of infection. 50% of the mice receiving saline died; 85.7% of the mice receiving vancomycin survived; 75% of the mice receiving HXZQ survived; and 87.5% of the mice receiving a 1:1 saline dilution of HXZQ survived. The HXZQ-treated groups were C. difficile PCR positive with loads less than that of the untreated mice. The weight loss in the vancomycin plus HXZQ 1:1 treated group; the vancomycin-treated group; and the untreated group were 3.08%, 4.06%, and 9.62%, respectively. our results showed that HXZQ can protect mice from CDAD-related death as effectively as vancomycin and the combination of vancomycin and HXZQ may give even better protection.

Local Antimicrobial Therapy with Combined Aminoglycoside and Vancomycin Compared to Aminoglycoside Monotherapy in the Surgical Management of Osteomyelitis and Fracture-Related Infection.

We investigated the effect of combination aminoglycoside and vancomycin local antibiotic treatment compared to aminoglycoside alone in the surgical management of bone infection. Data including patient demographics, type of surgery, microbiological characteristics, BACH score, duration of antibiotic treatment and clinical outcomes were collected. Failure of therapy was a composite of recurrence of infection, continued or new antimicrobial therapy, or reoperation with suspected or confirmed infection at one year after index surgery. A total of 266 patients met the inclusion criteria. 252 patients reached the final follow-up and were included in the final analysis. 113 patients had treatment with aminoglycoside alone and 139 patients had combination aminoglycoside and vancomycin. There was no difference in the failure rate between groups; 10/113 (8.8%) in the aminoglycoside alone and 12/139 (8.6%) in the combination group, p = 0.934. Multivariate analysis showed that there was no added benefit of combination therapy (OR 1.54: 95% CI 0.59-4.04, p = 0.38). BACH score and low BMI were associated with increased risk of failure (BACH OR 3.49: 95% CI 1.13-10.76, p = 0.03; Low BMI OR 0.91: 95% CI 0.84-0.99, p = 0.037). The form of the carrier material (pellets or injectable paste) had no effect on failure rate (p = 0.163). The presence of aminoglycoside resistance had no effect on failure rate (OR 0.39: 95% CI 0.05-3.01, p = 0.37). Clinical outcome was not improved by the addition of vancomycin to aminoglycoside alone as local therapy for the management of bone infection.

Development of a Galleria mellonella Infection Model to Evaluate the Efficacy of Antibiotic-Loaded Polymethyl Methacrylate (PMMA) Bone Cement.

Prosthetic joint infections (PJIs) can have disastrous consequences for patient health, including removal of the device, and placement of cemented implants is often required during surgery to eradicate PJIs. In translational research, in vivo models are widely used to assess the biocompatibility and antimicrobial efficacy of antimicrobial coatings and compounds. Here, we aim to utilize Galleria mellonella implant infection models to assess the antimicrobial activity of antibiotic-loaded bone cement (ALBC) implants. Therefore, we used commercially available bone cement loaded with either gentamicin alone (PALACOS R+G) or with a combination of gentamicin and vancomycin (COPAL G+V), compared to bone cement without antibiotics (PALACOS R). Firstly, the in vitro antimicrobial activity of ALBC was determined against Staphylococcus aureus. Next, the efficacy of ALBC implants was analyzed in both the G. mellonella hematogenous and early-stage biofilm implant infection model, by monitoring the survival of larvae over time. After 24 h, the number of bacteria on the implant surface and in the tissue was determined. Larvae receiving dual-loaded COPAL G+V implants showed higher survival rates compared to implants loaded with only gentamicin (PALACOS R+G) and the control implants without antibiotics (PALACOS R). In conclusion, G. mellonella larvae infection models with antibiotic-loaded bone cements are an excellent option to study (novel) antimicrobial approaches.

Infectious keratitis in pediatric population aged less than two years: a tertiary eye institute experience

BackgroundInfectious keratitis is a serious ocular condition, which can lead to corneal scarring, vision loss, and even blindness. Pediatric infectious keratitis accounts for about 13% of all cases, although there is a lack of comprehensive data regarding keratitis in less than two years of age population group. This study was aimed to determine predisposing factors, clinical characteristics, microbial profile, and management of infectious keratitis in a population of children aged less than two years.Materials and methodsA retrospective study was carried out in a tertiary eye institute over a period of 18 years from July 2005 to December 2022. Collected data was analyzed for demographics, predisposing factors, clinical features, and treatment methods.ResultsFifty-seven cases of keratitis were identified. Age of the patients ranged from 1 to 24 months (Median: 6, interquartile range: 2–10). Thirty cases were male (52.6%). Predisposing factors were identified in 39 cases (68.4%): consisting of prior ocular trauma (n = 15), previous intraocular surgery (n = 11), ocular surface disease (n = 10), nasolacrimal duct obstruction (n = 4), prematurity (n = 3), developmental delay (n = 2), TORCH infection (n = 1), and contact lens (n = 1). Corneal thinning was observed in 29 eyes (50.9%), which progressed to perforation in 13 eyes (22.8%). Three patients developed endophthalmitis (95% CI, 1.5–13.4%). Most eyes had negative smear (60.4%) and culture (59.6%) results. Pseudomonas aeruginosa was the most common microorganism (11 of 21). Candida albicans was isolated in one case. In vitro susceptibility results showed good coverage of the combined ceftazidime and vancomycin regimen (100%). Surgical procedures were carried out in 35 eyes (61.4%) and 15 eyes required tectonic procedures (26.3%).ConclusionDespite good coverage of medical treatment over cultured isolates, surgical tectonic intervention was required in nearly a quarter of cases to resolve the corneal infection. This finding indicates the necessity of prompt patient referring, corneal sampling and initiation of the treatment.

Efficacy and Safety Factors Related to Plasma Concentration-Optimized Polymyxin B Therapy in Treating Carbapenem-Resistant Gram-Negative Bacterial Infections in China.

Polymyxin B (PMB)-based combination therapies are used to treat severe carbapenem-resistant gram-negative bacterial (CR-GNB) infections. This observational study investigated the relationship between clinical factors, including PMB concentration, and clinical efficacy and safety. Polymyxin B regimens were optimized through therapeutic drug monitoring (TDM) and area under the concentration-time curve (AUC). In all, 382 samples were tested from 130 patients. Logistic regression was used to analyze the relationships between variables with clinical efficacy and 30-day mortality factors were analyzed by Cox regression. The sensitivity and specificity of Cmin and AUC for the occurrence of acute kidney injury (AKI) were determined by ROC curve analysis. The clinical effectiveness of PMB was 65.4%. Multivariate logistic regression analysis revealed that lung infection, continuous renal replacement therapy, and C-reactive protein were independent factors significantly associated with efficacy. AKI occurred in 14.6% of the patients during treatment; age > 73 years (OR: 3.63; 95% CI: 1.035-12.727; P = 0.044), Cmin greater than 2.3 µg/mL (OR: 7.37; 95% CI: 1.571-34.580; P = 0.011), combined vancomycin (OR: 9.47; 95% CI: 1.732-51.731; P = 0.009), and combined piperacillin-tazobactam (OR: 21.87; 95% CI: 3.139-152.324; P = 0.002) were independent risk factors. The identified PMB cut-offs for predicting AKI were Cmin = 2.3 µg/mL and AUC = 82.0 mg h/L. Polymyxin B-based combination regimens are effective in treating CR-GNB infections, particularly bloodstream infections, but have shown unsatisfactory for lung infections. Cmin ≥ 2.3 µg /mL and AUC ≥ 82.0 mg h/L may increase PMB-associated AKI incidence. PMB dose should be adjusted based on TDM to ensure efficacy.

Synergistic Effect of Combination Antibiotics against Multidrug-Resistant Salmonella enterica serovar Typhi

Background: Infection caused by multidrug-resistant (MDR) Salmonella enterica serovar Typhi (S. Typhi) is a major health problem in low- and middle-income countries (LMICs). S. Typhi has been reported to be resistant to fluoroquinolones and cephalosporins. Objective: To find out the anti-microbial activity of combination antibiotics against resistant S. typhi. Materials and Methods: First, single antibiotic disks of ciprofloxacin, imipenem and vancomycin with the concentrations of 20, 40, 60 and 80 μg/ml were prepared and applied against sensitive S. typhi to confirm its susceptibility. Later, a resistant strain of Shigella flexneri was treated with single antibiotic (ciprofloxacin, vancomycin and imipenem) at the highest concentration (80 μg/ml) to determinets resistant behavior by measuring the zones of inhibition obtained from the disc diffusion assay. Co-culture was performed between the sensitive and resistant strains to develop the resistant strain of S. typhi. Combinations of antibiotics were used for susceptibility testing against the newly resistant strain of S. typhi by using Kirby–Bauer disk diffusion method. Experiments were carried out in triplicates and the average reading was recorded. Results: The study showed that different concentrations of the combination of vancomycin and imipenem (20, 40, 60, 80 μg/ml) exhibited 18, 20, 24- and 29-mm respective zone of inhibition (ZOI) against S. typhi. A combination of ciprofloxacin and imipenem also exhibited optimum ZOI. It was observed in this study that a single antibiotic treatment did not show any activity against newly resistant strains of S. typhi. Conclusions: The combination therapy can be used as a beneficial treatment approach in multi-drug resistant S. typhi infections. Dhaka Univ. J. Pharm. Sci. 23(1): 37-42, 2024 (June)

Effect of gallium nitrate on the antibacterial activity of vancomycin in methicillin-sensitive and resistant Staphylococcus aureus.

The extension of multidrug-resistant strains of Staphylococcus aureus (S. aureus) is one of the main health challenges in the world, which requires serious solutions to deal with it. Combination therapies using conventional antibiotics and new antibacterial compounds that target different bacterial pathways are effective methods against resistant bacterial infections. Gallium is an iron-like metal that competes with iron for uptake into bacteria and has the potential to disrupt iron-dependent vital processes in bacteria. In this study, we explored the antibacterial effects of gallium nitrate (Ga(NO3)3) and vancomycin alone and in combination with each other on methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) using microdilution assay and checkerboard test, respectively. Then, their effect on the formation and destruction of biofilms was investigated. Finally, the amount of ROS production in the presence of these two compounds in bacteria was evaluated. The results indicated that the vancomycin/ Ga(NO3)3 combination reduced the MIC of vancomycin in the MRSA strain and had an additive effect on it. Vancomycin plus Ga(NO3)3 reduced the formation of biofilms and increased the destruction of biofilms formed in both strains, especially in the MRSA strain. ROS production was also higher in the combination of vancomycin with Ga(NO3)3 compared to vancomycin alone, especially in MRSA. Therefore, our results showed that Ga(NO3)3 enhances the antibacterial activity of vancomycin and this combination therapy can be considered as a new strategy for the treatment of MRSA infections.

Staphylococcus aureus persistence in osteocytes: weathering the storm of antibiotics and autophagy/xenophagy.

Staphylococcus aureus is a major causative pathogen of osteomyelitis. Intracellular infections of resident bone cells including osteocytes can persist despite gold-standard clinical intervention. The mechanisms by which intracellular S. aureus evades antibiotic therapy are unknown. In this study, we utilised an in vitro S. aureus infection model of human osteocytes to investigate whether antibiotic-mediated dysregulation of autophagy contributes to this phenomenon. Infected or non-infected osteocyte-like cells were exposed to combinations of rifampicin, vancomycin, and modulators of autophagy. Intracellular bacterial growth characteristics were assessed using colony-forming unit (CFU) analysis, viable bacterial DNA abundance, and the rate of escape into antibiotic-free medium, together with measures of autophagic flux. Rifampicin, alone or in combination with vancomycin, caused a rapid decrease in the culturability of intracellular bacteria, concomitant with stable or increased absolute bacterial DNA levels. Both antibiotics significantly inhibited autophagic flux. However, modulation of autophagic flux did not affect viable bacterial DNA levels. In summary, autophagy was shown to be a factor in the host-pathogen relationship in this model, as its modulation affected the growth state of intracellular S. aureus with respect to both their culturability and propensity to escape the intracellular niche. While rifampicin and vancomycin treatments moderately suppressed autophagic flux acutely, this did not explain the paradoxical response of antibiotic treatment in decreasing S. aureus culturability whilst failing to clear bacterial DNA and hence intracellular bacterial load. Thus, off-target effects of rifampicin and vancomycin on autophagic flux in osteocyte-like cells could not explain the persistent S. aureus infection in these cells.

Altering the gut microbiome and TME in advanced liver cancers: A phase II study of nivolumab, tadalafil, and oral vancomycin in refractory HCC or liver-dominant metastatic CRC or PDAC.

e14642 Background: The gut-liver axis shapes the environment that promotes liver disease. In murine models of liver cancer, our group showed that altering gut microbiome with oral vancomycin can induce an antitumor effect by modifying bile acids (BA) that then recruit natural killer T cells (NKTC). However, these NKTC were met by an immunosuppressive counter-regulatory response where myeloid-derived suppressor cells (MDSC) accumulated, impairing their cytotoxicity. Tadalafil, a PDE5 inhibitor, can suppress these MDSC in the TME. The aim of this study was to examine if the immunomodulatory effects of oral vancomycin and tadalafil can enhance nivolumab activity in advanced primary liver cancer or liver metastases. Methods: This is a phase II study of adult patients (pts) with refractory hepatocellular carcinoma (HCC) or liver-dominant metastatic colorectal (mCRC) or pancreatic (mPDAC) cancers. Pts received IV nivolumab 480mg on D1, oral vancomycin 125mg every 6 hours on D1-21, and tadalafil 10mg once daily in 28d cycles until disease progression or unacceptable toxicity. Primary endpoint was best overall response (BOR) according to RECIST v1.1. Secondary endpoints included safety/tolerability and mOS. Correlative studies were performed on paired stool, blood, and tumor biopsies. Results: From 6/2019 - 7/2021, 22 heavily pretreated pts were enrolled: 6 HCC, 9 PDAC, 7 CRC. Median age was 63y (41-82), and 27% were female. Molecular testing showed MSS, TMB low to intermediate (1.57-13.35), and frequent mutations in KRAS and TP53. The BOR was SD (3pts, 18.75%), followed by PD (13pts, 81.25%); there were no PR or CR (ORR = 0%). Six pts had symptomatic deterioration prior to restaging scans. At a median follow-up of 4m (0.9-23.0m), all 22 pts had died of progressive disease with mOS of 4m. When stratified by site of origin, mOS was 9.5m (95%CI: 1.3-21.9m) in HCC and 3.6m (95%CI: 1.9-6.6m) in liver metastases (log-rank test, p=0.27). The most common grade 3-4 trAEs were electrolyte disturbances and anemia. The stool microbiome composition of Bacteroides species did not change with treatment as detected by shotgun sequencing. Plasma secondary BA, measured by the mixed meal test, decreased with treatment (p&lt;0.05, n=18, two-way ANOVA). The classical to non-classical monocytes ratio increased with treatment in flow cytometry analysis of PBMC immune cells (p&lt;0.05, n=14, one-way ANOVA). Transcriptomic analysis of treated liver tumor biopsies showed an increase in BA metabolism. Conclusions: Although well tolerated, the combination of oral vancomycin and tadalafil with nivolumab did not produce any meaningful clinical responses. Correlative studies suggested enhanced activation of BA metabolization, but TME immune profiling did not reveal substantial changes in regulatory suppressor cells or NKTC activity. Clinical trial information: NCT03785210 .

An elderly male with septic arthritis and bacteremia

Rhodococcus hoagii is a gram positive actinomycete found in horses and cattle. Humans can be infected by ingestion or inhalation through contaminated food or soil. The organism usually infects immunosuppressed hosts with pneumonia being the common presentation. We present a case of an 89 years old, apparently immunocompetent host presenting with fever, encephalopathy and arthritis who grew Rhodococcus hoagii in blood and synovial fluid, The patient responded well to a combination of vancomycin, azithromycin and imipenem-cilastatin. Our case demonstrates that extra-pulmonary manifestations such as septic arthritis and bacteremia can be seen in immune competent hosts.

Variables that predict hospital stay and the outcome of Fournier gangrene at King Abdulaziz University Hospital: a retrospective study

BackgroundThe aggressive nature of Fournier gangrene and the associated health issues can result in a more complex clinical course and potentially a longer hospital stay. This study aimed to assess factors that affect the length of hospital stay (LHS) and its relation to the outcome of Fournier gangrene patients.MethodsA retrospective study was performed at King Abdulaziz University Hospital (KAUH), Saudi Arabia, on patients diagnosed with Fournier gangrene between 2017 and 2023. Data about length of hospital stay (LHS), age, BMI, clinical and surgical data and outcome was obtained.ResultsThe mean age of the studied patients was 59.23 ± 11.19 years, the mean body mass index (BMI) was 26.69 ± 7.99 kg/m2, and the mean duration of symptoms was 10.27 ± 9.16 days. The most common presenting symptoms were swelling or induration (64%), 88% had comorbidities with diabetes mellitus (DM) (84%), and 76% had uncontrolled DM. of patients, 24% had a poly-microbial infection, with E. coli being the most common (52%). The mean length of hospital stay (LHS) was 54.56 ± 54.57 days, and 24% of patients had an LHS of more than 50 days. Longer LHS (> 50 days) was associated with patients who did not receive a compatible initial antibiotic, whereas shorter LHS was associated with patients who received Impenem or a combination of vancomycin and meropenem as alternative antibiotics following incompatibility. Reconstruction patients had significantly longer LHS and a higher mean temperature. However, none of the studied variables were found to be predictors of long LHS in the multivariate regression analysis.ConclusionKnowledge of the values that predict LHS allows for patient-centered treatment and may be useful in predicting more radical treatments or the need for additional treatment in high-risk patients. Future multicenter prospective studies with larger sample sizes are needed to assess the needed variables and predictors of long LHS.