Vancomycin Monotherapy Research Articles

Paediatric acute kidney injury induced by vancomycin monotherapy versus combined vancomycin and meropenem.

Increasing reports of the combined use of vancomycin (VAN) and piperacillin/tazobactam leading to higher nephrotoxicity have led to carbapenems being recommended as an alternative option to combine with VAN when nephrotoxicity is a major concern. However, whether carbapenems also increase the nephrotoxicity of VAN is unclear. This study aimed to determine whether meropenem is a suitable drug to combine with VAN based on whether meropenem enhances the nephrotoxicity of VAN. This retrospective cohort study enrolled hospitalized children ranging in age from 1month to 18years at two tertiary hospitals from 1 February 2017 to 1 February 2018. Patients treated with either VAN or combined VAN and meropenem (VM) for more than 48hours were eligible for inclusion. Those with underlying kidney diseases or abnormal age-adjusted baseline serum creatinine (SCr) at admission were excluded. Propensity score matching (PSM) was applied to the patients to balance factors associated with acute kidney injury (AKI). In addition, VAN trough concentrations were also compared. AKI was defined as an increase in SCr by ≥50% from baseline or by ≥0.3mg/dL sustained over at least two consecutive measurements ranging from the time of initiation until 72hours after the completion of VAN therapy. The eligibility criteria were met by 183 of 243 identified patients: 101 patients received VAN alone and 82 received VM. PSM resulted in 154 hospitalized children being included (77 patients in each group). The incidence of AKI was 10.7% (8/77) in both of the compared groups, while the VAN trough concentration was significantly higher in the VM group (9.0mg/L) than in the VAN group (6.6mg/L, P=0.007) after controlling for confounders. Despite the elevated VAN trough concentration, meropenem did not increase the nephrotoxicity of VAN and might therefore be an acceptable antibiotic to combine with VAN when necessary.

1062. Daptomycin/Ceftaroline in Combination vs. Vancomycin for the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia

BackgroundVancomycin has historically been the mainstay of therapy for MRSA bacteremia, but severe infections due to vancomycin-intermediate Staphylococcus aureus have emerged. In vitro studies have shown that the combination of a β-lactam antibiotic, such as ceftaroline with daptomycin, was synergistic against MRSA. The purpose of this study was to compare outcomes in patients who received daptomycin and ceftaroline in combination vs. vancomycin for the treatment of MRSA bacteremia.MethodsThis was a retrospective exploratory cohort study approved by the institutional review board at Cooper University Hospital. Patients were included if they received daptomycin/ceftaroline (cases) or vancomycin (controls) for the treatment of MRSA bacteremia between November 2010 and March 2017. Cases were matched 1:1 with controls based on source of MRSA bacteremia, age within 10 years, and renal function. The primary endpoint was clinical cure, defined as the improvement of signs and symptoms of bacteremia. Secondary endpoints included microbiologic cure, time to sterilization of blood cultures, duration of hospital stay, overall mortality, and MRSA-related mortality.ResultsForty-one cases were included. There was no statistical difference between the two groups in microbiologic cure, time to sterilization of blood cultures, overall mortality, or MRSA-related mortality. There were no significant differences between patients in each group including in those with ICU admissions and who required vasopressors. Cases were significantly more likely to have hardware compared with the control group (43.9% vs. 12.2%; P = 0.0014). Clinical cure was achieved in 27 patients (65.9%) in the case group and 26 patients (63.4%) in the control group (P = 0.8173). Patients in the case group had a statistically longer mean hospital duration (29 days vs. 21 days, respectively, P = 0.0206) and more secondary complications such as bone infection (P = 0.0076).ConclusionTime to sterilization of blood cultures and overall mortality were similar in both groups. Patients in the combination group had longer hospital stays compared with vancomycin monotherapy. Daptomycin/ceftaroline combination therapy is an option for complicated MRSA bacteremia. Larger studies should be conducted to further evaluate this combination.Disclosures All authors: No reported disclosures.

Efficacy of chimeric ectolysin P128 in drug-resistant Staphylococcus aureus bacteraemia in mice.

P128 is a recombinant chimeric ectolysin with potent antistaphylococcal activity. P128 was evaluated as monotherapy and in combination with two standard-of-care (SoC) antibiotics, vancomycin and daptomycin, in mouse models of Staphylococcus aureus bacteraemia. Healthy BALB/c mice were challenged (intraperitoneally) with 109 cfu of MRSA strain COL or USA300 and treated with a single dose of P128 (0.2-10 mg/kg). Drug synergy was tested using a single dose of P128 (0.2 or 2.5 mg/kg) along with sub-therapeutic dose levels of vancomycin (27.5 or 55 mg/kg) or daptomycin (12.5 mg/kg). Bacterial load was checked in peritoneal fluid and in blood, at different time intervals. Synergy against drug-resistant strains was tested using the P128/vancomycin combination against vancomycin-resistant S. aureus (VRSA). In MRSA bacteraemia, P128, vancomycin and daptomycin monotherapy resulted in 31%, 46% and 46% survival, respectively. The P128/vancomycin and P128/daptomycin combinations afforded increased survival of 85% and 88%, respectively. P128 showed a rapid bactericidal effect with a reduction of cfu in both the peritoneal fluid and the blood within 1 h. In VRSA bacteraemia, a mouse-equivalent therapeutic dose of vancomycin (110 mg/kg) failed to rescue animals. P128 (1-20 mg/kg) as monotherapy resulted in dose-dependent efficacy. Survival (37%) with 2.5 mg/kg P128 increased to 63% with the P128/vancomycin combination. P128 exerted a rapid bactericidal effect in vivo and rescued animals from fatal invasive MRSA and VRSA infections. P128/SoC antibiotic combinations exerted a synergistic effect. P128 restored the susceptibility of VRSA to vancomycin. P128 is a novel, potent therapeutic agent for antibiotic-resistant, systemic S. aureus infections.

Vancomycin plus nafcillin salvage for the treatment of persistent methicillin-resistant Staphylococcus aureus bacteremia following daptomycin failure: a case report and literature review.

Background:Evidence supporting beta-lactam plus vancomycin synergy for methicillin-resistant Staphylococcus aureus (MRSA) continues to grow. Current in vivo evidence demonstrates that combination therapy is associated with shorter time to blood sterilization than vancomycin monotherapy. However, this combination has not been reported as salvage therapy for persistent MRSA bacteremia.Case report:We report a case of an 81-year-old male who was successfully treated with vancomycin plus nafcillin after failing vancomycin monotherapy, daptomycin monotherapy, and daptomycin plus gentamicin combination therapy. The patient originally presented with sepsis from a suspected urinary tract infection. Blood cultures drawn on days 1, 3, 5, 15, 19, 23, and 28 remained positive for MRSA despite multiple antimicrobial therapy changes. On day 29, therapy was changed to vancomycin plus nafcillin. Blood cultures drawn on day 32 remained negative. After 11 days, nafcillin was changed to piperacillin–tazobactam due to an infected decubitus ulcer. The combination was continued for 42 days after achieving blood sterility, 71 days after the patient originally presented. Evidence regarding salvage therapy for persistent bacteremia is sparse and is limited to case reports and case series.Conclusion:This case report supports that vancomycin plus an anti-staphylococcal beta-lactam combination should be further studied as salvage therapy for persistent MRSA bacteremia.

Comparative incidence and excess risk of acute kidney injury in hospitalised patients receiving vancomycin and piperacillin/tazobactam in combination or as monotherapy

Combination therapy with vancomycin and piperacillin/tazobactam (TZP) has been associated with increased risk of acute kidney injury (AKI) compared with monotherapy with either agent. This retrospective, matched cohort study was conducted to assess the comparative incidence of AKI due to combination therapy in patients receiving vancomycin and TZP in combination or as monotherapy. Patients aged ≥18 years admitted to Albany Medical Center (Albany, NY) between September 2013 and August 2014 who had received therapy for at least two consecutive days were included. Patients who were pregnant, neutropenic, had AKI on admission or with cystic fibrosis were excluded. Patients were matched on baseline risk of AKI. The main outcome of interest was AKI, defined as an increase in serum creatinine of ≥0.3 mg/L or ≥50% within 48 h. Secondary outcomes evaluated were length of hospital and ICU stay and inpatient mortality associated with AKI. The risk of AKI was 7.0%, 8.5% and 26.8% in the vancomycin monotherapy, TZP monotherapy and combination groups, respectively (P < 0.001). In the multivariate analysis, combination therapy was independently associated with an increased odds of AKI (adjusted odds ratio = 4.406, 95% confidence interval 1.472-13.188) compared with vancomycin monotherapy. The excess risk of combination therapy was 11.3%. In this matched cohort study, there was an increased incidence of AKI in patients receiving vancomycin and TZP combination therapy. Further research is needed to determine the individual strategies to best prevent inpatient AKI in patients receiving this combination therapy.

Vancomycin Monotherapy May Be Insufficient to Treat Methicillin-resistant Staphylococcus aureus Coinfection in Children With Influenza-related Critical Illness.

BackgroundCoinfection with influenza virus and methicillin-resistant Staphylococcus aureus (MRSA) causes life-threatening necrotizing pneumonia in children. Sporadic incidence precludes evaluation of antimicrobial efficacy. We assessed the clinical characteristics and outcomes of critically ill children with influenza–MRSA pneumonia and evaluated antibiotic use.MethodsWe enrolled children (<18 years) with influenza infection and respiratory failure across 34 pediatric intensive care units 11/2008–5/2016. We compared baseline characteristics, clinical courses, and therapies in children with MRSA coinfection, non-MRSA bacterial coinfection, and no bacterial coinfection.ResultsWe enrolled 170 children (127 influenza A, 43 influenza B). Children with influenza–MRSA pneumonia (N = 30, 87% previously healthy) were older than those with non-MRSA (N = 61) or no (N = 79) bacterial coinfections. Influenza–MRSA was associated with increased leukopenia, acute lung injury, vasopressor use, extracorporeal life support, and mortality than either group (P ≤ .0001). Influenza-related mortality was 40% with MRSA compared to 4.3% without (relative risk [RR], 9.3; 95% confidence interval [CI], 3.8–22.9). Of 29/30 children with MRSA who received vancomycin within the first 24 hours of hospitalization, mortality was 12.5% (N = 2/16) if treatment also included a second anti-MRSA antibiotic compared to 69.2% (N = 9/13) with vancomycin monotherapy (RR, 5.5; 95% CI, 1.4, 21.3; P = .003). Vancomycin dosing did not influence initial trough levels; 78% were <10 µg/mL.ConclusionsInfluenza–MRSA coinfection is associated with high fatality in critically ill children. These data support early addition of a second anti-MRSA antibiotic to vancomycin in suspected severe cases.

Vancomycin Versus Vancomycin Plus Rifampin for the Treatment of Acute Pulmonary Exacerbations of Cystic Fibrosis.

This study aimed to compare the change in pulmonary function in children and adolescents with cystic fibrosis (CF) who were infected with methicillin-resistant Staphylococcus aureus (MRSA) treated with either vancomycin (VAN) alone or vancomycin plus rifampin (VAN-RIF). Included patients were ages 6 to 20 years; hospitalized for an acute pulmonary exacerbation (APE) of CF from May 1, 2012, to April 30, 2014; had a respiratory tract culture positive for MRSA within 1 month of index hospital admission; received at least 48 consecutive hours of VAN or VAN-RIF; and had admission and discharge pulmonary function tests. The primary end point was change in percent predicted forced expiratory volume in 1 second (FEV1). A total of 39 encounters met inclusion criteria: 24 in the VAN group (mean age 15.1 years) and 15 in the VAN-RIF group (mean age 13.7 years). There were no between-group differences in mean percent change in FEV1 (32.6% ± 28.8% vs. 21.1% ± 12.1%; p = 0.091), mean percent change in forced vital capacity (22.6% ± 25.8% vs. 14% ± 9.4%; p = 0.127), or return to baseline FEV1 (20 [83.3%] vs. 14 [93.3%] patients; p = 0.631). Median (IQR) length of stay (13 days [11-14 days] vs. 13 days [9-14 days]; p = 0.6) and median (IQR) time to readmission (82 days [43-129 days] vs. 147 days [78-219 days]; p = 0.2) were similar between the VAN and VAN-RIF groups, respectively. Vancomycin monotherapy appears to be adequate when treating APEs of CF in children and adolescents with moderate lung disease and high MRSA VAN minimum inhibitory concentrations. Therefore, the addition of RIF may be unnecessary; however, larger studies are needed to confirm these findings.

Pediatric acute kidney injury induced by concomitant vancomycin and piperacillin-tazobactam.

Vancomycin is very commonly used in combination with piperacillin-tazobactam (PTZ) as the initial empiric treatment for moderate-severe infection, whenever coverage for both methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa is required. The combination of vancomycin and PTZ in adults has recently been reported to significantly increase the risk of acute kidney injury (AKI) relative to vancomycin monotherapy; such reports in pediatrics, however, are sparse. A retrospective chart review was conducted of pediatric patients, aged 0-14 years, who were admitted to the general wards or intensive care unit and developed AKI after receiving vancomycin and PTZ concomitantly for >48h. AKI is defined as a decrease in estimated glomerular filtration rate ≥50% from baseline. Cases were identified by reviewing the Adverse Drug Reaction program database at King Saud University Medical City in Saudi Arabia from January 2015 to June 2016. Eight children admitted to the present hospital and who received concomitant vancomycin and PTZ treatment for pneumonia (n = 7) or febrile neutropenia (n = 1) developed drug-induced nephrotoxicity. Drug Interaction Probability Scale (DIPS) score for causation assessment was 9 in all cases (highly probable). Caution in utilizing the combination of vancomycin and PTZ is warranted in pediatric patients. Health-care professionals should be vigilant if this combination is to be initiated, and ensure close monitoring of renal function. Antibiotic therapy de-escalation should be considered as soon as culture results are available.

Outcomes of Vancomycin plus a β-Lactam versus Vancomycin Only for Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia.

The objective of this retrospective study was to compare the rates of treatment failure, which was a composite of clinical and microbiologic failure, of patients receiving vancomycin and a β-lactam to those receiving vancomycin only for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Patients 16 to 89 years of age with MRSA bacteremia admitted to a university-affiliated hospital from 1 January 2014 to 31 December 2016 were screened for study inclusion. Patients were eligible if they received >48 h of vancomycin and a β-lactam (combination group) or vancomycin only (standard group) within 48 h after bacteremia onset. A total of 182 patients were screened: 47 were included in the standard group, and 63 were in the combination group. The combination group had a higher baseline body mass index (29.2 ± 8.0 kg/m2 versus 25.8 ± 7.1 kg/m2, P = 0.022), acute physiologic assessment and chronic health evaluation-II (APACHE-II) score (median [interquartile range], 21 [15 to 26] versus 16 [10 to 22], P = 0.003), and incidence of septic shock (31.8% versus 14.9%, P = 0.047). Using multivariate analysis, combination therapy was the only variable that decreased treatment failures (odds ratio [95% confidence interval], 0.337 [0.142 to 0.997]), while vancomycin MIC > 1 mg/liter and male gender increased treatment failures (4.018 [1.297 to 12.444] and 2.971 [1.040 to 8.488], respectively). The 30-day mortality rates (15.0% versus 14.9%, P = 1.000) and the incidence of adverse drug events (19.1% versus 23.4%, P = 0.816) were not statistically different between the combination and standard groups. Combination therapy of vancomycin with a β-lactam led to significantly fewer treatment failures than vancomycin monotherapy for MRSA bacteremia.

Oral Vancomycin Monotherapy Versus Combination Therapy in Solid Organ Transplant Recipients With Uncomplicated Clostridium difficile Infection: A Retrospective Cohort Study

IntroductionSolid organ transplant (SOT) recipients are at high risk of Clostridium difficile infection (CDI) and CDI recurrence due to their suppressed immune systems and antibiotic exposure. A combination of metronidazole and oral vancomycin is often prescribed for SOT recipients with uncomplicated CDI despite any clinical practice guidelines supporting the need for combination therapy. This study aims to compare the CDI recurrence rates of metronidazole/vancomycin combination therapy to oral vancomycin monotherapy in SOT recipients after a first episode of uncomplicated CDI. MethodsA single-center retrospective cohort study evaluated SOT recipients diagnosed with uncomplicated CDI who were treated with vancomycin monotherapy or vancomycin/metronidazole combination therapy. The primary endpoint was CDI recurrence defined as a second CDI episode within 8 weeks of completing index CDI therapy. The secondary endpoints were time between the end of CDI therapy and recurrence, length of total hospitalization after the index CDI, and length of hospitalization after index CDI diagnosis. ResultsFifteen patients (25%) of 61 subjects experienced CDI recurrence. There was no statistically significant difference in CDI recurrence rate between the vancomycin monotherapy group and combination therapy group (23% versus 27%, respectively; P = .715). The median total length of hospitalization between the vancomycin monotherapy and combination therapy groups was statistically significant (9 versus 14 days, respectively; P = .047). DiscussionThere was no difference found in recurrence rate between oral vancomycin monotherapy versus combination therapy. The study result weakens the practice of prescribing combination therapy for uncomplicated CDI in SOT recipients.

A Comparison of Nephrotoxicity in Non–Intensive Care Unit Medical-Surgical Patients Receiving Vancomycin Alone Versus Vancomycin With Piperacillin-Tazobactam

Background Recent studies have identified an increase in nephrotoxicty in patients receiving vancomycin plus piperacillin-tazobactam (PT) when compared with vancomycin monotherapy. To date, studies have evaluated all hospitalized patients or intensive care unit patients only. The purposes of this study were to examine the incidence of acute kidney injury (AKI) in patients who received vancomycin either as monotherapy or with PT in a non–intensive care unit medical-surgical setting and to identify potential risk factors for the development of AKI. Methods A retrospective chart review was performed to identify patients who received vancomycin either as monotherapy or in combination with PT for at least 48 hours. Patients were evaluated for development of AKI, defined as serum creatinine increase of 50% from baseline. Statistical analysis included demographic, univariate, and multivariable analyses. Results One hundred eighty-nine patients met inclusion criteria. More patients in the vancomycin + PT group developed AKI than in the vancomycin monotherapy group (18.4% vs 5.6%, P = 0.008). After multivariable logistic regression of patients receiving vancomycin, PT, African American, and perioperative patients remained statistically associated with AKI. These risk factors gave odds ratios of 3.9, 3.8, and 4.0, respectively. Conclusions Patients receiving PT in addition to vancomycin were more likely to develop AKI compared with those receiving vancomycin monotherapy. African American and perioperative patients may have a higher risk.

Treatment of Clostridium Difficile Infection in Community Teaching Hospital: A Retrospective Study

Clostridium difficile infection (CDI) is responsible for 15 – 25% cases of health-care associated diarrhea. The CDI treatment algorithm used at our hospital is adapted from the Infectious Diseases Society of America 2010 C. difficile guideline. The primary objective of this study was to assess the treatment adherence to our algorithm; this was defined as therapy consisting of the appropriate antibiotic, dose, route, interval and duration indicated based on the disease severity and episode within 24 hours of diagnosis. In addition, our study also described the population and their risk factors for CDI at our hospital. This was a single-centre, retrospective cohort chart review of CDI cases that were diagnosed at admission or during hospitalization from June 1st 2017 to June 30th 2018. Sixty cases were included, of which adherence to our algorithm was 50%. Overall, severe CDI had the highest treatment non-adherence (83%) and the biggest contributing factor was prescribing the wrong antibiotic (72%). In severe CDI, which warrants vancomycin monotherapy, wrong antibiotic consisted of metronidazole monotherapy (55%) or dual therapy with metronidazole and vancomycin (45%). Patients were mostly older, females being treated for an initial episode of mild to moderate CDI. Common risk factors identified were age over 65 years (80%), use of antibiotics (83%) and proton pump inhibitors (PPI) (68%) within the previous three months. The use of a PPI in this study, a modifiable risk factor without a clear indication was 35%. The conclusion was that there is an area for antimicrobial stewardship intervention in CDI treatment at our hospital is prescribing the right antibiotic based on the CDI indication. In severe CDI, an emphasis should be on prescribing vancomycin monotherapy as the drug of choice. PPI use should be reassessed for tapering when appropriate.

Clostridium difficile treatment in neutropenic patients: Clinical outcomes of metronidazole, vancomycin, combinations, and switch therapy.

Clostridium difficile infection treatment guidelines exist for immunocompetent patients; however, there is a paucity of data evaluating clinical outcomes and time to C. difficile-associated diarrhea resolution in neutropenic patients. To assess clinical outcomes in neutropenic patients treated with metronidazole, oral vancomycin, the combination of metronidazole plus oral vancomycin, and switch of metronidazole to oral vancomycin. This retrospective, observational cohort study assessed adult neutropenic inpatients with C. difficile-associated diarrhea treated with metronidazole, oral vancomycin, combination (metronidazole and oral vancomycin), or switch therapy (metronidazole to oral vancomycin). The primary outcome was time to diarrhea resolution based on treatment regimen. Secondary outcomes included C. difficile-associated diarrhea resolution of diarrhea by day 14, recurrence, and occurrence of major complications. Overall, 44 patients met full inclusion criteria (52.2% metronidazole monotherapy, 22.7% combination, and 25.0% switch therapy). Two patients on oral vancomycin monotherapy were excluded due to insufficient sample size. Overall time to C. difficile-associated diarrhea resolution was 9.1 ± 10.7 days. The Cox regression results suggested both switch and combination therapy were associated with 65.5% (p = 0.002) and 65.9% (p = 0.046) longer time to C. difficile-associated diarrhea resolution compared to metronidazole monotherapy, respectively. An increasing absolute neutrophil count was associated with an increase in C. difficile-associated diarrhea resolution (p = 0.007). Switch or combination therapy was associated with a prolonged time to C. difficile-associated diarrhea resolution. The decision to use switch or combination therapy may represent a surrogate marker for more severe disease and need for therapy escalation. It is unknown if initial therapy with oral vancomycin would provide better outcomes as this could not be assessed.

Microbiology of Vertebral Osteomyelitis and Implications on Empiric Therapy

BackgroundThe management of vertebral osteomyelitis (VO) includes empiric antibiotic therapy while clinical cultures are being processed. Optimal antimicrobial therapy for VO, particularly when Gram-negative (GN) organisms are involved, is an area of ongoing debate. Narrow spectrum and oral antimicrobial therapy are preferred. The objective of this study was to identify characteristics of local pathogens and to formulate an institution-specific antibiotic protocol for empiric treatment of VO.MethodsWe conducted a retrospective case series study of adults diagnosed with VO from August 1, 2010 to August 31, 2015 at Palmetto Health Hospitals in Columbia, South Carolina. Cases identified by ICD-9 codes were included in the analysis if they met clinical, imaging and microbiology, criteria.ResultsAnalysis is based on 150 cases of VO with a mean age of 61 years, a male predominance (91; 61%), and an average body mass index of 29kg/m2. Comorbidities included diabetes mellitus (69; 46%), tobacco use (33; 22%), and hemodialysis (20; 13%). Thirty-seven (25%) cases had recent related injury or vertebral surgery, and 14 (9%) had prior hardware. Bone, disc, or adjacent tissue cultures were obtained in 129 (86%) of cases; 60 (40%) of these had >1 sample taken. The remaining 14% had blood cultures alone. Thirty-six cases (24%) had culture negative VO. In the remaining 114 cases, 132 organisms were isolated. A total of 111 (84%) organisms were Gram-positive cocci (GPC). Of those, the majority was Staphylococcus aureus. (66; 59%) (26/66 were methicillin-resistant), coagulase-negative staphylococci (20; 18%) and Streptococcus spp. (17; 15%). Enterobacteriaceae accounted for 13/17 Gram-negative bacilli (GNB), with only one isolate of Pseudomonas aeruginosa. Of the GNB, 11/17 were susceptible to either ceftriaxone or ciprofloxacin.ConclusionThere was a predominance of VO due to GPC suggesting that intravenous vancomycin monotherapy may be reasonable for empiric therapy in noncritically ill patients while awaiting Gram stain and clinical culture results. Addition of either ceftriaxone or ciprofloxacin to vancomycin would increase cumulative antimicrobial coverage from 84 to 92%.Disclosures All authors: No reported disclosures.

Establishment of an AUC0-24 Threshold for Nephrotoxicity Is a Step towards Individualized Vancomycin Dosing for Methicillin-Resistant Staphylococcus aureus Bacteremia.

Unlike vancomycin trough concentrations, data on the utility of vancomycin pharmacokinetic (PK) parameters, namely, the area under the concentration-time curve from 0 to 24 h (AUC0-24), in predicting acute kidney injury (AKI) are limited. Our aim was to investigate this relationship in patients receiving vancomycin therapy for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B). A single-center retrospective observational cohort study involving 127 consecutive MRSA-B patients was conducted to examine the incidence of AKI (defined as serum creatinine of ≥0.5 mg/liter and a 50% increase from baseline) and vancomycin exposure parameters associated with nephrotoxicity. Bayesian estimation was used to predict individual vancomycin AUC0-24 All patients received vancomycin monotherapy for a minimum of 14 days following the diagnosis of MRSA-B. AKI was observed in 15.7% of patients (20/127). Clinical characteristics were similar between patients with and without AKI. At steady state, higher vancomycin trough concentrations were associated with AKI (17.2 mg/liter versus 13.1 mg/liter; P = 0.003). A vancomycin AUC0-24 threshold for AKI of >563 mg · h/liter was detected by classification and regression tree (CART) analysis; patients with exposures above this threshold were significantly more likely to experience AKI than patients with lower vancomycin exposures (40% [8/20] versus 11.2% [12/107]; P = 0.002). This parameter remained an independent predictor of AKI on multivariate logistic regression (odds ratio [OR], 5.07; 95% confidence interval [CI], 1.57 to 16.29; P = 0.006) and was a better predictor of nephrotoxicity than vancomycin trough concentrations. Overall, AKI is associated with higher vancomycin exposure as measured by AUC0-24 These results suggest that individualized patient dosing may be possible with dose modifications directed toward established pharmacodynamic targets while balancing AKI risks.

Vancomycin Prophylaxis for Total Joint Arthroplasty: Incorrectly Dosed and Has a Higher Rate of Periprosthetic Infection Than Cefazolin.

In total joint arthroplasty (TJA), vancomycin is used as perioperative antibiotic prophylaxis in patients with penicillin allergy or in patients colonized with methicillin-resistant Staphylococcus aureus (MRSA). Although vancomycin dosing should be weight-based (15mg/kg), not all surgeons are aware of this; a fixed 1-g dose is instead frequently administered. (1) Is there a difference in the risk of periprosthetic joint infection (PJI) in patients receiving vancomycin or cefazolin prophylaxis after primary TJA? (2) What proportion of patients is adequately dosed with vancomycin? (3) Compared with actual fixed dosing, does weight-based dosing result in a greater proportion of patients staying above the recommended 15-mg/L level at the beginning and end of surgery? (4) Are patients overdosed with vancomycin at greater risk of developing nephrotoxicity and acute kidney injury? A single-institution, retrospective study was performed on 1828 patients undergoing primary TJAs who received vancomycin prophylaxis between 2008 and 2014. During the same period, 5810 patients underwent primary TJA and received cefazolin monotherapy. A chart review was performed to obtain patient characteristics, antibiotic dose and timing of administration, and microbiology data. Adequate vancomycin dosing was defined as 15mg/kg and within the 125-mg range. Vancomycin levels were calculated at the beginning and end of surgery using pharmacokinetic equations. Levels of 15mg/L were considered adequate. Logistic regression, chi square tests, and analysis of variance were performed. Among primary TJAs, patients receiving vancomycin had a higher rate of PJI (32 of 1828 [2%]) compared with patients receiving cefazolin prophylaxis (62 of 5810 [1%]; adjusted odds ratio, 1.587 [1.004-2.508]; p=0.048). Ten percent of PJIs in the vancomycin underdosed group (two of 20) was caused by MRSA, and no patients with adequate dosing or overdosing of vancomycin developed PJI with MRSA. Of all procedures in which vancomycin monotherapy was used, 28% (518 of 1828) was adequately dosed according to weight-based dosage recommendations. Furthermore, 94% (1726 of 1828) of patients received a fixed 1-g dose of vancomycin, of whom 64% (1105 of 1726) were underdosed. All patients had vancomycin infusion initiated within 2 hours before incision. A weight-based protocol would have resulted in fewer patients having unacceptably low vancomycin levels (<15mg/L) compared with those with actual fixed dosing, both for the beginning of surgery at the time of incision (zero of 1828 [0%] versus 471 of 1828 [26%]; odds ratio, 0.001 [0.000-0.013]; p<0.001) and at the end of surgery (33 of 1828 [2%] versus 746 of 1828 [41%]; odds ratio, 0.027 [0.019-0.038]; p<0.001). Between the vancomycin dosage groups, there were no differences in the rate of nephrotoxicity (underdosed: 12 of 1130 [1%], adequately dosed: five of 518 [1%], overdosed: four of 180 [2%], p=0.363) and acute kidney injury (underdosed: 28 of 1130 [2%], adequately dosed: 10 of 518 [2%], overdosed: six of 180 [3%], p=0.561). The majority of patients given vancomycin prophylaxis are underdosed according to the weight-based dosage recommendations, and MRSA did not occur in patients who were adequately dosed with vancomycin. Surgeons should thus ensure that their patients are adequately dosed with vancomycin using the recommendation of 15mg/kg and that the dose of vancomycin is administered in a timely fashion. Furthermore, and based on the findings of this study, we have moved toward limiting the utilization of vancomycin prophylaxis for patients undergoing elective arthroplasty at our institution. Level III, therapeutic study.

Combinatory antibiotic therapy increases rate of bacterial kill but not final outcome in a novel mouse model of Staphylococcus aureus spinal implant infection

BackgroundManagement of spine implant infections (SII) are challenging. Explantation of infected spinal hardware can destabilize the spine, but retention can lead to cord compromise and biofilm formation, complicating management. While vancomycin monotherapy is commonly used, in vitro studies have shown reduced efficacy against biofilm compared to combination therapy with rifampin. Using an established in vivo mouse model of SII, we aim to evaluate whether combination therapy has increased efficacy compared to both vancomycin alone and infected controls.MethodsAn L-shaped, Kirschner-wire was transfixed into the L4 spinous process of 12-week-old C57BL/6 mice, and inoculated with bioluminescent Staphylococcus aureus. Mice were randomized into a vancomycin group, a combination group with vancomycin plus rifampin, or a control group receiving saline. Treatment began on post-operative day (POD) 7 and continued through POD 14. In vivo imaging was performed to monitor bioluminescence for 35 days. Colony-forming units (CFUs) were cultured on POD 35.ResultsBioluminescence peaked around POD 7 for all groups. The combination group had a 10-fold decrease in signal by POD 10. The vancomycin and control groups reached similar levels on POD 17 and 21, respectively. On POD 25 the combination group dropped below baseline, but rebounded to the same level as the other groups, demonstrating a biofilm-associated infection by POD 35. Quantification of CFUs on POD 35 confirmed an ongoing infection in all three groups.ConclusionsAlthough both therapies were initially effective, they were not able to eliminate implant biofilm bacteria, resulting in a rebound infection after antibiotic cessation. This model shows, for the first time, why histologic-based, static assessments of antimicrobials can be misleading, and the importance of longitudinal tracking of infection. Future studies can use this model to test combinations of antibiotic therapies to see if they are more effective in eliminating biofilm prior to human trials.

Empirical combination of a β-lactam to vancomycin may not improve outcomes of methicillin-susceptible Staphylococcus aureus bacteremia, compared to vancomycin monotherapy.

To evaluate effect of empirical combination of a β-lactam to vancomycin and vancomycin monotherapy in Staphylococcus aureus bacteremia (MSSA-B), we conducted a retrospective cohort study. Electronic medical records of individuals who were diagnosed with MSSA-B between January 2005 and February 2015 at a tertiary care center were reviewed. Patients were classified into three groups according to empirical antibiotic regimen (BL group, β-lactam; VAN group, vancomycin; BV group, combination of β-lactam and vancomycin), and 30-day all-cause mortality of each group was compared. During the study period, 561 patients with MSSA-B were identified. After exclusion of 198 patients (36 with poly-microbial infection, 114 expired within 2days, and 48 already received parenteral antibiotics) and a matching process, 46 patients for each group were included. Baseline characteristics were similar except for severity and comorbidity scores. The 30-day mortality for all three groups were not significantly different (BL 4.3%, VAN 6.5%, BV 8.7%; P = 0.909). In a multivariate analysis, type of empirical antibiotic regimen was not statistically associated with 30-day all-cause mortality. In comparison with the VAN group, the BV group yielded a HR of 0.579 (95% CI = 0.086-3.890, P = 0.574). Pitt bacteremia score was the only significant factor for mortality. The empirical combination of a β-lactam to vancomycin was not associated with lower mortality in treating MSSA-B, compared to vancomycin monotherapy.

Comparison of Rates of Acute Kidney Injury with Vancomycin/Piperacillin-Tazobactam vs. Vancomycin/Meropenem Combination Therapy

BackgroundVancomycin is historically correlated with renal toxicity, especially in conjunction with other nephrotoxins. Recent reports have identified nephrotoxicity associated with vancomycin in conjunction with β-lactam antibiotic therapy, reporting increased rates of acute kidney injury (AKI) with vancomycin/piperacillin-tazobactam (VPT) therapy as compared with vancomycin monotherapy. Similarly, increased rates of AKI have been reported with VPT as compared with vancomycin/cefepime. Little data exists comparing VPT to the combination of vancomycin/meropenem (VM). The purpose of this study was to compare the incidence of nephrotoxicity between these two antibiotic combinations.MethodsA single-center cohort study was performed at a large tertiary care community hospital utilizing retrospective review of electronic medical records. Adult in-patients treated from June to October of 2015 were included. Evaluable patients received at least 48 hours of either VPT or VM combination therapy and were followed for up to 10 days of combination therapy. Data collection included patient demographics, AKI risk factors, days of antibiotic therapy, and serum creatinine. The primary endpoint was incidence of AKI as defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria. Secondary endpoints included time to AKI and incidence of new dialysis treatment.ResultsOf 564 patients screened, a total of 202 patients met inclusion criteria, with 101 patients in each combination therapy group. Baseline serum creatinine and estimated creatinine clearance were not different between groups. The incidence of AKI was higher in the VPT group as compared with the VM group (17.82% vs. 4.95%, respectively, P = 0.004). Time to AKI onset was longer in the VPT group compared with the VM group (3.2 days vs. 1.4 days, P = 0.045). Patients in the VM group had a higher incidence of ICU admissions (56.4% vs. 40.6%, P = 0.024) and mean arterial pressure (MAP) less than 65mmHg (60.4% vs. 44.6%, P = 0.029). No patients in either group required new dialysis therapy.ConclusionDespite a greater incidence of AKI risk factors in the VM group, VPT therapy was associated with an increased risk of AKI as compared with VM therapy. Prospective studies are needed to further evaluate this finding.Disclosures All authors: No reported disclosures.

Combination Therapy With Vancomycin and Ceftaroline for Refractory Methicillin-resistant Staphylococcus aureus Bacteremia: A Case Series

PurposeAlthough vancomycin has been the mainstay of therapy for methicillin-resistant Staphylococcus aureus (MRSA) infections, its effectiveness has been challenged. Combination therapy may be used for patients with persistent MRSA bacteremia refractory to initial therapy. Studies have reported in vitro synergy between vancomycin and ceftaroline; however, clinical experience with this therapy is limited. Here, we report our experience with 5 cases of vancomycin-refractory MRSA bacteremia treated with the combination of vancomycin and ceftaroline. MethodsBetween January 2014 and August 2016, 5 patients were identified who received vancomycin and ceftaroline combination therapy due to persistent bacteremia or deterioration of their clinical status on vancomycin alone (despite a vancomycin MIC within the susceptible range). FindingsFive patients presented with MRSA bacteremia secondary to endocarditis (n = 2), epidural abscess (n = 2), or left iliopsoas abscess (n = 1). Four of the 5 patients experienced microbiologic cure, and 1 patient transitioned to palliative care. ImplicationsThis case series serves to describe additional clinical experience with vancomycin and ceftaroline combination therapy. This combination may be considered when vancomycin monotherapy does not lead to microbiological and/or clinical improvement in patients with metastatic MRSA bacteremia. Additional studies are warranted to further define its role in salvage therapy for persistent MRSA bacteremia.