Association of SARS-CoV-2 status and antibiotic-resistant bacteria with inadequate empiric therapy in hospitalized patients: a US multicenter cohort evaluation (July 2019 - October 2021).

BACKGROUND: Antibiotic usage and antibiotic resistance (ABR) patterns changed during the COVID-19 pandemic. Inadequate empiric antibiotic therapy (IET) is a significant public health problem and contributes to ABR. We evaluated factors associated with IET before and during the COVID-19 pandemic to determine the impact of the pandemic on antibiotic management. METHODS: This multicenter, retrospective cohort analysis included hospitalized US adults who had a positive bacterial culture (specified gram-positive or gram-negative bacteria) from July 2019 to October 2021 in the BD Insights Research Database. IET was defined as antibacterial therapy within 48 h that was not active against the bacteria. ABR results were based on susceptibility testing and reports from local facilities. Multivariate analysis was used to identify risk factors associated with IET in patients with any positive bacterial culture and ABR-positive cultures, including multidrug-resistant (MDR) bacteria. RESULTS: Of 278,344 eligible patients in 269 hospitals, 56,733 (20.4%) received IET; rates were higher in patients with ABR-positive (n = 93,252) or MDR-positive (n = 39,000) cultures (34.9% and 45.0%, respectively). Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-positive patients had significantly higher rates of IET (25.9%) compared with SARS-CoV-2-negative (20.3%) or not tested (19.7%) patients overall and in the ABR and MDR subgroups. Patients with ABR- or MDR-positive cultures had more days of therapy and longer lengths of stay. In multivariate analyses, ABR, MDR, SARS-CoV-2-positive status, respiratory source, and prior admissions were identified as key IET risk factors. CONCLUSIONS: IET remained a persistent problem during the COVID-19 pandemic and occurred at higher rates in patients with ABR/MDR bacteria or a co-SARS-CoV-2 infection.

Morbidity and mortality of hospitalised patients with candidemia during the various severe acute respiratory syndrome coronavirus 2 pandemic waves: A multicentre evaluation of 248 US hospitals.

BACKGROUND: Studies evaluating outcomes of COVID-19 patients with candidemia are limited and have only evaluated a single timepoint during the pandemic. OBJECTIVES: To compare the prevalence and outcomes associated with candidemia in patients based on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) status and through the various pandemic waves (1 March 2020-5 March 2022). PATIENTS/METHODS: Multicentre, retrospective cohort analysis of data from 248 US medical facilities using the BD Insights Research Database (Becton, Dickinson and Company, Franklin Lakes, New Jersey, USA). Eligible patients were adults aged ≥18 years who were hospitalised for >1 day, had a SARS-CoV-2 test and a positive blood culture for Candida spp. RESULTS: During the study time frame, there were 2,402,879 hospital admissions; 234,903 (9.7%) and 2,167,976 (90.3%) patients were SARS-CoV-2 positive and negative, respectively. A significantly higher rate of candidemia/1000 admissions was observed in SARS-CoV-2-positive patients compared to SARS-CoV-2-negative patients (3.18 vs. 0.99; p < .001). The highest candidemia rate for SARS-CoV-2-positive patients was observed during the Alpha SARS-CoV-2 wave (June 2020-August 2020) with the lowest candidemia rate during the Omicron wave. Hospital mortality was significantly higher in SARS-CoV-2-positive patients compared to SARS-CoV-2-negative patients with candidemia (59.6% vs. 30.8%; p < .001). When evaluating the mortality rate through the various pandemic waves, the rate for the overall population did not change. CONCLUSIONS: Our study indicates high morbidity and mortality for hospitalised patients with COVID-19 and candidemia which was consistent throughout the pandemic. Patients with COVID-19 are at an increased risk for candidemia; importantly, the magnitude of which may differ based on the circulating variant.

A Multicenter Comparison of Prevalence and Predictors of Antimicrobial Resistance in Hospitalized Patients Before and During the Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic.

Background: Antibacterial therapy is frequently used in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) without evidence of bacterial infection, prompting concerns about increased antimicrobial resistance (AMR). We evaluated trends in AMR before and during the SARS-CoV-2 pandemic. Methods: This multicenter, retrospective cohort analysis included hospitalized adults aged ≥18 years with >1-day inpatient admission and a record of discharge or death from 271 US facilities in the BD Insights Research Database. We evaluated rates of AMR events, defined as positive cultures for select gram-negative and gram-positive pathogens from any source, with nonsusceptibility reported by commercial panels before (1 July 2019-29 February 2020) and during (1 March 2020-30 October 2021) the SARS-CoV-2 pandemic. Results: Of 5 518 666 admissions evaluated, AMR rates per 1000 admissions were 35.4 for the prepandemic period and 34.7 for the pandemic period (P ≤ .0001). In the pandemic period, AMR rates per 1000 admissions were 49.2 for SARS-CoV-2-positive admissions, 41.1 for SARS-CoV-2-negative admissions, and 25.7 for patients untested (P ≤ .0001). AMR rates per 1000 admissions among community-onset infections during the pandemic were lower versus prepandemic levels (26.1 vs 27.6; P < .0001), whereas AMR rates for hospital-onset infections were higher (8.6 vs 7.7; P < .0001), driven largely by SARS-CoV-2-positive admissions (21.8). AMR rates were associated with overall antimicrobial use, rates of positive cultures, and higher use of inadequate empiric therapy. Conclusions: Although overall AMR rates did not substantially increase from prepandemic levels, patients tested for SARS-CoV-2 infection had a significantly higher rate of AMR and hospital-onset infections. Antimicrobial and diagnostic stewardship is key to identifying this high-risk AMR population.

Epidemiology and outcomes of culture-positive bloodstream pathogens prior to and during the SARS-CoV-2 pandemic: a multicenter evaluation.

BACKGROUND: Bloodstream infections (BSIs) are an important cause of morbidity and mortality in hospitalized patients. We evaluate incidence of community- and hospital-onset BSI rates and outcomes before and during the SARS-CoV-2 pandemic. METHODS: We conducted a retrospective cohort study evaluating patients who were hospitalized for ≥ 1 day with discharge or death between June 1, 2019, and September 4, 2021, across 271 US health care facilities. Community- and hospital-onset BSI and related outcomes before and during the SARS-CoV-2 pandemic, including intensive care admission rates, and overall and ICU-specific length of stay (LOS) was evaluated. Bivariate correlations were calculated between the pre-pandemic and pandemic periods overall and by SARS-CoV-2 testing status. RESULTS: Of 5,239,692 patient admissions, there were 20,113 community-onset BSIs before the pandemic (11.2/1000 admissions) and 39,740 (11.5/1000 admissions) during the pandemic (P ≤ 0.0062). Corresponding rates of hospital-onset BSI were 2,771 (1.6/1000 admissions) and 6,864 (2.0/1000 admissions; P < 0.0062). Compared to the pre-pandemic period, rates of community-onset BSI were higher in patients who tested negative for SARS-CoV-2 (15.8/1000 admissions), compared with 9.6/1000 BSI admissions among SARS-CoV-2-positive patients. Compared with patients in the pre-pandemic period, SARS-CoV-2-positive patients with community-onset BSI experienced greater ICU admission rates (36.6% vs 32.8%; P < 0.01), greater ventilator use (10.7% vs 4.7%; P < 0.001), and longer LOS (12.2 d vs 9.1 d; P < 0.001). Rates of hospital-onset BSI were higher in the pandemic vs the pre-pandemic period (2.0 vs 1.5/1000; P < 0.001), with rates as high a 7.3/1000 admissions among SARS-CoV-2-positive patients. Compared to the pre-pandemic period, SARS-CoV-2-positive patients with hospital-onset BSI had higher rates of ICU admission (72.9% vs 55.4%; P < 0.001), LOS (34.8 d vs 25.5 d; P < 0.001), and ventilator use (52.9% vs 21.5%; P < 0.001). Enterococcus species, Staphylococcus aureus, Klebsiella pneumoniae, and Candida albicans were more frequently detected in the pandemic period. CONCLUSIONS AND RELEVANCE: This nationally representative study found an increased risk of both community-onset and hospital-onset BSI during the SARS-CoV-2 pandemic period, with the largest increased risk in hospital-onset BSI among SARS-CoV-2-positive patients. SARS-CoV-2 positivity was associated with worse outcomes.

Ceftolozane-tazobactam activity against clinical isolates of Pseudomonas aeruginosa from ICU patients with pneumonia: United States, 2015-2018.

OBJECTIVES: To report on the activity of ceftolozane-tazobactam and comparators against Pseudomonas aeruginosa isolates collected from hospitalized patients with pneumonia in US intensive care units (ICUs) between 2015 and 2018. Activity against all P. aeruginosa and common resistant phenotypes are described to better inform decision-making and support antimicrobial stewardship efforts. METHODS: In total, 781 P. aeruginosa isolates were collected from 28 US hospitals. These isolates were tested for susceptibility to ceftolozane-tazobactam and comparators by Clinical and Laboratory Standards Institute (CLSI) broth microdilution methodology using CLSI (2020) breakpoints. Phenotypes analysed included piperacillin-tazobactam-non-susceptible (NS), cefepime-NS, ceftazidime-NS, meropenem-NS and difficult-to-treat resistance (DTR). RESULTS: Ceftolozane-tazobactam was the most potent agent tested (minimum inhibitory concentration to inhibit 50% and 90% of isolates of 0.5 and 2 mg/L, respectively, inhibiting 97.2% at the susceptible breakpoint of ≤4 mg/L). Traditional first-line antipseudomonal ß-lactam antibiotics (piperacillin-tazobactam, cefepime and ceftazidime) demonstrated <33% susceptibility when P. aeruginosa was NS to one or more agent. Although escalation of therapy to meropenem is commonly employed clinically, meropenem susceptibility ranged from 33.6% to 44.9% if P. aeruginosa was NS to any traditional first-line antipseudomonal ß-lactam agent. Conversely, ceftolozane-tazobactam remained active against isolates that were NS to other agents, inhibiting 88.4% of isolates NS to piperacillin-tazobactam, 85.0% of isolates NS to cefepime and ceftazidime, and 90.3% of isolates NS to meropenem. Ceftolozane-tazobactam also maintained activity against 73.0% of DTR isolates. CONCLUSIONS: Ceftolozane-tazobactam maintained high activity against P. aeruginosa isolated from hospitalized patients with pneumonia in US ICUs, and had the greatest activity against isolates NS to one or more antipseudomonal ß-lactams and DTR isolates.

Collective assessment of antimicrobial susceptibility among the most common Gram-negative respiratory pathogens driving therapy in the ICU.

OBJECTIVES: To describe the pathogen predominance and to evaluate the probability of covering the most common Gram-negative pathogens collectively in both empirical and early adjustment prescribing scenarios in ICU patients with respiratory infections. METHODS: Data were collected from an international cohort of hospitals as part of the SMART Surveillance Program (2018). Susceptibility testing (mg/L) was performed by broth microdilution methods. RESULTS: 7171 Gram-negative respiratory isolates from adult ICU patients across 209 hospitals from 56 different countries were studied. Overall, the most common ICU respiratory pathogens isolated were Pseudomonas aeruginosa (25%), Klebsiella pneumoniae (18%), Acinetobacter baumannii (14%), and Escherichia coli (11%), with inter-regional differences among these pathogens. Among Enterobacterales, 36% were ESBL positive. When the collective susceptibility profile of this set of pathogens (P. aeruginosa plus Enterobacterales; comprising 78% of all organisms isolated) was performed, ceftolozane/tazobactam (84%), followed by meropenem (81%), provided the most reliable in vitro activity in the empirical prescribing scenario compared with other ß-lactam antibiotics. P. aeruginosa co-resistance was common among first-line ß-lactam antibiotics. If P. aeruginosa was non-susceptible to piperacillin/tazobactam, less than one-third were susceptible to meropenem or ceftazidime. In contrast, ceftolozane/tazobactam offered in vitro coverage in over two-thirds of these resistant pathogens. CONCLUSIONS: Ceftolozane/tazobactam demonstrated high cumulative susceptibility levels and in vitro activity in both empirical and adjustment antibiotic prescribing scenarios. High frequency of co-resistance undermines reliable coverage for Gram-negative pathogens already resistant to first-line agents. Ceftolozane/tazobactam would offer additional coverage in this setting.

Effect of Inadequate Empiric Antibacterial Therapy on Hospital Outcomes in SARS-CoV-2-Positive and -Negative US Patients With a Positive Bacterial Culture: A Multicenter Evaluation From March to November 2020.

BACKGROUND: Increased utilization of antimicrobial therapy has been observed during the coronavirus disease 2019 pandemic. We evaluated hospital outcomes based on the adequacy of antibacterial therapy for bacterial pathogens in US patients. METHODS: This multicenter retrospective study included patients with ≥24 hours of inpatient admission, ≥24 hours of antibiotic therapy, and discharge/death from March to November 2020 at 201 US hospitals in the BD Insights Research Database. Included patients had a test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a positive bacterial culture (gram-positive or gram-negative). We used generalized linear mixed models to evaluate the impact of inadequate empiric therapy (IET), defined as therapy not active against the identified bacteria or no antimicrobial therapy in the 48 hours following culture, on in-hospital mortality and hospital and intensive care unit length of stay (LOS). RESULTS: Of 438 888 SARS-CoV-2-tested patients, 39 203 (8.9%) had positive bacterial cultures. Among patients with positive cultures, 9.4% were SARS-CoV-2 positive, 74.4% had a gram-negative pathogen, 25.6% had a gram-positive pathogen, and 44.1% received IET for the bacterial infection. The odds of mortality were 21% higher for IET (odds ratio [OR], 1.21; 95% CI, 1.10-1.33; P < .001) compared with adequate empiric therapy. IET was also associated with increased hospital LOS (LOS, 16.1 days; 95% CI, 15.5-16.7 days; vs LOS, 14.5 days; 95% CI, 13.9-15.1 days; P < .001). Both mortality and hospital LOS findings remained consistent for SARS-CoV-2-positive and -negative patients. CONCLUSIONS: Bacterial pathogens continue to play an important role in hospital outcomes during the pandemic. Adequate and timely therapeutic management may help ensure better outcomes.

A multicenter analysis of the clinical microbiology and antimicrobial usage in hospitalized patients in the US with or without COVID-19.

BACKGROUND: Past respiratory viral epidemics suggest that bacterial infections impact clinical outcomes. There is minimal information on potential co-pathogens in patients with coronavirus disease-2019 (COVID-19) in the US. We analyzed pathogens, antimicrobial use, and healthcare utilization in hospitalized US patients with and without severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). METHODS: This multicenter retrospective study included patients with > 1 day of inpatient admission and discharge/death between March 1 and May 31, 2020 at 241 US acute care hospitals in the BD Insights Research Database. We assessed microbiological testing data, antimicrobial utilization in admitted patients with ≥24 h of antimicrobial therapy, and length of stay (LOS). RESULTS: A total of 141,621 patients were tested for SARS-CoV-2 (17,003 [12.0%] positive) and 449,339 patients were not tested. Most (> 90%) patients tested for SARS-CoV-2 had additional microbiologic testing performed compared with 41.9% of SARS-CoV-2-untested patients. Non-SARS-CoV-2 pathogen rates were 20.9% for SARS-CoV-2-positive patients compared with 21.3 and 27.9% for SARS-CoV-2-negative and -untested patients, respectively. Gram-negative bacteria were the most common pathogens (45.5, 44.1, and 43.5% for SARS-CoV-2-positive, -negative, and -untested patients). SARS-CoV-2-positive patients had higher rates of hospital-onset (versus admission-onset) non-SARS-CoV-2 pathogens compared with SARS-CoV-2-negative or -untested patients (42.4, 22.2, and 19.5%, respectively), more antimicrobial usage (68.0, 45.2, and 25.1% of patients), and longer hospital LOS (mean [standard deviation (SD)] of 8.6 [11.4], 5.1 [8.9], and 4.2 [8.0] days) and intensive care unit (ICU) LOS (mean [SD] of 7.8 [8.5], 3.6 [6.2], and 3.6 [5.9] days). For all groups, the presence of a non-SARS-CoV-2 pathogen was associated with increased hospital LOS (mean [SD] days for patients with versus without a non-SARS-CoV-2 pathogen: 13.7 [15.7] vs 7.3 [9.6] days for SARS-CoV-2-positive patients, 8.2 [11.5] vs 4.3 [7.9] days for SARS-CoV-2-negative patients, and 7.1 [11.0] vs 3.9 [7.4] days for SARS-CoV-2-untested patients). CONCLUSIONS: Despite similar rates of non-SARS-CoV-2 pathogens in SARS-CoV-2-positive, -negative, and -untested patients, SARS-CoV-2 was associated with higher rates of hospital-onset infections, greater antimicrobial usage, and extended hospital and ICU LOS. This finding highlights the heavy burden of the COVID-19 pandemic on healthcare systems and suggests possible opportunities for diagnostic and antimicrobial stewardship.

Daptomycin-ß-Lactam Combinations in a Rabbit Model of Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus Endocarditis.

Beta-lactams enhance the in vitro activity of daptomycin against methicillin-resistant strains of Staphylococcus aureus Experiments were performed in a rabbit model of aortic valve endocarditis caused by methicillin-resistant daptomycin-nonsusceptible S. aureus strain CB5054 to determine if a cephalosporin, ceftriaxone, administered as a once-daily dose of 100 mg/kg of body weight, or a carbapenem, ertapenem, administered as a once-daily dose of 40 mg/kg, improved the efficacy of daptomycin, administered as a once-daily dose of 12 mg/kg. Daptomycin was ineffective alone in reducing organism densities compared to untreated controls in vegetations and spleen, but densities were 1.4 log10 CFU/g lower in kidney. The combination of daptomycin plus ceftriaxone or daptomycin plus ertapenem reduced bacterial densities in all tissues compared to single agents, with 0.6 to 1.0 log10 CFU/g fewer organisms in vegetations, 1.5 to 2.5 log10 CFU/g fewer organisms in spleen, and 1.8 to 2.5 log10 CFU/g fewer organisms in kidney, although differences were statistically significant only in spleen for daptomycin plus ceftriaxone and in kidney for daptomycin plus ertapenem. Drug exposures in rabbits were less than those achievable in humans, which may have limited the in vivo activity, particularly in vegetations.

Comparative Effectiveness of Vancomycin Versus Daptomycin for MRSA Bacteremia With Vancomycin MIC >1 mg/L: A Multicenter Evaluation.

PURPOSE: Clinical studies comparing vancomycin with alternative therapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia are limited. The objective of this study was to compare outcomes of early daptomycin versus vancomycin treatment for MRSA bacteremia with high vancomycin MICs in a geographically diverse multicenter evaluation. METHODS: This nationwide, retrospective, multicenter (N = 11), matched, cohort study compared outcomes of early daptomycin with vancomycin for MRSA bloodstream infection (BSI) with vancomycin MICs 1.5 to 2 µg/mL. Matching variables, based on propensity regression analysis, included age, intensive care unit (ICU), and type of BSI. Outcomes were as follows: (1) composite failure (60-day all-cause mortality, 7-day clinical or microbiologic failure, 30-day BSI relapse, or end-of-treatment failure (EOT; discontinue/change daptomycin or vancomycin because of treatment failure or adverse event]); (2) nephrotoxicity; and (2) day 4 BSI clearance. FINDINGS: A total of 170 patients were included. The median (interquartile range) age was 60 years (50-74); the median (range) Acute Physiology and Chronic Health Evaluation II score was 15 (10-18); 31% were in an ICU; and 92% had an infectious disease consultation. BSI types included endocarditis/endovascular (39%), extravascular (55%), and central catheter (6%). The median daptomycin dose was 6 mg/kg, and the vancomycin trough level was 17 mg/L. Overall composite failure was 35% (59 of 170): 15% due to 60-day all-cause mortality, 14% for lack of clinical or microbiologic response by 7 days, and 17% due to failure at end of therapy (discontinue/change because of treatment failure or adverse event). Predictors of composite failure according to multivariate analysis were age >60 years (odds ratio, 3.7; P < 0.01) and ICU stay (odds ratio, 2.64; P = 0.03). Notable differences between treatment groups were seen with: (1) end of therapy failure rates (11% vs 24% for daptomycin vs vancomycin; P = 0.025); (2) acute kidney injury rates (9% vs 23% for daptomycin vs vancomycin; P = 0.043); and (3) day 4 bacteremia clearance rates for immunocompromised patients (n = 26) (94% vs 56% for daptomycin vs vancomycin; P = 0.035). IMPLICATIONS: Results from this multicenter study provide, for the first time, a geographically diverse evaluation of daptomycin versus vancomycin for patients with vancomycin-susceptible MRSA bacteremia with vancomycin MIC values >1 µg/mL. Although the overall composite failure rates did not differ between the vancomycin and daptomycin groups when intensively matched according to risks for failure, the rates of acute kidney injury were significantly lower in the daptomycin group. These findings suggest that daptomycin is a useful therapy for clinicians treating patients who have MRSA bacteremia. Prospective, randomized trials should be conducted to better assess the potential significance of elevated vancomycin MIC.

Clinical Outcomes of Daptomycin for Vancomycin-resistant Enterococcus Bacteremia.

PURPOSE: In light of recent evidence suggesting enhancement of daptomycin activity against vancomycin-resistant Enterococcus (VRE) by ampicillin and other ß-lactam antibiotics, we evaluated the safety profile and clinical efficacy of daptomycin with and without concomitant ß-lactam antimicrobials in the treatment of VRE (faecium or faecalis) bacteremia from multiple centers across the United States. METHODS: Data were collected retrospectively as part of a larger multicenter registry (The Cubicin Outcomes Registry and Experience). Efficacy and clinical outcomes in patients with VRE bacteremia who received at least 3 days of daptomycin with or without concomitant ß-lactams were analyzed. Although all the cases involved daptomycin-susceptible VRE, additional analysis was performed to examine whether the adjunctive ß-lactam would play a more pivotal role in cases where the daptomycin MIC was in the upper limit of the susceptibility range, indicating that daptomycin monotherapy efficacy may be relatively compromised compared with cases with lower daptomycin MICs. FINDINGS: Two hundred sixty-two patients from 33 hospitals were evaluated. Most patients had at least one significant comorbidity, such as solid-organ or bone marrow transplantation (16%), neutropenia (36%), dialysis dependency (20%), or critical illness (36%) requiring care in an intensive care unit. Overall treatment success was 86% (n = 225/262), and treatment success for patients taking concomitant ß-lactams was 86% (n = 105/122). Logistic regression identified treatment failure to be associated with sepsis (odds ratio = 3.42; P = 0.009) and an elevated daptomycin MIC (3-4 µg/mL) (odds ratio = 3.23, P = 0.013). No significant increase in clinical failure was seen among patients with elevated daptomycin MIC who received concomitant ß-lactam therapy (clinical success, 88% vs 79% for MIC ≤2 vs 3-4 µg/mL, respectively; P = 0.417). Of 262 patients, 33 (13%) experienced ≥1 adverse event possibly related to daptomycin (increased creatine kinase in 8 patients). IMPLICATIONS: Overall, daptomycin was effective and well tolerated for VRE bacteremia, with lower effectiveness noted with daptomycin MIC of 3 to 4 µg/mL. Concomitant ß-lactam therapy with daptomycin may improve clinical outcomes in this setting. Further studies are needed to characterize the potential benefit of concomitant ß-lactams with daptomycin.

Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline.

PURPOSE: Guidelines recommend daptomycin combination therapy as an option for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia after vancomycin failure. Recent data suggest that combining daptomycin with a ß-lactam may have unique benefits; however, there are very limited clinical data regarding the use of ceftaroline with daptomycin. METHODS: All 26 cases from the 10 medical centers in which ceftaroline plus daptomycin was used for treatment of documented refractory staphylococcal bacteremia from March 2011 to November 2012 were included. In vitro (synergy studies, binding assays, cathelicidin LL-37 killing assays), and in vivo (virulence assays using a murine subcutaneous infection model) studies examining the effects of ceftaroline with daptomycin were also performed. FINDINGS: Daptomycin plus ceftaroline was used in 26 cases of staphylococcal bacteremia (20 MRSA, 2 vancomycin-intermediate S aureus, 2 methicillin-susceptible S aureus [MSSA], 2 methicillin-resistant S epidermidis). Bacteremia persisted for a median of 10 days (range, 3-23 days) on previous antimicrobial therapy. After daptomycin plus ceftaroline was started, the median time to bacteremia clearance was 2 days (range, 1-6 days). In vitro studies showed ceftaroline synergy against MRSA and enhanced MRSA killing by cathelicidin LL-37 and neutrophils. Ceftaroline also induced daptomycin binding in MSSA and MRSA to a comparable degree as nafcillin. MRSA grown in subinhibitory concentrations of ceftaroline showed attenuated virulence in a murine subcutaneous infection model. IMPLICATIONS: Ceftaroline plus daptomycin may be an option to hasten clearance of refractory staphylococcal bacteremia. Ceftaroline offers dual benefit via synergy with both daptomycin and sensitization to innate host defense peptide cathelicidin LL37, which could attenuate virulence of the pathogen.

Multicenter evaluation of the clinical outcomes of daptomycin with and without concomitant ß-lactams in patients with Staphylococcus aureus bacteremia and mild to moderate renal impairment.

Patients with underlying renal disease may be vulnerable to vancomycin-mediated nephrotoxicity and Staphylococcus aureus bacteremia treatment failure. In light of recent data demonstrating the successful use of ß-lactam plus daptomycin in very difficult cases of S. aureus bacteremia, we examined safety and clinical outcomes for patients who received daptomycin with or without concomitant ß-lactams. We identified 106 patients who received daptomycin for S. aureus bacteremia, had mild or moderate renal insufficiency according to FDA criteria, and enrolled in the Cubicin Outcomes Registry and Experience (CORE), a multicenter registry, from 2005 to 2009. Daptomycin treatment success was 81%. Overall treatment efficacy was slightly enhanced with the addition of a ß-lactam (87% versus 78%; P = 0.336), but this trend was most pronounced for bacteremia associated with endocarditis or bone/joint infection or bacteremia from an unknown source (90% versus 57%; P = 0.061). Factors associated with reduced daptomycin efficacy (by logistic regression) were an unknown source of bacteremia (odds ratio [OR] = 7.59; 95% confidence interval [CI] = 1.55 to 37.2), moderate renal impairment (OR = 9.11; 95% CI = 1.46 to 56.8), and prior vancomycin failure (OR = 11.2; 95% CI = 1.95 to 64.5). Two patients experienced an increase in creatine phosphokinase (CPK) that resolved after stopping daptomycin. No patients developed worsening renal insufficiency related to daptomycin. In conclusion, daptomycin appeared to be effective and well tolerated in patients with S. aureus bacteremia and mild to moderate renal insufficiency. Daptomycin treatment efficacy might be enhanced with ß-lactam combination therapy in primary endovascular and bone/joint infections. Additional studies will be necessary to confirm these findings.

Reduced susceptibility to host-defense cationic peptides and daptomycin coemerge in methicillin-resistant Staphylococcus aureus from daptomycin-naive bacteremic patients.

BACKGROUND: We hypothesized that, for methicillin-resistant Staphylococcus aureus (MRSA), in vitro daptomycin susceptibility could be influenced by exposures to endogenous host defense peptides (HDPs) prior to clinical exposure to daptomycin. METHODS: Two endovascular HDPs were used: thrombin-induced platelet microbicidal protein (tPMP) and human neutrophil defensin-1 (hNP-1) from neutrophils. Forty-seven unique MRSA isolates obtained from bacteremic patients in multicenter prospective clinical trials were studied. Clinical characteristics, microbiologic parameters, prior vancomycin therapy, and susceptibilities to tPMP, hNP-1, and daptomycin were compared using univariate and multivariate analyses. RESULTS: All strains were daptomycin susceptible. Daptomycin minimum inhibitory concentrations (MICs) were inversely related to in vitro tPMP (but not hNP-1) killing. Strains with a daptomycin MIC of 1 mg/L exhibited significantly less killing by tPMP, compared with strains with an MIC of ≤ 0.5 mg/L. Prior vancomycin therapy did not influence this relationship. Regression tree modeling confirmed that reduced tPMP-induced killing in vitro was the strongest predictor of higher daptomycin MICs within the daptomycin-susceptible range. CONCLUSIONS: Among daptomycin-susceptible MRSA isolates from patients who had never received daptomycin, higher daptomycin MICs tracked with increased resistance to killing by platelet-derived but not neutrophil-derived HDPs. These findings support the notion that endogenous exposure of MRSA to specific HDPs may play a role in selecting strains with an intrinsically higher daptomycin MIC phenotype.

Ampicillin enhances daptomycin- and cationic host defense peptide-mediated killing of ampicillin- and vancomycin-resistant Enterococcus faecium.

We studied an ampicillin- and vancomycin-resistant Enterococcus faecium (VRE) isolate from a patient with endocarditis and bacteremia refractory to treatment with daptomycin (6 mg/kg of body weight) plus linezolid. Blood cultures cleared within 24 h of changing therapy to daptomycin (12 mg/kg) plus ampicillin. We examined the effects of ampicillin on daptomycin-induced growth inhibition and killing, surface charge, and susceptibility to several prototypical host defense cationic antimicrobial peptides. MICs and time-kill curves with daptomycin were assessed in the presence and absence of ampicillin. The impact of ampicillin on surface charge was assessed by flow cytometry and a poly-l-lysine binding assay. The effects of ampicillin preexposures upon VRE killing by five distinct cationic peptides of different structure, charge, origin, and mechanism of action were analyzed using the epidermal cathelicidin LL-37, thrombin-induced platelet microbicidal proteins (tPMPs), and a synthetic congener modeled after tPMP microbicidal domains (RP-1), human neutrophil peptide-1 (hNP-1), and polymyxin B (bacteria derived). Fluoroscein-Bodipy-labeled daptomycin was used to evaluate daptomycin binding to VRE membranes in the presence or absence of ampicillin. In media containing ampicillin (25 to 100 mg/liter), daptomycin MICs decreased from 1.0 to 0.38 mg/liter. Based on time-kill analysis and an in vitro pharmacodynamic model, ampicillin enhanced daptomycin activity against the study VRE from a bacteriostatic to a bactericidal profile. VRE grown in ampicillin (25 to 150 mg/liter) demonstrated an incremental reduction in its relative net positive surface charge. When grown in the presence (versus absence) of ampicillin (25 and 100 mg/liter), the VRE strain (i) was more susceptible to killing by LL-37, tPMPs, hNP-1, and RP-1 but not to polymyxin B and (ii) exhibited greater binding to Bodipy-labeled daptomycin. We conclude that ampicillin induces reductions in net positive bacterial surface charge of VRE, correlating with enhanced bactericidal effects of cationic calcium-daptomycin and a diverse range of other cationic peptides in vitro. While the mechanism(s) of such ß-lactam-mediated shifts in surface charge remains to be defined, these finding suggest a potential for ß-lactam-mediated enhancement of activity of both daptomycin and innate host defense peptides against antibiotic-resistant bacteria.

Retrospective observational study comparing vancomycin versus daptomycin as initial therapy for Staphylococcus aureus infections.

BACKGROUND: Data comparing alternatives to vancomycin for the treatment of Staphylococcus aureus infections with vancomycin MIC >1 are lacking. OBJECTIVE: We evaluated outcomes of S aureus infections based on whether daptomycin or vancomycin was used as initial therapy at a single institution, where the majority of S aureus infections had vancomycin MICs of 2 mg/L. METHODS: A retrospective chart review was conducted at a 450-bed private acute care hospital. All patients >18 years of age who received initial vancomycin or daptomycin for at least 3 days to treat an S aureus infection between November 2006 and July 2008 were included. Patients with endocarditis, osteomyelitis, or a central nervous system infection and/or those being treated for an S aureus respiratory tract infection were excluded. RESULTS: A total of 165 patients (median age 68 years, range 24-95 years; 56% male) were included: 57 (35%) received daptomycin and 108 (65%) received vancomycin; 78% had vancomycin MIC values of 2 mg/L. The median antibiotic-related length of stay was significantly shorter with daptomycin than with vancomycin (7.5 vs 10.0 days; P = 0.035). Relapse rates in the clinically evaluable population were 25% and 23% for daptomycin and vancomycin, respectively; for the subset with S aureus bacteremia with vancomycin MICs of 2 mg/L, rates were 0% (0/9 patients) and 26% (6/23 patients) for daptomycin and vancomycin, respectively (P = 0.089). Thirty-day all-cause mortality was 6% (10/165 patients) and did not differ significantly by treatment: 7% (4/57 patients) versus 6% (6/108 patients) for daptomycin and vancomycin, respectively (P = 0.708). CONCLUSION: In this setting, in which the majority of S aureus infections had vancomycin MIC values of 2 mg/L, we found the median antibiotic-related length of stay to be significantly shorter with daptomycin than with vancomycin. Prospective studies are needed to determine whether daptomycin confers benefits over vancomycin in specific infection types under conditions that are unfavorable for vancomycin, such as higher vancomycin MICs.

Factors influencing time to vancomycin-induced clearance of nonendocarditis methicillin-resistant Staphylococcus aureus bacteremia: role of platelet microbicidal protein killing and agr genotypes.

BACKGROUND: Vancomycin susceptibility, the accessory gene global regulator (agr) genotype and function, staphylococcal cassette chromosome (SCC) mec type, and susceptibility to cationic thrombin-induced platelet microbicidal protein 1 (tPMP-1) have been individually predictive of duration of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. This investigation evaluated the interrelationship of these factors with time to clearance of MRSA bacteremia during vancomycin therapy in patients without endocarditis. METHODS: Vancomycin minimum inhibitory concentration and in vitro killing, agr function (delta-hemolysin activity), agr group, SCCmec type, and survival in tPMP-1 killing assays were determined for 29 MRSA bacteremia isolates. RESULTS: Increased resistance to tPMP-1 killing was observed with agr group III MRSA (P = .025) and MRSA with reduced or absent agr function (P = .023). The median time to clearance of MRSA bacteremia was earlier for agr group III (3 days) versus group I (10.5 days) or II (15 days) (P = .001). In multivariate analysis, agr group II, reduced tPMP-1 killing in vitro, and prior vancomycin exposure were significant independent predictors of longer MRSA bacteremia duration. CONCLUSIONS: Specific genotypic, phenotypic, and clinical parameters appear to correlate with persistent MRSA bacteremia. The interrelationship of these and other factors probably contributes to vancomycin-mediated clearance of MRSA bacteremia.

Susceptibility relationship between vancomycin and daptomycin in Staphylococcus aureus: facts and assumptions.

The decrease in vancomycin treatment efficacy that is accompanying increases in vancomycin minimum inhibitory concentration (MIC) within the susceptible range (so-called MIC creep) has led to the suggestion that vancomycin is losing its potency in treating serious Staphylococcus aureus infections. Understanding the clinical importance of the microbiological effects of glycopeptides on bacterial lipopeptides and lipoglycopeptides will be crucial in treating serious meticillin-resistant S aureus infections. We review the observed effects of reduced glycopeptide susceptibility on the activities of daptomycin in S aureus in vitro and in vivo. Factors associated with loss of susceptibility and ways to reduce the risk of resistance to daptomycin are reviewed, including the importance of prompt mechanical reduction of bacterial inoculum through surgery or through potent or combination antibiotic therapy, as well as optimisation of daptomycin pharmacodynamic exposure.