Novel insights into negative pressure wound healing from an in situ porcine perspective.

Negative pressure wound therapy (NPWT) is used clinically to promote tissue formation and wound closure. In this study, a porcine wound model was used to further investigate the mechanisms as to how NPWT modulates wound healing via utilization of a form of NPWT called the vacuum-assisted closure. To observe the effect of NPWT more accurately, non-NPWT control wounds containing GranuFoam™ dressings, without vacuum exposure, were utilized. In situ histological analysis revealed that NPWT enhanced plasma protein adsorption throughout the GranuFoam™, resulting in increased cellular colonization and tissue ingrowth. Gram staining revealed that NPWT decreased bacterial dissemination to adjacent tissue with greater bacterial localization within the GranuFoam™. Genomic analysis demonstrated the significant changes in gene expression across a number of genes between wounds treated with non-NPWT and NPWT when compared against baseline tissue. However, minimal differences were noted between non-NPWT and NPWT wounds, including no significant differences in expression of collagen, angiogenic, or key inflammatory genes. Similarly, significant increases in immune cell populations were observed from day 0 to day 9 for both non-NPWT and NPWT wounds, though no differences were noted between non-NPWT and NPWT wounds. Furthermore, histological analysis demonstrated the presence of a foreign body response (FBR), with giant cell formation and encapsulation of GranuFoam™ particles. The unique in situ histological evaluation and genomic comparison of non-NPWT and NPWT wounds in this pilot study provided a never-before-shown perspective, offering novel insights into the physiological processes of NPWT and the potential role of a FBR in NPWT clinical outcomes.

Evaluation of the INCREMENT-CPE, Pitt Bacteremia and qPitt Scores in Patients with Carbapenem-Resistant Enterobacteriaceae Infections Treated with Ceftazidime-Avibactam.

BACKGROUND: The aim of this study was to evaluate the predictive performance of the INCREMENT-CPE (ICS), Pitt bacteremia score (PBS) and qPitt for mortality among patients treated with ceftazidime-avibactam for carbapenem-resistant Enterobacteriaceae (CRE) infections. METHODS: Retrospective, multicenter, cohort study of patients with CRE infections treated with ceftazidime-avibactam between 2015 and 2019. The primary outcome was 30-day all-cause mortality. Predictive performance was determined by assessing discrimination, calibration and precision. RESULTS: In total, 109 patients were included. Thirty-day mortality occurred in 18 (16.5%) patients. There were no significant differences in discrimination of the three scores [area under the curve (AUC) ICS 0.7039, 95% CI 0.5848-0.8230, PBS 0.6893, 95% CI 0.5709-0.8076, and qPitt 0.6847, 95% CI 0.5671-0.8023; P > 0.05 all pairwise comparisons]. All scores showed adequate calibration and precision. When dichotomized at the optimal cut-points of 11, 3, and 2 for the ICS, PBS, and qPitt, respectively, all scores had NPV > 90% at the expense of low PPV. Patients in the high-risk groups had a relative risk for mortality of 3.184 (95% CI 1.35-8.930), 3.068 (95% CI 1.094-8.606), and 2.850 (95% CI 1.016-7.994) for the dichotomized ICS, PBS, and qPitt, scores respectively. Treatment-related variables (early active antibiotic therapy, combination antibiotics and renal ceftazidime-avibactam dose adjustment) were not associated with mortality after controlling for the risk scores. CONCLUSIONS: In patients treated with ceftazidime-avibactam for CRE infections, mortality risk scores demonstrated variable performance. Modifications to scoring systems to more accurately predict outcomes in the era of novel antibiotics are warranted.

Real-World Experience with Ceftolozane-Tazobactam for Multidrug-Resistant Gram-Negative Bacterial Infections.

Our objective was to describe the prescribing practices, clinical characteristics, and outcomes of patients treated with ceftolozane-tazobactam (C/T) for multidrug-resistant (MDR) Gram-negative infections. This was a multicenter, retrospective, cohort study at eight U.S. medical centers (2015 to 2019). Inclusion criteria were age ≥18 years and receipt of C/T (≥72 hours) for suspected or confirmed MDR Gram-negative infection. The primary efficacy outcome, evaluated among patients with MDR Pseudomonas aeruginosa infections, was composite clinical failure, namely, 30-day all-cause mortality, 30-day recurrence, and/or failure to resolve or improve infection signs or symptoms after C/T treatment. In total, 259 patients were included, and P. aeruginosa was isolated in 236 (91.1%). The MDR and extremely drug-resistant phenotypes were detected in 95.8% and 37.7% of P. aeruginosa isolates, respectively. The most common infection source was the respiratory tract (62.9%). High-dose C/T was used in 71.2% of patients with a respiratory tract infection (RTI) overall but in only 39.6% of patients with an RTI who required C/T renal dose adjustment. In the primary efficacy population (n = 226), clinical failure and 30-day mortality occurred in 85 (37.6%) and 39 (17.3%) patients, respectively. New C/T MDR P. aeruginosa resistance was detected in 3 of 31 patients (9.7%) with follow-up cultures. Hospital-acquired infection and Acute Physiological and Chronic Health Evaluation II (APACHE II) score were independently associated with clinical failure (adjusted odds ratio [aOR], 2.472 and 95% confidence interval [CI], 1.322 to 4.625; and aOR, 1.068 and 95% CI, 1.031 to 1.106, respectively). Twenty-five (9.7%) patients experienced ≥1 adverse effect (9 acute kidney injury, 13 Clostridioides difficile infection, 1 hepatotoxicity, 2 encephalopathy, and 2 gastrointestinal intolerance). C/T addresses an unmet medical need in patients with MDR Gram-negative infections.

Activity of pulmonary vancomycin exposures versus planktonic and biofilm isolates of methicillin-resistant Staphylococcus aureus from cystic fibrosis sputum.

Vancomycin is commonly used to treat methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with cystic fibrosis (CF) lung disease. However, there are limited data to support the in vitro activity of this agent against MRSA isolated from CF sputum. The primary objective of this study was to evaluate the activity of vancomycin at pulmonary concentrations (intravenous and inhaled) against four clinical MRSA CF sputum isolates in planktonic and biofilm time-kill (TK) experiments. Vancomycin minimum inhibitory concentrations (MICs) were determined for these isolates at standard inoculum (SI) (~106 CFU/mL) and high inoculum (HI) (~108 CFU/mL) as well as in biofilms cultivated using physiological medium representing the microenvironment of the CF lung. Vancomycin concentrations of 10, 25, 100 and 275 µg/mL were evaluated in TK experiments against planktonic MRSA at varying inocula and versus biofilm MRSA. Vancomycin MICs increased from 0.5 µg/mL when tested at SI to 8-16 µg/mL at HI. Vancomycin MICs were further increased to 16-32 µg/mL in biofilm studies. In TK experiments, vancomycin displayed bactericidal activity (≥3 log10 killing at 24 h) against 1/4 and 0/4 planktonic MRSA isolates at SI and HI, respectively, whereas vancomycin was bactericidal against 0/4 isolates against MRSA biofilms. Based on these findings, vancomycin monotherapy appears unlikely to eradicate MRSA from the respiratory tract of patients with CF, even at high concentrations similar to those observed with inhaled therapy. Novel vancomycin formulations with enhanced biofilm penetration or combination therapy with other potentially synergistic agents should be explored.

Real-World Experience With Ceftazidime-Avibactam for Multidrug-Resistant Gram-Negative Bacterial Infections.

BACKGROUND: We conducted this study to describe the clinical characteristics, microbiology, and outcomes of patients treated with ceftazidime-avibactam (CZA) for a range of multidrug-resistant Gram-negative (MDR-GN) infections. METHODS: This is a multicenter, retrospective cohort study conducted at 6 medical centers in the United States between 2015 and 2019. Adult patients who received CZA (≥72 hours) were eligible. The primary outcome was clinical failure defined as a composite of 30-day all-cause mortality, 30-day microbiological failure, and/or failure to resolve or improve signs or symptoms of infection on CZA. RESULTS: In total, data from 203 patients were evaluated. Carbapenem-resistant Enterobacteriaceae (CRE) and Pseudomonas spp were isolated from 117 (57.6%) and 63 (31.0%) culture specimens, respectively. The most common infection sources were respiratory (37.4%), urinary (19.7%), and intra-abdominal (18.7%). Blood cultures were positive in 22 (10.8%) patients. Clinical failure, 30-day mortality, and 30-day recurrence occurred in 59 (29.1%), 35 (17.2%), and 12 (5.9%) patients, respectively. On therapy, CZA resistance developed in 1 of 62 patients with repeat testing. Primary bacteremia or respiratory tract infection and higher SOFA score were positively associated with clinical failure (adjusted odds ratio [aOR] = 2.270, 95% confidence interval [CI] = 1.115-4.620 and aOR = 1.234, 95% CI = 1.118-1.362, respectively). Receipt of CZA within 48 hours of infection onset was protective (aOR, 0.409; 95% CI, 0.180-0.930). Seventeen (8.4%) patients experienced a potential drug-related adverse effect (10 acute kidney injury, 3 Clostridioides difficile infection, 2 rash, and 1 each gastrointestinal intolerance and neutropenia). CONCLUSIONS: Ceftazidime-avibactam is being used to treat a range of MDR-GN infections including Pseudomonas spp as well as CRE.

Effect of Continuous and Sequential Therapy among Veterans Receiving Daptomycin or Linezolid for Vancomycin-Resistant Enterococcus faecium Bacteremia.

Vancomycin-resistant Enterococcus faecium bloodstream infections (VREF-BSI) cause significant mortality, highlighting the need to optimize their treatment. We compared the effectiveness and safety of daptomycin (DAP) and linezolid (LZD) as continuous or sequential therapy for VREF-BSI in a national, retrospective, propensity score (PS)-matched cohort study of hospitalized Veterans Affairs patients (2004 to 2014). We compared clinical outcomes and adverse events among patients treated with continuous LZD, continuous DAP, or sequential LZD followed by DAP (LZD-to-DAP). Secondarily, we analyzed the impact of infectious diseases (ID) consultation and source of VREF-BSI. A total of 2,630 patients were included in the effectiveness analysis (LZD [n = 1,348], DAP [n = 1,055], LZD-to-DAP [n = 227]). LZD was associated with increased 30-day mortality versus DAP (risk ratio [RR], 1.11; 95% confidence interval [CI], 1.01 to 1.22; P = 0.042). After PS matching, this relationship persisted (RR, 1.13; 95% CI, 1.02 to 1.26; P = 0.015). LZD-to-DAP switchers had lower mortality than those remaining on LZD (RR, 1.29; 95% CI, 1.03 to 1.63; P = 0.021), suggesting a benefit may still be derived with sequential therapy. LZD-treated patients experienced more adverse events, including a ≥50% reduction in platelets (RR, 1.07; 95% CI, 1.03 to 1.11; P = 0.001). DAP was associated with lower mortality than was LZD in patients with endocarditis (RR, 1.20; 95% CI, 1.02 to 1.41; P = 0.024); however, there was no statistically significant association between treatment group and mortality with regard to other sources of infection. Therefore, source of infection appears to be important in selection of patients most likely to benefit from DAP over LZD.

Relationship between vancomycin tolerance and clinical outcomes in Staphylococcus aureus bacteraemia.

BACKGROUND: Previous data have demonstrated the clinical importance of vancomycin MIC values in Staphylococcus aureus bacteraemia (SAB); however, the impact of vancomycin tolerance (VT) is unknown. OBJECTIVES: To compare the frequency of clinical failure between patients with VT and non-VT isolates in SAB. METHODS: This was a retrospective cohort study of patients with SAB, excluding treatment <48 h or polymicrobial bacteraemia. The primary outcome was clinical failure (composite of 30 day mortality, non-resolving signs and symptoms, and 60 day recurrence). Vancomycin MIC and MBC were determined by broth microdilution. The association between VT (MBC/MIC ≥32) and clinical failure was evaluated by multivariable Poisson regression. RESULTS: Of the 225 patients, 26.7% had VT isolates. VT was associated with clinical failure (48.0% overall) in unadjusted analysis [68.3% (n = 41/60) versus 40.6% (n = 67/165); P < 0.001] and this relationship persisted in multivariable analysis (adjusted risk ratio, 1.74; 95% CI, 1.36-2.24; P < 0.001). The association between VT and clinical failure was also consistent within strata of methicillin susceptibility [methicillin susceptible (n = 125, risk ratio, 1.67; 95% CI, 1.20-2.32; P = 0.002); methicillin resistant (n = 100, risk ratio, 1.69; 95% CI, 1.14-2.51; P = 0.010)]. Among methicillin-susceptible SAB cases treated with ß-lactam therapy, VT remained associated with clinical failure (risk ratio, 1.77; 95% CI, 1.19-2.61; P = 0.004). CONCLUSIONS: VT was associated with clinical failure in SAB, irrespective of methicillin susceptibility or definitive treatment. VT may decrease the effectiveness of cell-wall-active therapy or be a surrogate marker of some other pathogen-specific factor associated with poor outcomes. Future research should evaluate if bactericidal non-cell-wall-active agents improve outcomes in VT SAB.

Comparative Effectiveness and Safety of Standard-, Medium-, and High-Dose Daptomycin Strategies for the Treatment of Vancomycin-Resistant Enterococcal Bacteremia Among Veterans Affairs Patients.

Background: Vancomycin-resistant Enterococcus bloodstream infections (VRE-BSIs) are associated with significant mortality. Daptomycin exhibits concentration-dependent activity vs VRE in vitro, yet the clinical impact of higher-dose strategies remains unclear. Methods: We performed a national retrospective cohort study of hospitalized Veterans Affairs patients treated with standard-dose (6 mg/kg total body weight), medium-dose (8 mg/kg total body weight), or high-dose (≥10 mg/kg total body weight) daptomycin for VRE-BSI. Patient-related, microbiological, and outcomes data were abstracted from clinical databases. The primary outcome was overall survival, evaluated by Cox regression. Secondary outcomes included 30-day mortality, time to microbiological clearance, and creatine phosphokinase (CPK) elevation. Results: A total of 911 patients were included (standard dose, n = 709; medium dose, n = 142; high dose, n = 60). Compared to high-dose daptomycin, both standard-dose (hazard ratio [HR], 2.68; 95% confidence interval; [CI], 1.33-3.06; P = .002) and medium-dose (HR, 2.66; 95% CI, 1.33-3.92; P = .003) daptomycin were associated with poorer survival. After adjusting for confounders, the relationship between poorer survival and standard-dose (adjusted HR [aHR], 2.58; 95% CI, 1.27-4.88; P = .004) and medium-dose (aHR, 2.52; 95% CI, 1.27-5.00; P = .008) daptomycin persisted. Thirty-day mortality was significantly lower among high-dose daptomycin-treated patients compared with other dosing strategies (risk ratio, 0.83; 95% CI, .74-.94; P = .015). Compared with standard-dose daptomycin, both medium-dose (HR, 0.78; 95% CI, .55-.90; P = .012) and high-dose daptomycin (HR, 0.70; 95% CI, .41-.84; P = .006) were associated with significantly improved microbiological clearance. No difference in the risk of CPK elevation was observed between the treatment groups (P = .504). Conclusions: High-dose daptomycin was associated with improved survival and microbiological clearance in VRE-BSI.

Vancomycin 24-Hour Area under the Curve/Minimum Bactericidal Concentration Ratio as a Novel Predictor of Mortality in Methicillin-Resistant Staphylococcus aureus Bacteremia.

While previous studies have examined the association between vancomycin (VAN) exposure and MIC with regard to outcomes in methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B), none have explored if a relationship exists with the VAN minimum bactericidal concentration (MBC). The objective of this study was to evaluate the VAN 24-h area under the curve (AUC24)/MBC ratio as a pharmacodynamic predictor of mortality. This retrospective cohort study included patients treated with VAN for MRSA-B with the primary outcome of 30-day all-cause mortality. Data collected included patient demographics, comorbidities, antimicrobial treatment data, therapeutic drug levels, and laboratory and microbiological data. Vancomycin MICs and MBCs were determined by Etest (MIC only) and broth microdilution (BMD). The vancomycin AUC24 was determined by pharmacokinetic maximum a posteriori probability Bayesian (MAP-Bayesian) analysis. The most significant breakpoint for 30-day mortality was determined by classification and regression tree (CART) analysis. The association between pharmacodynamic parameters (VAN AUC24/MICBMD, VAN AUC24/MICEtest, and AUC24/MBCBMD) and mortality were determined by χ(2) and multivariable Poisson regression. Overall mortality in this cohort (n = 53) was 20.8% (n = 11/53), and all corresponding MRSA blood isolates were VAN susceptible (MIC range, 0.5 to 2 µg/ml; MIC50, 1 µg/ml; MIC90, 1 µg/ml). The CART-derived breakpoints for mortality were 176 (VAN AUC24/MBC) and 334 (VAN AUC24/MICBMD). In multivariable analysis, the association between a VAN AUC24/MBC of ≥176 and survival persisted, but VAN AUC24/MICBMD values (≥334 or ≥400) were not associated with improved mortality. In conclusion, VAN AUC24/MBC was a more important predictor of 30-day mortality than VAN AUC24/MIC for MRSA-B.

Comparison of the Effectiveness and Safety of Linezolid and Daptomycin in Vancomycin-Resistant Enterococcal Bloodstream Infection: A National Cohort Study of Veterans Affairs Patients.

BACKGROUND: Vancomycin-resistant Enterococcus bloodstream infections (VRE-BSIs) are becoming increasingly common. Linezolid and daptomycin are the primary treatment options for VRE-BSI, but optimal treatment is unclear. METHODS: This was a national retrospective cohort study comparing linezolid and daptomycin for the treatment of VRE-BSI among Veterans Affairs Medical Center patients admitted during 2004-2013. The primary outcome was treatment failure, defined as a composite of (1) 30-day all-cause mortality; (2) microbiologic failure; and (3) 60-day VRE-BSI recurrence. Poisson regression was conducted to determine if antimicrobial treatment was independently associated with clinical outcomes. RESULTS: A total of 644 patients were included (linezolid, n = 319; daptomycin, n = 325). Overall, treatment failure was 60.9% (n = 392/644), and 30-day all-cause mortality was 38.2% (n = 246/644). Linezolid was associated with a significantly higher risk of treatment failure compared with daptomycin (risk ratio [RR], 1.37; 95% confidence interval [CI], 1.13-1.67; P = .001). After adjusting for confounding factors in Poisson regression, the relationship between linezolid use and treatment failure persisted (adjusted RR, 1.15; 95% CI, 1.02-1.30; P = .026). Linezolid was also associated with higher 30-day mortality (42.9% vs 33.5%; RR, 1.17; 95% CI, 1.04-1.32; P = .014) and microbiologic failure rates (RR, 1.10; 95% CI, 1.02-1.18; P = .011). No difference in 60-day VRE-BSI recurrence was observed between treatment groups. CONCLUSIONS: Treatment with linezolid for VRE-BSI resulted in significantly higher treatment failure in comparison to daptomycin. Linezolid treatment was also associated with greater 30-day all-cause mortality and microbiologic failure in this cohort.

Tigecycline for the Treatment of Severe and Severe Complicated Clostridium difficile Infection.

INTRODUCTION: Clostridium difficile infection (CDI) is a common cause of nosocomial diarrhea. Metronidazole and vancomycin are the primary treatment options for CDI, but increasing rates of antimicrobial resistance and severe, refractory disease have prompted the need for alternative agents. Tigecycline has previously demonstrated favorable in vitro activity against C. difficile isolates, but clinical data on its use in the treatment of CDI are severely lacking. The objective of this study was to describe our experience using tigecycline in the treatment of severe and severe complicated CDI. METHODS: This was a retrospective case series of hospitalized patients with severe and severe complicated CDI who were treated with tigecycline. Disease severity assessments were determined according to current practice guidelines. Diagnosis of toxigenic CDI was confirmed by polymerase chain reaction and patients were excluded if they received tigecycline for <48 h. Data were collected by review of the electronic medical record. The primary outcome was clinical cure. Secondary outcomes were sustained response, hospital mortality, and 28-day all-cause mortality. RESULTS: A total of 7 cases of severe and complicated CDI were reviewed. Intravenous tigecycline administered as a 100-mg loading dose followed by 50 mg twice daily resulted in clinical cure in 85.7% (n = 6/7) of cases. The majority of patients (n = 4/5) were treated with the novel triple therapy combination of tigecycline, vancomycin, and metronidazole and resulted in clinical cure in 80% (n = 4/5) cases. Sustained response at 28 days was 100% among evaluable cases (n = 5/5). Hospital mortality did not occur in any patients, and 28-day all-cause mortality was 28.6% (n = 2/7). CONCLUSION: Tigecycline appears to be a reasonable addition to the therapeutic regimen in the treatment of severe or complicated CDI, including cases that are refractory to standard therapy. A prospective clinical trial confirming these observational findings is warranted.

Evaluation of ceftaroline activity against heteroresistant vancomycin-intermediate Staphylococcus aureus and vancomycin-intermediate methicillin-resistant S. aureus strains in an in vitro pharmacokinetic/pharmacodynamic model: exploring the "seesaw effect".

A "seesaw effect" in methicillin-resistant Staphylococcus aureus (MRSA) has been demonstrated, whereby susceptibility to ß-lactam antimicrobials increases as glyco- and lipopeptide susceptibility decreases. We investigated this effect by evaluating the activity of the anti-MRSA cephalosporin ceftaroline against isogenic pairs of MRSA strains with various susceptibilities to vancomycin in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model. The activities of ceftaroline at 600 mg every 12 h (q12h) (targeted free maximum concentration of drug in serum [fC(max)], 15.2 µg/ml; half-life [t(1/2)], 2.3 h) and vancomycin at 1 g q12h (targeted fC(max), 18 µg/ml; t(1/2), 6 h) were evaluated against 3 pairs of isogenic clinical strains of MRSA that developed increased MICs to vancomycin in patients while on therapy using a two-compartment hollow-fiber PK/PD model with a starting inoculum of ~10(7) CFU/ml over a 96-h period. Bacterial killing and development of resistance were evaluated. Expression of penicillin-binding proteins (PBPs) 2 and 4 was evaluated by reverse transcription (RT)-PCR. The achieved pharmacokinetic parameters were 98 to 119% of the targeted values. Ceftaroline and vancomycin were bactericidal against 5/6 and 1/6 strains, respectively, at 96 h. Ceftaroline was more active against the mutant strains than the parent strains, with this difference being statistically significant for 2/3 strain pairs at 96 h. The level of PBP2 expression was 4.4× higher in the vancomycin-intermediate S. aureus (VISA) strain in 1/3 pairs. The levels of PBP2 and PBP4 expression were otherwise similar between the parent and mutant strains. These data support the seesaw hypothesis that ceftaroline, like traditional ß-lactams, is more active against strains that are less susceptible to vancomycin even when the ceftaroline MICs are identical. Further research to explore these unique findings is warranted.

Evaluation of Daptomycin Non-Susceptible Staphylococcus aureus for Stability, Population Profiles, mprF Mutations, and Daptomycin Activity.

INTRODUCTION: Despite studies examining daptomycin non-susceptible (DNS) Staphylococcus aureus, examination of the stability and population profiles is limited. The objective was to evaluate the stability, population profiles, and daptomycin activity against DNS isolates. METHODS: The stability of 12 consecutive clinical DNS strains was evaluated by minimum inhibitory concentration (MICs) and population analysis profiles before and after 5 days of serial passage. Two pairs of DNS S. aureus having the same daptomycin MIC but different daptomycin population profiles were evaluated via an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model of simulated endocardial vegetations for 96 h against daptomycin 6 and 10 mg/kg/day. The sequence of mprF was determined for these isolates before and after 96 h of daptomycin exposure in the in vitro PK/PD model. RESULTS: Daptomycin MIC values were 2-4 mg/L (via Microscan) for the 12 clinical isolates; 9 were confirmed DNS and 3 were within 1 tube dilution of Microscan (daptomycin MIC 1 mg/L). All were stable to serial passage. There was variation in the isolates susceptibility to daptomycin on population analysis (daptomycin population AUC 14.01-26.85). The killing patterns of daptomycin 6 and 10 mg/kg/day differed between isolates with a left-shift and right-shift population profile to daptomycin. Two strains developed additional mprF mutations during daptomycin exposure in the in vitro PK/PD model resulting in P314L, L826F, S337L and a novel Q326Stop mutation. CONCLUSIONS: The collection of DNS isolates was stable and displayed variation in susceptibility to daptomycin on population profile. Further research examining this clinical relevance is warranted.

Daptomycin-nonsusceptible vancomycin-intermediate staphylococcus aureus vertebral osteomyelitis cases complicated by bacteremia treated with high-dose daptomycin and trimethoprim-sulfamethoxazole.

We report two cases of daptomycin (DAP)-nonsusceptible (DNS) vancomycin-intermediate Staphylococcus aureus (VISA) vertebral osteomyelitis cases complicated by bacteremia treated with high-dose daptomycin and trimethoprim-sulfamethoxazole. Both patients responded rapidly and favorably to this combination. The clinical isolates from the two patients were tested post hoc in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model to confirm the bactericidal activity and enhancement of daptomycin and trimethoprim-sulfamethoxazole. The combination of high-dose daptomycin and trimethoprim-sulfamethoxazole should be explored further for the treatment of DNS VISA strains.

Evaluation of the novel combination of high-dose daptomycin plus trimethoprim-sulfamethoxazole against daptomycin-nonsusceptible methicillin-resistant Staphylococcus aureus using an in vitro pharmacokinetic/pharmacodynamic model of simulated endocardial vegetations.

Daptomycin-nonsusceptible (DNS) Staphylococcus aureus is found in difficult-to-treat infections, and the optimal therapy is unknown. We investigated the activity of high-dose (HD) daptomycin plus trimethoprim-sulfamethoxazole de-escalated to HD daptomycin or trimethoprim-sulfamethoxazole against 4 clinical DNS methicillin-resistant S. aureus (MRSA) isolates in an in vitro pharmacokinetic/pharmacodynamic model of simulated endocardial vegetations (10(9) CFU/g). Simulated regimens included HD daptomycin at 10 mg/kg/day for 14 days, trimethoprim-sulfamethoxazole at 160/800 mg every 12 h for 14 days, HD daptomycin plus trimethoprim-sulfamethoxazole for 14 days, and the combination for 7 days de-escalated to HD daptomycin for 7 days and de-escalated to trimethoprim-sulfamethoxazole for 7 days. Differences in CFU/g (at 168 and 336 h) were evaluated by analysis of variance (ANOVA) with a Tukey's post hoc test. Daptomycin MICs were 4 µg/ml (SA H9749-1, vancomycin-intermediate Staphylococcus aureus; R6212, heteroresistant vancomycin-intermediate Staphylococcus aureus) and 2 µg/ml (R5599 and R5563). Trimethoprim-sulfamethoxazole MICs were ≤0.06/1.19 µg/ml. HD daptomycin plus trimethoprim-sulfamethoxazole displayed rapid bactericidal activity against SA H9749-1 (at 7 h) and R6212 (at 6 h) and bactericidal activity against R5599 (at 72 h) and R5563 (at 36 h). A ≥8 log(10) CFU/g decrease was observed with HD daptomycin plus trimethoprim-sulfamethoxazole against all strains (at 48 to 144 h), which was maintained with de-escalation to HD daptomycin or trimethoprim-sulfamethoxazole at 336 h. The combination for 14 days and the combination for 7 days de-escalated to HD daptomycin or trimethoprim-sulfamethoxazole was significantly better than daptomycin monotherapy (P < 0.05) and trimethoprim-sulfamethoxazole monotherapy (P < 0.05) at 168 and 336 h. Combination therapy followed by de-escalation offers a novel bactericidal therapeutic alternative for high-inoculum, serious DNS MRSA infections.

Ceftaroline fosamil for community-acquired bacterial pneumonia and acute bacterial skin and skin structure infection.

INTRODUCTION: Bacterial resistance is increasing on a global basis, making treatment options more limited. The development of new agents to meet this threat is a matter of urgency. Ceftaroline fosamil , a member of an advanced cephalosporin class of antimicrobials, is currently approved by the US Food and Drug Administration for use in for acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia. Ceftaroline displays activity against Gram-positive and Gram-negative bacteria, including both methicillin-susceptible and resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae (including penicillin- and ceftriaxone-resistant strains), respiratory pathogens (such as Moraxella catarrhalis and Haemophilus influenzae, including beta-lactamase-producing strains) and limited coverage against Enterobacteriaceae. AREAS COVERED: Chemistry, mechanism of action, spectrum of activity, resistance, pharmacokinetics/pharmacodynamics, indications for use, safety and special populations are covered in this review. EXPERT OPINION: Ceftaroline's unique activity against MRSA and penicillin- and ceftriaxone-resistant S. pneumoniae strains is due to its high affinity for penicillin binding protein (PBP)-2a and PBP-2x, respectively. In randomized, double-blinded, clinical trials, ceftaroline fosamil was found to be non-inferior to ceftriaxone for the treatment CABP and to vancomycin plus aztreonam for ABSSSI. Substantial differences between the cephalosporins exist. Ceftaroline has unique characteristics that may make it useful in specific clinical circumstances, especially against multi-drug-resistant Gram-positive organisms.

Evaluation of standard- and high-dose daptomycin versus linezolid against vancomycin-resistant Enterococcus isolates in an in vitro pharmacokinetic/pharmacodynamic model with simulated endocardial vegetations.

Daptomycin MICs for enterococci are typically 1- to 2-fold higher than those for Staphylococcus aureus, and there is an imminent need to establish the optimal dose for appropriate treatment of enterococcal infections. We investigated the bactericidal activity of daptomycin at various dose exposures compared to that of linezolid against vancomycin-resistant enterococcus (VRE) in an in vitro pharmacokinetic/pharmacodynamic model utilizing simulated endocardial vegetations over 96 h. Daptomycin at doses of 6, 8, 10, and 12 mg/kg of body weight/day and linezolid at a dose of 600 mg every 12 h were evaluated against two clinical vancomycin-resistant Enterococcus faecium strains (EFm11499 and 09-184D1051), one of which was linezolid resistant (09-184D1051), and one clinical vancomycin-resistant Enterococcus faecalis strain (EFs11496). Daptomycin MICs were 4, 2, and 0.5 µg/ml for EFm11499, 09-184D1051, and EFs11496, respectively. Bactericidal activity, defined as a ≥ 3 log(10) CFU/g reduction from the initial colony count, was demonstrated against all three isolates with all doses of daptomycin; however, bactericidal activity was not sustained with the daptomycin 6- and 8-mg/kg/day regimens. Linezolid was bacteriostatic against EFm11499 and displayed no appreciable activity against 09-184D1051 or EFs11496. Concentration-dependent killing was displayed with more sustained reduction in colony count (3.58 to 6.46 and 5.89 to 6.56 log(10) CFU/g) at 96 h for the simulated regimen of daptomycin at doses of 10 and 12 mg/kg/day, respectively (P ≤ 0.012). No E. faecium mutants with reduced susceptibility were recovered at any dosage regimen; however, the E. faecalis strain developed reduced daptomycin susceptibility with daptomycin at 6, 8, and 10 but not at 12 mg/kg/day. Daptomycin displayed a dose-dependent response against three VRE isolates, with high-dose daptomycin producing sustained bactericidal activity. Further research is warranted.

Evaluation of ceftaroline activity versus ceftriaxone against clinical isolates of Streptococcus pneumoniae with various susceptibilities to cephalosporins in an in vitro pharmacokinetic/pharmacodynamic model.

Drug resistance in Streptococcus pneumoniae, a frequent pathogen in community-acquired pneumonia, is increasing. Ceftaroline (active metabolite of ceftaroline fosamil) is a broad-spectrum intravenous cephalosporin with activity in vitro against drug-resistant Gram-positive organisms. We investigated ceftaroline at 600 mg every 12 h (q12h) (maximum concentration of the free, unbound drug in serum [fC(max)] is 15.2 µg/ml, and half-life [T(1/2)] is 2.5 h) versus ceftriaxone at 1 g q24h (fC(max) = 23 µg/ml, T(1/2) = 8 h) against six clinical S. pneumoniae isolates in a one-compartment in vitro pharmacokinetic/pharmacodynamic 96-h model (starting inoculum of 10(7) CFU/ml). Differences in CFU/ml (at 24 to 96 h) were evaluated by analysis of variance with a Tukey's post hoc test. Bactericidal activity was defined as a ≥ 3 log(10) CFU/ml decrease from the initial inoculum. Ceftaroline MICs were 0.06, 0.015, ≤ 0.008, 0.25, 0.25, and 0.5 µg/ml, and ceftriaxone MICs were 0.5, 0.25, 0.25, 4, 4, and 8 µg/ml for SP 1477, SP 669, SP 132, SP 211, SP 90, and SP 1466, respectively. Against the ceftaroline- and ceftriaxone-susceptible strain SP 1477, ceftaroline displayed sustained bactericidal activity (3 to 96 h, -5.49 log(10) CFU/ml) and was significantly (P ≤ 0.012) better than ceftriaxone (72 to 96 h, -2.03 log(10) CFU/ml). Against the ceftriaxone-resistant strains, ceftaroline displayed sustained bactericidal activity at 96 h and was significantly better than ceftriaxone (SP211 [-5.91 log(10) CFU/ml, P ≤ 0.002], SP 90 [-5.26 log(10) CFU/ml, P ≤ 0.008], and SP1466 [-5.14 log(10) CFU/ml, P ≤ 0.042]). Ceftaroline was the more effective drug and displayed sustained bactericidal activity. Ceftaroline fosamil may provide a therapeutic option to treat ceftriaxone-resistant S. pneumoniae infections.