Renee-Claude Mercier

Influence of morbid obesity on the single-dose pharmacokinetics of daptomycin

ABSTRACT The present study characterized the single-dose pharmacokinetics of daptomycin dosed as 4 mg/kg of total body weight (TBW) in seven morbidly obese and seven age-, sex-, race-, and serum creatinine-matched healthy subjects. The glomerular filtration rate (GFR) was measured for both groups following a single bolus injection of [125I]sodium iothalamate. Noncompartmental analysis was used to determine the pharmacokinetic parameters, and these values were normalized against TBW, ideal body weight (IBW), and fat-free weight (FFW) for comparison of the two groups. All subjects enrolled in this study were female, and the mean (±standard deviation) body mass index was 46.2 ± 5.5 kg/m2 or 21.8 ± 1.9 kg/m2 for the morbidly obese or normal-weight group, respectively. The maximum plasma concentration and area under the concentration-time curve from dosing to 24 h were approximately 60% higher (P < 0.05) in the morbidly obese group than in the normal-weight group, and these were a function of the higher total dose received in the morbidly obese group. No differences in daptomycin volume of distribution (V), total clearance, renal clearance, or protein binding were noted between the two groups. Of TBW, FFW, or IBW, TBW provided the best correlation to V. In contrast, TBW overestimated GFR through creatinine clearance calculations using the Cockcroft-Gault equation. Use of IBW in the Cockcroft-Gault equation or use of the four-variable modification of diet in renal disease equation best estimated GFR in morbidly obese subjects. Further studies of daptomycin pharmacokinetics in morbidly obese patients with acute bacterial infections and impaired renal function are necessary to better predict appropriate dosage intervals.

Antimicrobial activity of tigecycline (GAR-936) against Enterococcus faecium and Staphylococcus aureus used alone and in combination.

Study Objective. To evaluate the antimicrobial properties of tigecycline, both alone and in combination with other antibiotics, against multidrug‐resistant strains of Enterococcus faecium and Staphylococcus aureus.

Site of infection rather than vancomycin MIC predicts vancomycin treatment failure in methicillin-resistant Staphylococcus aureus bacteraemia

BACKGROUND Therapeutic use of vancomycin is characterized by decreased susceptibilities and increasing reports of clinical failures. Few studies have examined the clinical outcomes of patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia treated with vancomycin. The primary objective was to compare clinical outcomes of patients with MRSA bacteraemia treated according to standard of care practices. METHODS Patients were included if: (i) admitted to University of New Mexico Hospital between 2002 and 2009; (ii) ≥18 years of age; (iii) had one blood culture positive for MRSA; and (iv) received vancomycin. Clinical outcomes were defined as cure, failure (relapse of infection 30 days after completion of therapy, death or change in therapy) or unevaluable. Patient demographics, source of bacteraemia, treatment regimen, and microbiological characteristics were determined. RESULTS Two hundred patients with MRSA bacteraemia were included. Sixty-one patients were unevaluable, leaving 139 patients for the final analysis. Seventy-two (51.8%) patients were cured and 67 (48.2%) experienced vancomycin failure. Vancomycin MIC(90) was 2 mg/L for both groups by Etest. Patients with endocarditis (P = 0.02) or pneumonia (P = 0.02) were more likely to fail therapy. Panton-Valentine leucocidin, loss of agr functionality and strain type were not predictors of outcomes in this study. CONCLUSIONS High failure rates were observed in patients with MRSA bacteraemia treated with vancomycin, despite high vancomycin troughs and low rates of nephrotoxicity. Predictors of vancomycin failure included endocarditis and pneumonia. In these situations, vancomycin provides suboptimal therapy.

β-Lactams Enhance Vancomycin Activity against Methicillin-Resistant Staphylococcus aureus Bacteremia Compared to Vancomycin Alone

ABSTRACT Vancomycin (VAN) is often used to treat methicillin-resistant Staphylococcus aureus (MRSA) bacteremia despite a high incidence of microbiological failure. Recent in vitro analyses of β-lactams in combination with VAN demonstrated synergistic activity against MRSA. The goal of this study was to examine the impact of combination therapy with VAN and a β-lactam (Combo) on the microbiological eradication of MRSA bacteremia compared to VAN alone. This was a retrospective cohort study of patients with MRSA bacteremia who received Combo therapy or VAN alone. Microbiological eradication of MRSA, defined as a negative blood culture obtained after initiation of therapy, was used to evaluate the efficacy of each regimen. A total of 80 patients were included: 50 patients in the Combo group and 30 patients in the VAN-alone group. Microbiological eradication was achieved in 48 patients (96%) in the Combo group compared to 24 patients (80%) in the VAN-alone group (P = 0.021). In a multivariable model, the Combo treatment had a higher likelihood of achieving microbiological eradication (adjusted odds ratio, 11.24; 95% confidence interval, 1.7 to 144.3; P = 0.01). In patients with infective endocarditis (n = 22), 11/11 (100%) who received Combo therapy achieved microbiological eradication compared to 9/11 (81.8%) treated with VAN alone, but the difference was not statistically significant (P = 0.20). Patients with MRSA bacteremia who received Combo therapy were more likely to experience microbiological eradication of MRSA than patients who received VAN alone.

Oritavancin: a new avenue for resistant Gram-positive bacteria

Oritavancin, a new semisynthetic glycopeptide has a spectrum of activity similar to vancomycin, although it exhibits potent antimicrobial activity against vancomycin-resistant staphylococci and enterococci species. It has a long-terminal half-life of 360 h, is highly protein bound and has been dosed once-daily in clinical trials. Oritavancin has been studied in complicated skin and skin structure infections where it was noninferior to the comparator group of vancomycin/cephalexin. Thus far, oritavancin has a favorable side-effect profile and appears promising in the treatment of multidrug resistant Gram-positive bacteria.

Influence of Platelets and Platelet Microbicidal Protein Susceptibility on the Fate of Staphylococcus aureus in an In Vitro Model of Infective Endocarditis

ABSTRACT Several lines of evidence indicate that platelets protect against endovascular infections such as infective endocarditis (IE). It is highly likely that a principal mechanism of this platelet host defense role is the release of platelet microbicidal proteins (PMPs) in response to agonists generated at sites of endovascular infection. We studied the ability of platelets to limit the colonization and proliferation of Staphylococcus aureus in an in vitro model of IE. Three isogenic S. aureus strains, differing in their in vitro susceptibility to thrombin-induced platelet microbicidal protein-1 (tPMP), were used: ISP479C (parental strain; highly susceptible to tPMP [tPMPs]); ISP479R (transposon mutant derived from ISP479; tPMP resistant [tPMPr]); or 757-5 (tPMPr transductant of the ISP479R genotype in the ISP479 parental background). Time-kill assays and in vitro IE models were used to examine the temporal relationship between thrombin-induced platelet activation and S. aureus killing. In time-kill studies, early platelet activation (30 min prior to bacterial exposure) correlated with a significant bactericidal effect against tPMPs ISP479C (r2 > 0.90,P < 0.02) but not against tPMPr strains, ISP479R or 757-5. In the IE model, thrombin activation significantly inhibited proliferation of ISP479C within simulated vegetations compared to strains ISP479R or 757-5 (P < 0.05). The latter differences were observed despite there being no detectable differences among the three S. aureus strains in initial colonization of simulated vegetations. Collectively, these data indicate that platelets limit intravegetation proliferation of tPMPs but not tPMPrS. aureus. These findings underscore the likelihood that platelets play an important antimicrobial host defense role in preventing and/or limiting endovascular infections due to tPMPs pathogens.

Epidemiology of Vancomycin-Induced Neutropenia in Patients Receiving Home Intravenous Infusion Therapy

Background: Vancomycin is frequently used to manage serious resistant gram-positive Infections. Neutropenia, whose epidemiology has not been well characterized, is a potentially serious adverse event associated with the use of vancomycin. Objective: To characterize the incidence and risk factors for development of vancomycin-induced neutropenia in patients treated with home intravenous vancomycin therapy. Methods: A retrospective chart review was conducted of adult patients receiving vancomycin therapy through the University of New Mexico Home Intravenous Infusion Clinic between January 1998 and December 2004. Data collection included demographics, comorbid conditions, dose and duration of vancomycin therapy, indications for vancomycin use, vancomycin concentrations, all concurrent medications, laboratory data, culture and susceptibility data, reasons for antibiotic alteration or discontinuations, all other recorded adverse events, management of adverse events, and outcomes of adverse events. Results: A total of 372 charts of patients managed through the clinic were reviewed and 114 patients treated with vancomycin were identified. Fourteen (12%) cases of vancomycin-induced neutropenia were identified; 4 (3.5%) cases included a reduction in absolute neutrophil count to 500 cells/mm3 or less. The mean ± SD duration of vancomycin therapy and time to neutropenia were 32 ± 29 and 26 ± 15 days, respectively. Laboratory monitoring was performed on a weekly basis and resolution of vancomycin-induced neutropenia occurred promptly after discontinuation. Total vancomycin doses used and serum concentrations were not associated with the development of neutropenia. Conclusions: Vancomycin-induced neutropenia may occur at a higher frequency than previously reported. Clinicians should monitor hematologic parameters at least weekly in patients receiving home intravenous vancomycin therapy.

Non-Transferrin-Bound Iron Is Associated with Enhanced Staphylococcus aureus Growth in Hemodialysis Patients Receiving Intravenous Iron Sucrose

Background: Hemodialysis vascular access infections are most frequently caused by Staphylococcus spp. The purpose of this study was to determine if S. aureus growth is enhanced after administration of IV iron sucrose and to establish a relationship between the appearance of non-transferrin-bound iron (NTBI) and S. aureus growth. Methods: Serum samples were obtained from 12 hemodialysis patients receiving maintenance doses of 100 mg of iron sucrose at baseline and 5, 30, 90, 220 min and 48 h after iron administration. Assays for NTBI and transferrin saturation were performed. S. aureus isolates were used to inoculate patient serum samples. Bacterial growth was determined by optical density. Results: Six of 12 patients had NTBI present within 30 min of the iron dose. NTBI was present more frequently in patients with baseline transferrin saturation values >30% (p < 0.05). Bacterial growth was significantly greater in patients who had NTBI present at 5, 90 and 220 min after iron administration compared to those who did not have NTBI present. Conclusions: Doses of 100 mg of iron sucrose are associated with the presence of NTBI and enhanced S. aureus growth.

Beneficial influence of platelets on antibiotic efficacy in an in vitro model of Staphylococcus aureus-induced endocarditis.

ABSTRACT Platelets contribute to antimicrobial host defense against infective endocarditis (IE) by releasing platelet microbicidal proteins (PMPs). We investigated the influence of thrombin-stimulated human platelets on the evolution of simulated IE in the presence and absence of vancomycin or nafcillin. Staphylococcus aureus strains differing in intrinsic susceptibility to PMPs or antibiotics were studied: ISP479C (thrombin-induced PMP-1 [tPMP-1] susceptible; nafcillin and vancomycin susceptible), ISP479R (tPMP-1 resistant; nafcillin and vancomycin susceptible), and GISA-NJ (tPMP-1 intermediate-susceptible; vancomycin intermediate-susceptible). Platelets were introduced and thrombin activated within the in vitro IE model 30 min prior to inoculation with S. aureus. At 0 to 24 h postinoculation, bacterial densities in chamber fluid and simulated endocardial vegetations (SEVs) were quantified and compared among groups. Activated platelets alone, or in combination with antibiotics, inhibited the proliferation of ISP479C in chamber fluid or SEVs over the initial 4-h period (P < 0.05 versus controls). Moreover, nafcillin-containing regimens exerted inhibitory effects beyond 4 h against ISP479C in both model phases. By comparison, activated platelets inhibited GISA-NJ proliferation in SEVs but not in chamber fluid. The combination of platelets plus nafcillin or vancomycin significantly inhibited proliferation of the GISA-NJ strain in SEVs compared to the effect of platelets or antibiotics alone (P < 0.05). In contrast, platelets did not significantly alter the antistaphylococcal efficacies of nafcillin or vancomycin against ISP479R. These data support our hypothesis that a beneficial antimicrobial effect may result from the interaction among platelets, PMPs, and anti-infective agents against antibiotic-susceptible or -resistant staphylococci that exhibit a tPMP-1-susceptible or -intermediate-susceptible phenotype.

Assessing Appropriateness of Antimicrobial Therapy: In the Eye of the Interpreter

To address the increase of drug-resistant bacteria and widespread inappropriate use of antimicrobials, many healthcare institutions have implemented antimicrobial stewardship programs to promote appropriate use of antimicrobials and optimize patient outcomes. However, a consensus definition of appropriate use is lacking. We conducted a multicenter observational study to compare 4 definitions of appropriateness--a study site-specific definition, use supported by susceptibility data, use supported by electronic drug information resources (Clinical Pharmacology/Micromedex), or study site principal investigator (PI) opinion-among patients receiving 1 or more of 13 identified antimicrobials. Data were collected for 262 patients. Overall, appropriateness with the 4 definitions ranged from 79% based on PI opinion to 94% based on susceptibility data. No single definition resulted in consistently high appropriate use for all target antimicrobials. For individual antimicrobials, the definitions with the highest rate of appropriate use were Clinical Pharmacology/Micromedex support (6 of 7 antimicrobials) and susceptibility data (5 of 7 antimicrobials). For specific indications, support from susceptibility data resulted in the highest rate of appropriate use (4 of 7 indications). Overall comparisons showed that appropriateness assessed by PI opinion differed significantly compared with other definitions when stratified by either target antimicrobial or indication. The significant variability in the rate of appropriate use highlights the difficulty in developing a standardized definition that can be used to benchmark judicious antimicrobial use.