Vanthida Huang

Characterisation of a Staphylococcus aureus strain with progressive loss of susceptibility to vancomycin and daptomycin during therapy

Following an initial response to vancomycin therapy, a patient with meticillin-resistant Staphylococcus aureus (MRSA) bacteraemia developed endocarditis, failed a second course of vancomycin and then failed daptomycin therapy. An increase in the vancomycin minimum inhibitory concentrations of four consecutive MRSA blood isolates from 2 microg/mL to 8 microg/mL was shown by Etest. Population analysis of four successive blood culture isolates recovered over the 10-week period showed that the MRSA strain became progressively less susceptible to both vancomycin and daptomycin. Retrospectively, the macro Etest method using teicoplanin indicated a decrease in vancomycin susceptibility in the second blood isolate. The patient improved after treatment with various courses of trimethoprim/sulfamethoxazole, quinupristin/dalfopristin and linezolid. Early detection of vancomycin-heteroresistant S. aureus isolates, which appeared to have clinical significance in this case, continues to be a challenge for the clinical laboratory. Development of suitable practical methods for this should be given priority. Concurrent development of resistance to vancomycin and daptomycin, whilst rare, must be considered in a patient who is unresponsive to daptomycin following vancomycin therapy.

Risk of serotonin syndrome with concomitant administration of linezolid and serotonin agonists.

Linezolid, an antimicrobial used to treat resistant gram‐positive bacteria, can inhibit monoamine oxidase, an enzyme that metabolizes serotonin and other biogenic amines. Inhibition of this enzyme can predispose patients who are concomitantly taking serotonin agonists to serotonin syndrome. Because of the potential of linezolid to inhibit monoamine oxidase, premarketing studies were conducted with drugs such as selective serotonin reuptake inhibitors. No cases of serotonin syndrome were recorded. After linezolid was released to the United States market, several case reports of serotonin syndrome emerged. A literature search revealed 13 cases of serotonin syndrome occurring with the concomitant use of linezolid and drugs possessing serotonergic properties. To direct clinical management of this potential drug interaction, we reviewed reports of serotonin syndrome to determine relevant drug interactions with linezolid and serotonergic drugs and to characterize similarities and differences in the reported cases. Clinicians should obtain complete drug histories to identify patients at risk, strictly monitor drug therapy including concomitant drugs, and receive education about this potential drug interaction and the symptoms of serotonin syndrome.

Pharmacodynamics of Cefepime Alone and in Combination with Various Antimicrobials against Methicillin-Resistant Staphylococcus aureus in an In Vitro Pharmacodynamic Infection Model

ABSTRACT Treatment options for gram-positive resistant bacteria are limited; therefore, efforts to evaluate therapy options in the critical care population are warranted. Cefepime has broad-spectrum activity against gram-negative and gram-positive organisms. We have previously demonstrated that the combination of cefepime with vancomycin, linezolid, or quinupristin-dalfopristin had an improved or enhanced effect against methicillin-resistant Staphylococcus aureus (MRSA). We investigated various regimens of cefepime alone and in combination against two clinical MRSA isolates (R2481 and R2484) in an established in vitro pharmacodynamic model. Human pharmacokinetic regimen simulations were as follows: cefepime, 2 g every 8 h (q8h) (C8) and 12 h (C12), continuous-infusion 2-g loading dose followed by 4 g alone or in combination with gentamicin and tobramycin (1.0 or 2.0 [G1 and G2 or TB1 and TB2] mg/kg of body weight q12h and 5.0 [G5 or TB5] mg/kg q24h), arbekacin (ARB) (100 mg q12h), linezolid (LIN) (600 mg q12h), tigecycline (TIG) (100 mg q24h), or daptomycin (DAP) (6 mg/kg q24h) for 48 h. The MICs for cefepime, gentamicin, tobramycin, ARB, LIN, TIG, and DAP for the two clinical MRSA isolates (R2481 and R2484) were 4 and 4, 0.25 and 0.5, 128 and 0.5, 0.5 and 0.125, 2 and 4, 0.25 and 0.25, and 0.0625 and 0.125 μg/ml, respectively. At 48 h, combinations of C12 and C8 plus ARB, G1, or G5 (range, −2.05- to −4.32-log10 decrease) demonstrated enhanced lethality against R2481 (resistant to tobramycin) (P < 0.05). A similar relationship was demonstrated against R2484 with cefepime plus ARB, gentamicin, or tobramycin (range, −2.05- to −3.63-log10 decrease) (P < 0.05). A 99.9% kill was achieved with cefepime plus aminoglycoside combinations as early as 2 h and maintained throughout the 48-h period. TIG was antagonistic when combined with C12 against both isolates. DAP alone achieved 99.9% kill for up to 48 h for both isolates and was the most active agent against R2481 and R2484 (−2.89- and −3.61-log10 decrease at 48 h); therefore, combination therapy did not enhance lethality. Overall, the most potent combinations noted were cefepime in combination with low- and high-dose aminoglycosides. Further investigations with combination therapies are warranted.

Characterization of heterogeneous vancomycin-intermediate resistance, MIC and accessory gene regulator (agr) dysfunction among clinical bloodstream isolates of staphyloccocus aureus

BackgroundThe development of hVISA has been associated with vancomycin clinical failures and is commonly misidentified in clinical microbiology laboratories. Therefore, the objectives of this present study was to improve the reliability of methodologies and criteria for identifying hVISA, evaluate the prevalence of hVISA among clinical bloodstream isolates of S. aureus and determine if there exists a relationship between accessory gene regulator (agr) dysfunction and the hVISA phenotype.MethodsThe presence of hVISA in 220 clinical S. aureus isolates (121 MSSA, 99 MRSA) from bloodstream infections was examined by CLSI broth microdilution, Macro & Standard Etest. Isolates which were classified as hVISA by Macro Etest, were additionally evaluated using a modified PAP-AUC method using a modified starting inoculum of 1010 CFU/mL, and growth on brain heart infusion agar with 4 mg/L vancomycin (BHIV4) at 108 and 1010 CFU/mL, and agr function was assessed by delta-hemolysin production.ResultsBroth microdilution MIC50/90 of S.aureus and hVISA was 1.0/2.0 and 1.5/2.0 mg/L (p= 0.02), respectively. Macro Etest identified 12 (5.5%) hVISA isolates; higher among MRSA (9.1%) versus MSSA (2.5%) (p = 0.03). The mean modified PAP-AUC ratios (> 0.8) of 7 MRSA strains and 3 MSSA strains were significantly different (p = 0.001). 58% of hVISA strains were found to be agr dysfunctional when 21% of MRSA strains were agr dysfunctional. hVISA was detected among S. aureus bloodstream isolates, which were classified as susceptible among clinical microbiology laboratories.ConclusionsEvaluating the correlation between Etest MICs and modified PAP-AUC ratio values will add further improvement of discriminating hVISA, and agr dysfunction may be predictive of strains which display a greater predilection to display the hVISA phenotype.

Poly-L-lactic Acid for Facial Lipoatrophy in HIV

Objective: To review the clinical data for poly-L-lactic acid, a synthetic polymer used as an intradermal injection for the treatment of HIV associated facial fat loss (lipoatrophy). Data Sources: A literature search was performed using MEDLINE (1966–August 2006). The search was limited to articles published in English and used the key words polylactic acid, polylactides, degradation, lipodystrophy, lipoatrophy, and HIV/AIDS. Dermik Laboratories was contacted to obtain unpublished information. Additional articles were retrieved from citations of selected references. Study Selection and Data Extraction: Relevant information on the pharmacology, pharmacokinetics, safety, and efficacy of poly-L-lactic acid from clinical trials were selected. Data Synthesis: Poly-L-lactic acid (Sculptra) is a biocompatible, biodegradable, synthetic polymer able to be tailored into various desired morphologic features. It is approved by the Food and Drug Administration for the correction of facial lipoatrophy in people with HIV. Six clinical trials have evaluated the use of intradermal injections of poly-L-lactic acid. Results showed that cutaneous thickness is improved in patients receiving poly-L-lactic acid. Adverse effects included nodule and hematoma formation, as well as pain at the injection site. Conclusions: Poly-L-lactic acid offers a treatment alternative for patients with HIV-associated lipoatrophy. Further research is required in nonwhite populations.

Evaluation of dalbavancin, tigecycline, minocycline, tetracycline, teicoplanin and vancomycin against community-associated and multidrug-resistant hospital-associated meticillin-resistant Staphylococcus aureus

Dalbavancin is an investigational semisynthetic lipoglycopeptide that is structurally related to teicoplanin. We examined the activity of dalbavancin (DAL) compared with tigecycline (TIG), minocycline (MIN), tetracycline (TET), teicoplanin (TEC) and vancomycin (VAN) against community-associated meticillin-resistant Staphylococcus aureus (CA-MRSA) and multidrug-resistant hospital-associated meticillin-resistant S. aureus (MDR HA-MRSA). Two hundred and twenty clinical isolates of CA-MRSA and MDR HA-MRSA were utilised. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were determined according to Clinical and Laboratory Standards Institute guidelines. Selective time-kill studies were performed against CA-MRSA and MDR HA-MRSA in triplicate. Overall, DAL exhibited low MIC values against all strains of MRSA. Time-kill studies with CA-MRSA demonstrated DAL=VAN>TIG>MIN=TEC>TET (P<0.006), and with MDR HA-MRSA demonstrated DAL=VAN=TEC>TIG=MIN>TET (P>0.05). DAL demonstrated potent activity against clinical strains of CA-MRSA and MDR HA-MRSA, including tetracycline-resistant S. aureus.

High vancomycin serum trough is not associated with reduction of mortality in methicillin-resistant Staphylococcus aureus bloodstream infections

The current Infectious Diseases Society of America (IDSA) and the American Society of Health-System Pharmacists (ASHP) guidelines recommend a vancomycin serum trough concentration of 15 to 20 mg/L in patients with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI). The objective of this study was to evaluate the mortality difference in MRSA BSI pre and post hospital-wide implementation of higher serum trough concentration per IDSA/ ASHP guidelines. This was a retrospective cohort study performed in an integrated hospital health system (2238 beds) in Southeast Michigan. We evaluated 1173 consecutive individual patients with MRSA BSI over a 9-year period. The vancomycin minimum inhibitory concentrations (MICs) were determined by Etest method for all isolates. Attainment of vancomycin serum trough concentration per IDSA/ASHP guidelines was implemented in January 2010 by clinical pharmacist as part of the antimicrobial stewardship program. During the study period, the mean vancomycin MIC was 1.57 ± 0.26 mg/L, the percentage of MRSA isolates with vancomycin MIC ≥ 2 mg/L was 17.5%, and the 30-day all-cause mortality was 16.5%. There was no difference in mortality during the 9-year period (p=0.193). There was no change in all-cause mortality for MRSA BSI after the hospital-wide implementation of higher vancomycin dose and serum trough concentration per IDSA/ ASHP guidelines. Prospective multicenter, controlled studies evaluating optimal dosing strategies for vancomycin are warranted. Correspondence to: Marcus J. Zervos, Division Head, Infectious Diseases, Henry Ford Health System, Professor of Medicine, Wayne State University School of Medicine, Detroit, MI 48202, USA, Tel: +1-313-916-2573; Fax: +1-313-9162993; E-mail: mzervos1@hfhs.org

Evaluation of a Formulary Change on Outcome of Infection and Antimicrobial Resistance in a Medical Intensive Care Unit

All patients in a 20-bed medical intensive care unit (ICU) were prospectively followed for a 4-month period (phase I: 390 patients/2379 patient days) to collect baseline information, and were then followed for an additional 4 months (phase II: 383 patients/2260 patient days) after a decrease in use of piperacillin-tazobactam substituted with cefepime. Total infections in phase I versus phase II were lower respiratory tract infection (LRTI), 214 patients (55%) versus 203 patients (53%); urinary tract infection (UTI), 94 patients (24%) versus 96 patients (25%); and sepsis of undetermined etiology, 70 patients (18%) versus 65 patients (17%). There were no significant differences in death (22 % vs. 19%), cure or improvement of infection (53% vs. 56%), readmission to the unit (3.5% vs. 3.2%), hospital risk of death (29.8 vs. 30.2), mean length of ICU stay (6.1 days vs. 5.9 days), or rates of nosocomial infection (6.3 vs. 5.1 for LRTI, 4.0 vs. 4.2 for UTI, soft tissue infection [STI] 0.8 vs. 0.0, bacteremia 0.8 vs. 1.0, and intravenous catheter infection 2.1 vs. 1.0 per 1000 patient days), in phase I and phase II, respectively. Costs of antimicrobial acquisition were

Evaluation of daptomycin activity against Staphylococcus aureus in an in vitro pharmacodynamic model under normal and simulated impaired renal function

548 versus

Methicillin-Resistant Staphylococcus aureus in the Community: Implications for Clinicians

433 per patient in phase I and phase II (P < 0.001). Mean per patient antimicrobial treatment costs of piperacillin-tazobactam were