Pharmacoeconomic analysis of the treatment of methicillin-resistant Staphylococcus aureus with daptomycin or vancomycin

Pharmacoeconomic analysis of the treatment of methicillin-resistant Staphylococcus aureus with daptomycin or vancomycin

Dec 2012

[Article in Spanish]

Rubio-Terrés C, Rubio-Rodríguez D, Majos N, Grau S.

Source

Carlos Rubio Terrés, Health value, C/ Virgen de Aránzazu, 21. 5ºB, 28034, Madrid, Spain. crubioterres@healthvalue.org.

Abstract

Introduction. 

The increased morbidity, mortality and high costs associated with bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA) is a major public health problem. Pharmacoeconomic analysis was performed to compare the efficiency of daptomycin (DAP) against vancomycin (VAN) in the treatment of this infection. 

Methods. 

Retrospective, deterministic and probabilistic cost-effectiveness analysis. The effectiveness of the treatments was estimated from the results of a randomized clinical trial, which compared DAP (6 mg / kg IV daily) and VAN (1 g IV every 12 hours), both with or without gentamicin (1 mg / kg IV every 8 hours). Resource utilization was estimated from the clinical trial of the drug datasheets and Spanish sources, the unit costs were obtained also from Spanish sources. Monte Carlo probabilistic analysis and deterministic analysis were performed. 

Results. 

The clinical trial cure rates were higher with DAP (44.4%, 95% CI 43.5 to 45.4%) than with VAN (31.8%, 95% CI 30.9 to 32.7%) not statistically significant (p = 0.2203) but with economic impact. With DAP would occur less costs due to treatment failure (rescue antibiotics, additional tests, prolonged hospital stay and adverse reactions) than with VAN. In the base case the average cost of disease per patient was € 12,329 to € 12,696 with DAP and VAN (difference of 367 €). DAP treatment was dominant (more effective, with lower costs than VAN) both in the deterministic and probabilistic analysis. In the Monte Carlo simulation, DAP was the most cost-effective treatment in 100% of the 10,000 simulations, for a willingness to pay € 12,000 per additional cure (approximate cost of MRSA bacteraemia episode). 

Conclusions. 

According to this model, daptomycin is more cost-effective than vancomycin in treating MRSA bacteremia. The higher cost of acquisition of daptomycin does not imply a higher cost of treating this infection.

PubMed

A Trial of Discontinuation of Empiric Vancomycin Therapy in Patients with Suspected Methicillin-Resistant Staphylococcus aureus Healthcare-Associated Pneumonia.

Dec 2012

Boyce JM, Pop OF, Abreu-Lanfranco O, Hung WY, Fisher A, Karjoo A, Thompson B, Protopapas Z.

Source

Hospital Epidemiology and Infection Control Program, Yale-New Haven Hospital, New Haven, CT.

Abstract

Background:

Healthcare-associated pneumonia (HCAP) guidelines recommend de-escalating initial antibiotic therapy based on results of lower respiratory tract cultures. In the absence of adequate lower respiratory cultures, physicians are sometimes reluctant to discontinue empiric vancomycin given for suspected methicillin-resistant Staphylococcus aureus (MRSA) HCAP. We evaluated a strategy of discontinuing vancomycin if both nasal and throat cultures were negative for MRSA when lower respiratory cultures were not available.Methods:An antimicrobial stewardship team identified patients receiving empiric vancomycin for suspected or proven HCAP, but for whom adequate lower respiratory cultures were not available. Nasal and throat swab specimens were obtained and plated on MRSA selective media. If both nasal and throat MRSA cultures were negative, the stewardship team recommended discontinuation of empiric vancomycin. Demographic and clinical aspects, a clinical pulmonary infection score (CPIS) on the day of the stewardship recommendation, and mortality of patients for whom vancomycin was discontinued were obtained by retrospective chart review.Results:A convenience sample of 91 patients with nasal and throat cultures negative for MRSA in the absence of adequate respiratory cultures had empiric vancomycin therapy discontinued. A retrospective review revealed that 88 (97%) of patients had a CPIS ≤ 6 on the day of the stewardship recommendation. In-hospital mortality (7.7%) was similar to a previous study of de-escalation of antibiotics in pneumonia patients without adequate cultures.

Conclusion:

In the absence of adequate lower respiratory cultures, it is reasonable to discontinue empiric vancomycin HCAP therapy in patients with negative MRSA nasal and throat cultures and CPIS.

 Antimicrobial Agents and Chemotherapy

Continuous high-dose vancomycin combination therapy for methicillin-resistant staphylococcal prosthetic hip infection: a prospective cohort study.

OCt 2012

Dubée V, Zeller V, Lhotellier L, Kitzis MD, Ziza JM, Mamoudy P, Desplaces N.

Source

Service de Médecine Interne et Rhumatologie, Paris, France.

Abstract

Few data are available on treatment and outcome of methicillin-resistant (MR) staphylococcal prosthetic joint infections. Vancomycin remains the treatment of choice for these infections, but its efficacy and safety in bone-and-joint infections are insufficiently documented. We conducted a prospective cohort study on 60 patients treated between November 2002 and December 2008 for chronic MR staphylococcal (44 S. epidermidis, nine other coagulase-negative Staphylococcus and seven S. aureus) prosthetic hip infections (PHIs). Twenty-two patients had previously undergone surgery for their PHI and 21 had previously received antibiotics. All patients had surgery (exchange arthroplasty for 58 patients, resection arthroplasty for two) and received an antibiotic regimen combining high-dose continuous intravenous vancomycin infusion (target serum concentration 30-40 mg/L) with another antibiotic for 6 weeks, followed by an additional 6 weeks of oral intake. Two years after surgery, infection was considered cured in 41 (68%) patients and only two relapses occurred after one-stage exchange arthroplasty. Nineteen (32%) patients experienced nephrotoxicity that was generally mild (RIFLE class R for 14 patients, class I for four patients and class F for one patient) and most often reversible. Continuous high-dose intravenous vancomycin combination therapy is an effective, feasible and reasonably safe treatment of chronic MR staphylococcal PHI.

Wiley Online

Orphan Drug AeroVanc for MRSA Lung Infection in CF

November 13, 2012

Savara Pharmaceuticals announced that the FDA has granted orphan drug status to AeroVanc (vancomycin hydrochloride inhalation powder) for the treatment of pulmonary methicillin-resistant Staphylococcus aureus (MRSA) infection in cystic fibrosis (CF) patients. AeroVanc is a proprietary inhaled dry powder form of vancomycin in a capsule-based device designed for self-administration.

Savara is currently preparing for its Phase 2a clinical study of AeroVanc's efficacy, to be carried out in 20 CF centers in the United States. AeroVanc has demonstrated positive safety and tolerability results in Phase 1 clinical studies conducted in healthy subjects and patients with cystic fibrosis, with a pharmacokinetic profile that supports its potential as a once- or twice-daily treatment for pulmonary MRSA infection.

Vancomycin administered by IV is the antibiotic of choice for the treatment of MRSA-related bronchopneumonia, however, IV administration, poor penetration into the lungs and systemic toxicities limit its use in a chronic setting. By delivering vancomycin directly to the site of infection, AeroVanc is expected to improve clinical efficacy and reduce adverse effects due to systemic drug exposure.

M P R 

Study determines best treatment timeline for MRSA-related pneumonia

Paul Tinder

A recent study at Henry Ford Hospital found that while the national practice guideline for treating MRSA-related pneumonia is seven to 21 days, effective treatment time could be achieved in half that time.

Researchers determined that patients treated for eight to 13 days on a therapy of either vancomycin or linezolid antibiotics experienced the highest rate of survival. The study is thought to be the first to evaluate MRSA-related pneumonia’s length of treatment.

The study was presented on Friday at the San Diego-based meeting of the Infectious Diseases Society of America.

“Based on our study, clinicians can effectively treat their patients within eight to 13 days, thus minimizing patients’ exposure to antibiotics and their side effects,” Hadeel Zainah, the study’s lead author, said.

The retrospective study involved the evaluation of the medical charts of 115 patients who were hospitalized with MRSA pneumonia. The patients received either linezolid, vancomycin or both.

Forty-percent of the patients were treated from eight to 13 days, 27 percent were treated for 14 to 20 days, and 13.9 percent of patients received treatment for more than 20 days. Patients treated between 14 and 20 days and for more than 20 days experienced lower survival rates.

Thirty-two of the patients died after 28 days.

The study did not evaluate if treatment duration affected length of stay or whether one antibiotic was more effective than the other.

MRSA-related pneumonia is a respiratory illness that can follow a bout of influenza. Symptoms include fever, chills, shortness of breath, headache, sore throat and cough.

Vaccine News Daily

Vancomycin versus linezolid in the treatment of methicillin-resistant Staphylococcus aureus meningitis in an experimental rabbit model.

Oct 2012

Calik S, Turhan T, Yurtseven T, Sipahi OR, Buke C.

Source

Department of Infectious Diseases and Clinical Microbiology, Urla State Hospital, Izmir, Turkey.

Abstract

Background: The aim of this study was to compare the antibacterial efficacy of vancomycin and linezolid in a rabbit model ofmethicillin-resistant Staphylococcus aureus (MRSA) meningitis. 

Material/Methods: Meningitis was induced by intracisternal inoculation of ATCC 43300 strain. After 16 h incubation time and development of meningitis, the vancomycin group received vancomycin 20 mg/kg every 12 h. The linezolid-10 and linezolid-20 groups received linezolid in 10 and 20 mg/kg dosages every 12 h, respectively. The control group did not receive any antibiotics. Cerebrospinal fluid bacterial counts were measured at the end of 16-h incubation time and at the end of 24-h treatment. 

Results: Bacterial counts were similar in all groups at 16 h. At the end of treatment the decrease in bacterial counts in the vancomycin group was approximately 2 logs higher than the linezolid-20 group (p>0.05) and approximately 4 logs higher than in the linezolid-10 group (p: 0.037) (Vancomycin group: -2.860±4.495 versus Linezolid-20: -0.724±4.360, versus Linezolid-10: 1.39±3.37). Full or partial bacteriological response was higher in vancomycin versus linezolid-10 (p: 0.01), but not vancomycin versus linezolid-20 or linezolid-10 versus-linezolid-20 groups. 

Conclusions: Our results suggest that linezolid is not statistically inferior to vancomycin in the treatment of MRSAmeningitis in an experimental rabbit model in 20 mg/kg q12 h dosage; however, it is inferior in 10 mg/kg q12 h dosage. Additional data should gathered to confirm these findings in advance of clinical trials to assess efficacy in humans.

PubMed

Impact of vancomycin minimum inhibitory concentration on clinical outcomes of patients with vancomycin-susceptible Staphylococcus aureus infections: a meta-analysis and meta-regression.

Oct 2012

Mavros MN, Tansarli GS, Vardakas KZ, Rafailidis PI, Karageorgopoulos DE, Falagas ME.

Source

Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece; Department of Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA.

Abstract

Although the vancomycin minimum inhibitory concentration (VMIC) susceptibility breakpoint for Staphylococcus aureus was recently lowered to ≤2mg/L, it is argued that isolates in the higher levels of the susceptible range may bear adverse clinical outcomes. Clinical outcomes (all-cause mortality and treatment failure) of patients with S. aureus infections by 'high-VMIC' (conventionally defined as VMIC >1mg/L but ≤2mg/L) and 'low-VMIC' (VMIC≤1mg/L) isolates were compared by performing a systematic review and meta-analysis. The effect of potential confounders was assessed by univariate meta-regression analyses. In total, 33 studies (6210 patients) were included. Most studies were retrospective (28/33), used the Etest (22/33) and referred to meticillin-resistant S. aureus (MRSA) infections (26/33) and bacteraemia (23/33). Irrespective of VMIC testing method, meticillin resistance and site of infection, the high-VMIC group had higher mortality [relative risk (RR)=1.21 (95% confidence interval 1.03-1.43); 4612 patients] and more treatment failures [RR=1.67 (1.26-2.21); 2049 patients] than the low-VMIC group. The results were not affected by the potential confounders and were reproduced in the subset of patients withMRSA infections [mortality, RR=1.19 (1.02-1.40), 2956 patients; treatment failure, RR=1.69 (1.26-2.25), 1793 patients]. In conclusion, infection by vancomycin-susceptible S. aureus with VMIC>1mg/L appears to be associated with higher mortality than VMIC≤1mg/L. Further research is warranted to verify these results and to assess the impact of VMIC on meticillin-susceptible S. aureus infections. Evaluation of alternative antimicrobial agents also appears justified.

Elsevier

Successful management of methicillin-resistant Staphylococcus aureus bacteremia unresponsive to Vancomycin by adding fosfomycin: a case report.

Jul 2012

Linasmita P.

Source

Division of Infectious Disease, Department of Medicine, Faculty ofMedicine, HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University, Nakhon Nayok, Thailand. paul_lin_md@yahoo.com

Abstract

BACKGROUND:

Vancomycin is the drug of choice for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. However, vancomycin treatment failures are occasionally observed with some strains that are considered susceptible to vancomycin according to Clinical and Laboratory Standards Institute breakpoints (vancomycin minimum inhibitory concentration [MIC] < or =2 microg/mL). Although fosfomycin has in vitro activity against MRSA, clinical data regarding the use of fosfomycin either alone or in combination for the management of MRSA bacteremia is limited.

CASE REPORT:

A 57-year-old woman who was on regular hemodialysis for chronic kidney disease presented with sepsis associated with possible infection of arteriovenous fistula. Blood culture grew MRSA with vancomycin MIC of 1.5 microg/mL. Despite placement of a double-lumen catheter for hemodialysis and treatment with vancomycin and serum concentrations monitoring to keep trough levels of 15 to 20 microg/mL, her blood cultures still continued to grow MRSA for over 10 days. Later intravenous fosfomycin was added to the regimen along with vancomycin. After three days of this combination, suppression of bacteremia was achieved.

CONCLUSION:

Combination of fosfomycin and vancomycin might be another option for the treatment of bacteremia due toMRSA with vancomycin MIC of 1.5 microg/mL that is not responsive to vancomycin alone.

PubMed

A comparison of linezolid with glycopeptides in severe MRSA pneumonia.

A comparison of linezolid with glycopeptides in severe MRSA pneumonia.

Expert Rev Anti Infect Ther. 2009 Oct

Abunasser J, Metersky ML.

Division of Pulmonary and Critical Care Medicine, University of Connecticut Health Center, Farmington, CT 06030-1225, USA. jafar_jamil@hotmail.com

Evaluation of: Luna CM, Bruno DA, García-Morato J et al. Effect of linezolid compared with glycopeptides in methicillin-resistant Staphylococcus aureus severe pneumonia in piglets. Chest 135(6), 1564-1571 (2009). Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a major pathogen in nosocomial infections and accounts for a large proportion of nosocomial pneumonia. However, there are limited antibiotics available for the treatment of this serious and potentially lethal infection. Until recently, the only effective antibiotic was vancomycin, but the oxazolidinones, such as linezolid, have been shown to be a valuable addition to the arsenal of antimicrobial agents that can be used for MRSA pneumonia.

Clinical trials have been conducted to compare vancomycin and linezolid head-to-head in pneumonia and, in post hoc subgroup analyses, showed that linezolid use was associated with improved survival. The ensuing debate over these results was dominated by two opinions; there were those who speculated on the mechanism by which linezolid achieved this benefit, namely attributing it to pharmacodynamics and pharmacokinetics, and others who criticized the methodology of the studies and questioned the validity of the results altogether.

This study by Luna and colleagues was designed with several goals in mind. The first was to attempt to generate an animal model of MRSA pneumonia in piglets by duplicating techniques used in animal models of Gram-negative pneumonia. Then they studied the effect of three antibiotics (vancomycin, linezolid and teicoplanin) on outcomes in the same model, while simultaneously measuring antibiotic levels in the serum, bronchoalveolar lavage fluid and lung tissue, in an attempt to attribute differences in survival to pharmacological properties of the drugs used.

Their results showed a survival benefit only for linezolid, despite the fact that all three antibiotics had levels above MIC in all the compartments sampled, leading them to speculate that linezolid may have improved outcomes by mechanisms not directly related to its antimicrobial actions.

Expert Reviews

Microbiology of drugs for treating multiply drug-resistant Gram-positive bacteria.

Microbiology of drugs for treating multiply drug-resistant Gram-positive bacteria

J Infect. 2009 Sep

Eliopoulos GM.

Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.

George M. Eliopoulos^{, a,}

Several new antimicrobials demonstrate in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and other Gram-positive bacteria. Data from large surveys indicate that linezolid, daptomycin, and tigecycline are almost universally active against MRSA. Linezolid and tigecycline inhibit both Enterococcus faecium and Enterococcus faecalis at low concentrations; daptomycin is somewhat more potent against the latter. The investigational agents dalbavancin and telavancin are more potent than vancomycin against vancomycin-susceptible organisms. Dalbavancin inhibits vanB type VRE at low concentrations, but is not active against vanA type VRE. Telavancin is less active against VRE than against vancomycin-susceptible enterococci, but minimum inhibitory concentrations are lower than those of vancomycin against VRE. With continued careful use of available antimicrobials, the vast majority of these organisms should remain susceptible to 1 or more of the agents discussed for the foreseeable future.

ScienceDirect/Trends in Microbiology

Increasing incidence of methicillin-resistant Staphylococcus aureus skin and soft-tissue infections: reconsideration of empiric antimicrobial therapy.

Increasing incidence of methicillin-resistant Staphylococcus aureus skin and soft-tissue infections: reconsideration of empiric antimicrobial therapy.
Am J Surg. 2007 Nov

Awad SS, Elhabash SI, Lee L, Farrow B, Berger DH.
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Michael E. DeBakey Veterans Affairs Hospital, MED VAMC, OCL (112), 2002 Holcombe Blvd, Houston, TX 77030, USA. sawad@bcm.tmc.edu

BACKGROUND: Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) rates are at an all time high. MRSA rates as high as 60% have been reported in patients presenting with skin and soft-tissue infections (SSTIs). Our objectives were to (1) examine the incidence of MRSA over a 7-year period in surgical patients with SSTIs, (2) examine the choice of empiric antibiotic therapy, and (3) evaluate the vancomycin minimum inhibitory concentration (MIC) in MRSA isolates.

METHODS: The medical records of all patients who underwent operative debridement of SSTIs from 2000 to 2006 were retrospectively reviewed. Demographic data such as age, race, and gender as well as co-morbid risk factors were collected. Preoperative American Society of Anesthesiologists (ASA) score, temperature, WBC, creatinine, HgbA1c, albumin, and empiric antimicrobial of choice were also included. Microbiology of all operative cultures was recorded. Available vancomycin MIC data were collected. All data are presented as mean +/- standard error of the mean. A chi-square test was used for statistical analysis.

RESULTS: From 2000 to 2006, 288 patients with operative debridement for SSTIs were identified. The mean age was 54 +/- 11 years. Fifty-two percent of patients had diabetes mellitus, 55% were tobacco users, 34% alcohol users, and 23% had hepatitis C. The mean temperature at presentation was 99.2 degrees +/- 1.5 degrees F. The mean white blood cell count was 13.8 +/- .9. The mean HgbA1c was 8.6 +/- 2.5. The mean body mass index was 30.1 +/- 8. Sixty-seven percent of patients had an ASA > or = 3. There was a significant increase in MRSA SSTIs in 2006 (77%) compared with 2000 (34%, P < .001). Correspondingly, there was a significant increase in empiric administration of vancomycin in 2006 (93%) compared with 2000 (18%, P < .001). The examination of vancomycin MIC shows a shift for MRSA isolates over this time period.

CONCLUSION: Our study shows a significant and ongoing increase in the incidence of MRSA in patients with SSTIs. Empiric coverage with an MRSA antimicrobial should be used as first-line therapy. However, given the observed increase in vancomycin MIC, alternative MRSA antimicrobials should be considered.

Elsevier