Clinical outcome with oral linezolid and rifampin following recurrent methicillin-resistant Staphylococcus aureus bacteremia despite prolonged vancomycin treatment.

Drug-resistant Gram-positive bacteria, especially Staphylococcus aureus, are emerging as the predominant organisms involved in both nosocomial and community-acquired infections. Since the 1980s, vancomycin has been the first-line antibiotic used to treat methicillin- resistant S aureus. However, allergy and intolerance to vancomycin, the increasing number of vancomycin clinical failures and the existence of vancomycin intermediate-susceptible isolates of S aureus suggest that new antibiotics are needed. This paper reports the only known case of a successful clinical outcome with long term oral linezolid and rifampin therapy in the management of recurrent and persistent methicillin-resistant S aureus bacteremia with metastatic infections despite prolonged vancomycin use. More than two years since the initiation of linezolid and rifampin, the study patient has been clinically well with no evidence of adverse drug reactions including cytopenia and hepatic toxicities. Physicians must be aware of the novel developments in antibiotic therapy to treat drug-resistant bacterial infections.     

Rifampin in the treatment of serious staphylococcal infections

Eight patients with serious staphylococcal infections such as endocarditis, meningitis, epidural abscess, shunt and graft infections were treated with nafcillin, cephalothin or vancomycin in combination with rifampin. In vitro antibiotic sensitivities demonstrated that the Staphylococcus aureus and Staphylococcus epidermidis were highly sensitive to rifampin with minimum inhibitory and bactericidal levels of .0078-.25 micrograms/ml. In all patients reviewed and reported, when serum bactericidal levels were measured before and after the addition of rifampin, there was a positive correlation between microbiological and clinical outcome. Thus, in selected patients with life-threatening infections caused by S. aureus and S. epidermidis rifampin should be considered an adjunctive therapy.     

Efficacy of vancomycin plus rifampin in experimental aortic-valve endocarditis due to methicillin-resistant Staphylococcus aureus: in vitro-in vivo correlations

Studies of in vitro and in vivo bactericidal interactions of vancomycin plus rifampin against Staphylococcus aureus have yielded conflicting results. In this study the efficacy of this drug combination in experimental endocarditis due to a methicillin-resistant strain of S. aureus was investigated. Left-sided endocarditis was induced in 84 rabbits by an infecting strain that had been found to be synergistically killed by vancomycin plus rifampin in vitro when tested by the timed-kill curve technique; in contrast, the checkerboard technique had indicated that the two drugs were antagonistic against this strain. Infected animals received no therapy, vancomycin alone (30 mg/kg per day), rifampin alone (20 mg/kg per day), or both drugs (in the same doses). The combination was significantly more effective than the single-drug regimens in terms of (1) reduction of mean methicillin-resistant S. aureus vegetation titers (P less than .05-.0005), (2) rate and incidence of sterilization of vegetations (P less than .0005), and (3) rate of "radical" cure of endocarditis (P less than .005). Vancomycin alone and vancomycin plus rifampin were equally effective in reducing mortality and sterilizing renal abscesses. The use of vancomycin prevented the in vivo development of resistance to rifampin. No evidence that rifampin exerted an antagonistic effect on the in vivo bactericidal activity of vancomycin was found.     

Analysis of 42 cases of septicemia caused by an epidemic strain of methicillin-resistant Staphylococcus aureus: evidence of resistance to vancomycin.

Recent case reports of vancomycin treatment failures in the United States, Japan, and France have prompted a retrospective analysis of 42 cases of septicemia caused by epidemic methicillin-resistant Staphylococcus aureus strain 15 (EMRSA-15), which is the most prevalent epidemic strain of methicillin-resistant S. aureus in the United Kingdom; all cases occurred in a teaching hospital in Manchester, United Kingdom, between 1994 and 1998. Mortality was lowest (4%) in patients with rifampin-susceptible isolates treated with vancomycin and rifampin. It rose to 38% in patients who were treated with both antibiotics but in whom the organism became resistant to rifampin during therapy, and it reached 78% in patients who had rifampin-resistant isolates or in whom rifampin was contraindicated (P<.0001; Fisher exact test, 2-tailed). All isolates were susceptible to vancomycin by conventional laboratory testing, but susceptibility was lost by growth in vancomycin in vitro, becoming resistant at a minimum inhibitory concentration of 8 mg/L. This was associated with accumulation of cell-wall material. The deoxyribonucleic acid fingerprint remained unchanged. This study suggests that rifampin played a key role in the prevention of deaths caused by an epidemic strain of methicillin-resistant S. aureus that readily gave rise to a subpopulation with reduced susceptibility to vancomycin.     

Predicting methicillin resistance and the effect of inadequate empiric therapy on survival in patients with Staphylococcus aureus bacteremia

BACKGROUND: The restriction of vancomycin hydrochloride use is recommended as a measure to decrease the emergence of vancomycin resistance in gram-positive organisms; however, vancomycin also is the treatment of choice for methicillin-resistant Staphylococcus aureus (MRSA) infections. If vancomycin use is restricted to patients with documented infections due to methicillin-resistant organisms, then patients with MRSA infections may not initially receive vancomycin. This study was performed to determine factors that predict MRSA bacteremia and if ineffective empiric antibiotic therapy increased the risk of death in patients with S aureus bacteremia. METHODS: We conducted a retrospective cohort study of all patients with clinically significant S aureus bacteremia (132 episodes in 128 patients) diagnosed between October 1, 1995, and January 1, 1998, at an urban acute care Veterans Affairs medical center (approximately 200 acute care beds) in Baltimore, Md. During the study period, vancomycin was a restricted antibiotic. Empiric use had to be approved by an attending physician specializing in infectious diseases. RESULTS: Compared with patients who had methicillin-sensitive S aureus bacteremia, patients with MRSA bacteremia were significantly older (70 vs 58 years; P<.01), more likely to have a history of MRSA (47% vs 6%; P<.01) and a nosocomial infection (76% vs 50%; P<.01), and less likely to use injection drugs (8% vs 32%; P<.01). In addition, compared with patients who had methicillin-sensitive S aureus bacteremia, patients with MRSA bacteremia were significantly less likely (45% vs 98%; P<.01) to receive effective antibiotic therapy during the first 48 hours of hospitalization. However, the risk of death due to ineffective empiric therapy was less than 1 (relative risk, 0.82; 95% confidence interval, 0.36-1.88) and did not change significantly when adjusted for age, occurrence of sepsis, or nosocomial infection. CONCLUSIONS: The results of this study support the safety of the restriction of vancomycin use in patients with clinically significant S aureus bacteremia. However, patients with a history of MRSA are more likely to have future MRSA infections and should receive empiric therapy using vancomycin for possible S aureus infections, particularly for nosocomial infections.     

Oral rifampin for eradication of Staphylococcus aureus carriage from healthy and sick populations: a systematic review of the evidence from comparative trials

BACKGROUND: Rifampin has been used for the eradication of Staphylococcus aureus (S. aureus) colonization in various populations of healthy and sick people. METHODS: We performed a systematic review of the evidence from randomized and nonrandomized controlled trials that compared the effectiveness and safety of a rifampin-based regimen with another regimen in eradicating S. aureus colonization from healthy and sick people. RESULTS: Nine comparative trials (6 of which were randomized controlled trials) were included in our analysis. S. aureus was eradicated more commonly in patients receiving rifampin-containing regimens compared to monotherapy with other systemic agents (ciprofloxacin, cloxacillin, minocycline, or vancomycin), both during early and late (>1 month after therapy) post treatment evaluations (odds ratio [OR] 46.2, 95% confidence interval [CI] 14.4-148, and OR 8.8, 95% CI 3.4-22.5 respectively, 4 studies included). There was no statistically significant difference between rifampin monotherapy and combinations of rifampin with other topical (bacitracin) or systemic (cloxacillin and minocycline) antibiotics in eradicating S. aureus both in early and late evaluations (OR 1.5, 95% CI 0.5-4.4, and OR 1.6, 95% CI 0.7-3.7, respectively, 3 studies included). Eradication of methicillin-resistant S. aureus (MRSA) varied according to the type and duration of the rifampin-containing regimen. It ranged from 25% for the combination of rifampin with trimethoprim/sulfamethoxazole for 5 days to 100% for the combination of oral rifampin and minocycline for 14 days. Discontinuation of rifampin due to drug-related toxicity was necessary in 2% of 282 studied patients. Development of resistance of S. aureus to rifampin during and after treatment with a regimen containing rifampin ranged from 0% to 40% (7 studies) and overall 17% of the 236 patients for whom relevant data was reported. CONCLUSION: The available evidence suggests that oral rifampin is an effective agent for the eradication of S. aureus carriage. However, development of antimicrobial resistance during and after treatment with rifampin occurs in a considerable proportion of patients; using rifampin in combination with another antimicrobial agent may decrease this resistance.     

Synercid plus vancomycin for the treatment of severe methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci infections: evaluation of 5 cases

Synercid (quinupristin/dalfopristin), the first semi-synthetic injectable streptogramin, is a promising alternative to glycopeptides against many Gram-positive multiresistant bacteria. Vancomycin is still considered an effective agent for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections but therapeutic failures with glycopeptides have been observed, even for the treatment of infections caused by S. aureus strains sensitive to vancomycin. Synercid, in combination with a glycopeptide, may address this problem without causing significant side effects due to the different toxicity patterns of the 2 antimicrobials. This study reports our experience with the combination of Synercid and vancomycin in 5 patients with severe infection caused by MRSA or methicillin-resistant coagulase-negative Staphylococcus.     

Successful salvage of peritoneal catheter in unresolved methicillin-resistant staphylococcus aureus peritonitis by combination treatment with daptomycin and rifampin

Peritoneal dialysis patients are at an increased risk of Gram-positive organism infections because of disrupted skin barrier function, presence of a peritoneal catheter, and a deficient immunological system. In particular, the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections is clinically challenging. Herein, we present a case of MRSA peritonitis that showed no response to a 14-day treatment with intraperitoneal vancomycin. To overcome unresponsiveness to vancomycin, we shifted the regimen to intraperitoneal daptomycin (given every 6 h through manual peritoneal dialysate exchanges) and oral rifampin (300 mg twice daily). The peritonitis resolved without sequelae or relapse. We suggest daptomycin and rifampin as an alternative combination therapy for MRSA infections that may otherwise remain unresolved.     

Methicillin-resistant staphylococci and their treatment in the intensive care unit

Methicillin resistance in Staphylococcus aureus (MRSA) and the coagulase-negative staphylococci (MRCNS) is widespread and continues to increase in prevalence, particularly in the health care setting. The clinical significance of methicillin resistance for patients with staphylococcal infections is not clear: studies in patients with bacteremia, pneumonia, and mediastinitis show a higher mortality with MRSA infection compared to methicillin-sensitive Staphylococcus aureus (MSSA) infection, though this may be due to underlying patient, pharmacodynamic, or microbiological differences. For serious methicillin-resistant staphylococcal infections, vancomycin-based regimens are preferred. Treatment alternatives for patients with severe methicillin-resistant infections who are unable to tolerate vancomycin include linezolid and quinupristin/dalfopristin; these agents should be considered second-line options, given the relative lack of clinical experience and the nonsignificant but consistent trends toward worse outcomes in bacteremia and pneumonia with these agents compared to vancomycin. For less severe infections, treatment options also include trimethoprim-sulfamethoxazole, or fluoroquinolones in combination with rifampin.     

Approaches to serious methicillin-resistant Staphylococcus aureus infections with decreased susceptibility to vancomycin: clinical significance and options for management

PURPOSE OF REVIEW: This review addresses therapeutic approaches to Staphylococcus aureus infections with diminished susceptibility to vancomycin, focusing on recently published data in English language medical literature between June 2006 and July 2007. RECENT FINDINGS: Knowledge regarding the potential limitations of vancomycin therapy for S. aureus infections continues to emerge. Recent changes include alteration of the Clinical Laboratory and Standards Institute vancomycin breakpoint for S. aureus and questions regarding the utility of the lower breakpoint of 2.0 mg/l. Interest continues in the accessory gene regulator (agr) locus and its impact on the activity of vancomycin. Newer options for drug therapy progress, with strengths and limitations becoming more apparent for each. SUMMARY: Newer antimicrobial agents active against methicillin-resistant S. aureus such as daptomycin and linezolid continue to show value. Older antimicrobial agents may play an important therapeutic role and warrant further examination. Work is needed to evaluate current agents against methicillin-resistant S. aureus in the setting of elevated vancomycin minimum inhibitory concentrations or clinical failure. Antimicrobial selection for methicillin-resistant S. aureus infections with reduced susceptibility to vancomycin should be governed by disease severity, susceptibility patterns, knowledge of the limitations of current susceptibility testing, and strengths and weaknesses of the agents being considered.     

Vancomycin-resistant Staphylococcus aureus: a new model of antibiotic resistance

Vancomycin has been the most reliable therapeutic agent against infections caused by meticillin-resistant Staphylococcus aureus (MRSA). However, in 1996 the first MRSA to acquire resistance to vancomycin, was isolated from a Japanese patient. The patient had contracted a post-operative wound infection that was refractory to long-term vancomycin therapy. Subsequent isolation of several vancomycin resistant S. aureus (VRSA) strains from USA, France, Korea, South Africa, and Brazil has confirmed that emergence of vancomycin resistance in S aureus is a global issue. A certain group of S. aureus, designated hetero-VRSA, frequently generate VRSA upon exposure to vancomycin, and are associated with infections that are potentially refractory to vancomycin therapy. Presence of hetero-VRSA may be an important indicator of the insidious decline of the clinical effectiveness of vancomycin in the hospitals. Vancomycin resistance is acquired by mutation and thickening of cell wall due to accumulation of excess amounts of peptidoglycan. This seems to be a common resistance mechanism for all VRSA strains isolated in the world so far.     

Combination therapy with daptomycin, vancomycin, and rifampin for recurrent, severe bone and prosthetic joint infections involving methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) infections are commonly treated with vancomycin (VAN) or another glycopeptide antibiotic. However, when vancomycin fails or infections recur, there are few other therapeutic options. Presented here are 2 cases where a novel combination of daptomycin, vancomycin, and rifampin resolved recurrent MRSA bone and prosthetic joint functions.     

A case of spontaneous methicillin-resistant Staphylococcus aureus meningitis in a health care worker.

Meningitis caused by Staphylococcus aureus is an unusual illness that is often associated with bacteremia, contiguous infection and/or a post-neurosurgical state. Until recently, most cases were caused by methicillin-susceptible strains, but there are a few reports of methicillinresistant S aureus strains causing meningitis. A new case of meningitis caused by methicillin-resistant S aureus in a neonatal intensive care nurse who did not have bacteremia or neurosurgery is reported. The patient made a full recovery after treatment with vancomycin and rifampin.     

Diagnosis and management of Staphylococcus aureus infections of the skin and soft tissue

Infections involving the skin and soft tissue are common and range from superficial, localized and sometimes self-limiting infections to deep, rapidly spreading and potentially life-threatening infections. Skin infections caused by Staphylococcus aureus include primary pyodermas, while those involving the soft tissues include cellulitis and pyomyositis. Surgical site infections and infections in intravenous drug users are also commonly caused by S. aureus. The severity of the infection determines the choice of treatment. There are few studies that have critically appraised the use of antibiotics in skin and soft tissue infections, and most guidelines are based on expert opinion. The beta-lactam group of antibiotics are the mainstay of treatment for methicillin-susceptible S. aureus infections. For methicillin-resistant S. aureus (MRSA) infections, both with community-acquired and hospital-acquired strains--which are becoming an increasing problem--the antibiotic choice is determined by local susceptibility patterns. Macrolides, clindamycin and cotrimoxazole are options for community-acquired MRSA, while vancomycin is reserved for treatment of infections caused by multiresistant MRSA strains and for patients with suspected endocarditis or severe sepsis. Although a number of the newer antibiotics such as linezolid and quinopristin/dalfopristin have been shown to have good activity against MRSA, these agents should only be used with specialist advice.     

Binding affinity for penicillin-binding protein 2a correlates with in vivo activity of beta-lactam antibiotics against methicillin-resistant Staphylococcus aureus

The beta-lactam antibiotics ticarcillin, nafcillin, imipenem, and ampicillin, which differ in antibacterial activity against methicillin-resistant strains of Staphylococcus aureus, were examined for affinity to penicillin-binding protein (PBP) 2a, which mediates methicillin resistance. The relative efficacy of each antibiotic was compared to vancomycin in a rabbit model of aortic valve endocarditis caused by either a methicillin-susceptible or methicillin-resistant strain of beta-lactamase-producing S. aureus. beta-lactamase inhibitors clavulanate and sulbactam were used in combination with ticarcillin and ampicillin, respectively. All beta-lactam antibiotics were effective against the susceptible strain. beta-lactam antibiotic activity in vitro and in vivo against the resistant strain correlated with its affinity for binding to PBP 2a. Lack of efficacy of beta-lactam antibiotics for the resistant strain was due to an inability to eradicate the resistant subpopulation of cells. Vancomycin was the most effective agent.     

万古霉素致失代偿期肝硬化患者重度血小板减少1例

万古霉素是一种糖肽类抗生素，临床主要用于治疗包括耐甲氧西林金黄色葡萄球菌在内的侵袭性革兰阳性菌感染。该药常见不良反应为皮疹、肾毒性及耳毒性，较少引起血小板减少。本文报道1例由万古霉素导致重度血小板减少的失代偿期肝硬化患者，为此类不良反应的临床监测及治疗提供参考。     

Community-associated methicillin-resistant Staphylococcus aureus: Reconsideration of therapeutic options

Methicillin resistance, long recognized as characteristic of nosocomial Staphylococcus aureus, has increasingly been identified in community-acquired strains in the past 15 years. The genotypes of community-associated methicillin-resistant S. aureus (MRSA) are different from nosocomial strains, and unlike nosocomial strains, they have a distinctive methicillin-resistance chromosomal cassette (designated type IV), are usually susceptible to multiple classes of antimicrobials other than β-lactams, carry a distinctive virulence factor (the Panton-Valentine leukocidin), cause mainly skin and soft tissue infection and less frequently, necrotizing pneumonia, and involve predominantly children and young adults. Outbreaks have been reported in certain segments of the population (eg, football players, wrestlers, prison inmates, and native people) that often do not have the established risk factors for MRSA. However, these strains have also caused infections likely acquired in an institutional health care setting. Delay in starting appropriate antibiotic therapy for severe infections caused by MRSA can be life-threatening. This requires a reconsideration of the empiric choice of an anti-staphylococcal β-lactam for seriously ill patients with suspected community-associated S. aureus infections.     

Methicillin-Resistant S. aureus Ventilator-Associated Pneumonia: Strategies to Prevent and Treat

Ventilator-associated pneumonias (VAPs) due to methicillin-resistant Staphylococcus aureus (MRSA) are rising in incidence and pose unique challenges in their prevention and treatment. Risk factors for the development of MRSA VAP include nasal carriage, prior antibiotic therapy, prolonged mechanical ventilation, poor infection control practices, head trauma/coma, and viral infection. Measures to prevent the development of MRSA VAP include general VAP prevention strategies and reduction of S. aureus nasal carriage. S. aureus possesses a variety of transferable genetic elements that encode proteins conferring resistance to several antibiotics, including beta-lactams and glycopeptides. Successful treatment of MRSA VAP with currently available antibiotics has been poor. Current management guidelines recommend glycopeptides as initial therapy for MRSA VAP. However vancomycin success rates are low, ranging from only 35 to 57%. This may be due to the poor penetration of vancomycin into the lung, and alternate dosing regimens to increase tissue levels need to be further studied. Treatment with linezolid, which penetrates well into the lung, is associated with higher cure and survival rates. Further data are needed to evaluate the efficacy of new antibiotics in MRSA VAP.     

Is methicillin-resistant Staphylococcus aureus an emerging community pathogen? A review of the literature.

OBJECTIVES: To discuss the historical epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) and review the literature suggesting that MRSA has become a community pathogen. DATA SOURCES: A search of the MEDLINE database was performed, encompassing all English or French language citations from 1966 to 1999 and containing the subjects and/or text words: 'Staphylococcus aureus', 'methicillin resistance', 'endocarditis', 'cellulites', 'pneumonia' and 'community-acquired'. Articles published in other languages that provided English or French abstracts were included. All relevant references cited in articles obtained from the MEDLINE database and book chapters were also included. DATA EXTRACTION: All articles obtained from the above sources were examined and were included in the review if a laboratory or epidemiological study of community-acquired MRSA was presented. DATA SYNTHESIS AND CONCLUSIONS: MRSA has emerged over the past 30 years to become a worldwide nosocomial pathogen and has recently been reported as a cause of community-acquired infections. The changing epidemiology of MRSA is likely because of two mechanisms: the movement of nosocomial MRSA strains into the community and the de novo appearance of community strains resulting from the transfer of genetic material from methicillin-resistant Gram-positive organisms to sensitive S aureus strains. The emergence of MRSA as a community pathogen has occurred at a slower rate than it did for penicillin-resistant S aureus (PRSA) in the 1950s and 1960s, possibly because the mechanism of methicillin resistance does not exhibit the same ease of transferability as that of penicillin resistance. Four case reports, seven case series, 10 case-control studies and two cohort studies on community-acquired MRSA were analyzed. Determining whether these reports involve new community-acquired strains rather than previously acquired nosocomial strains can be problematic. It appears, however, that MRSA strains of both nosocomial and community origin are now endemic in certain communities in different parts of the world. Few surveillance studies of nonhospitalized patient populations have been performed to date; thus, the true prevalence of MRSA in the community at large is essentially unknown, although it appears to be low. At present, the empirical treatment of community-acquired S aureus infections with a beta-lactamase-stable beta-lactam antibiotic is appropriate for most populations. However, empirical vancomycin therapy for serious S aureus infections should be strongly considered for patients with significant risk factors for previously-acquired nosocomial MRSA or for patients belonging to outpatient populations with a proven high prevalence of MRSA. Increasing vancomycin use will likely have a significant impact on the development of resistance in Gram-positive organisms.     

Successful vancomycin desensitization with a combination of rapid and slow infusion methods

Vancomycin, an antibiotic to which methicillin-resistant Staphylococcus aureus (MRSA) is sensitive, frequently induces hypersensitivity reactions. Lowering the vancomycin infusion rate and/or premedicating with antihistamine effectively reduce hypersensitivity in most cases. However, vancomycin desensitization is sometimes the only way to ensure safe use. Two types of desensitization protocols have been reported, and these utilize different infusion intervals; rapid desensitization and slow desensitization. We herein report a case of vancomycin hypersensitivity with methicillin-resistant Staphylococcus aureus infection. A combination of the two desensitization protocols, rapid desensitization followed by slow desensitization, effectively inhibited the hypersensitivity reaction during vancomycin infusion, and methicillin-resistant Staphylococcus aureus was successfully eradicated.