Desensitization in the management of vancomycin hypersensitivity

Vancomycin is the preferred antimicrobial agent in the treatment of methicillin-resistant staphylococcal infections. One of the well-known hypersensitivity reactions to this agent is the "red-man syndrome," which is believed to involve drug-induced histamine release in certain individuals. Although rate and/or dose reductions may be effective in some cases, some hypersensitivity reactions necessitate the discontinuation of vancomycin. In this article one patient is described who developed vancomycin-associated reactions consistent with the red-man syndrome despite having tolerated vancomycin administration previously. This case was managed by sequential increments in vancomycin administration over several days that allowed for therapeutic doses of the drug to be administered. Prior to desensitization, vancomycin administration at a lowered rate and dose was unsuccessfully attempted, despite the presence of combination antihistamine therapy. A loss of skin prick test reactivity to vancomycin was demonstrated after successful desensitization. This desensitization method may be useful in managing certain refractory cases of vancomycin hypersensitivity.     

An alarming problem in the therapy of infective endocarditis: the development of antibiotic-resistant strains]

We shall focus on infective endocarditis due to Enterococcus spp and Staphylococcus aureus, both able to develop resistance to antibiotics with different mechanisms. Vancomycin-resistant strains produce some of the most challenging nososocomial infections. Enterococci develop resistance practically to all classes of antibiotics. Vancomycin-resistant strains, in the '90s, passed from 2% to more than 25%. Five types of vancomycin-resistance were reported (from van A to van E), linked to the presence of certain classes of genes regulating the production of abnormal precursors of peptidoglycan which inhibit the action of vancomycin. Staphylococcus aureus is a fearful organism whose infections can reach a mortality rate of 80%. In 1943, as soon as penicillin G was introduced into therapy, Staphylococcus strains producers of beta-lactamase were identified. After beta-lactamase-resistant penicillins were introduced into therapy, methicillin-resistant Staphylococcus strains appeared in the '60s. In 1996 the first strain of methicillin-resistant and vancomycin-resistant Staphylococcus aureus was isolated. In 2001, in Japan, the first case of infective endocarditis due to Staphylococcus aureus resistant to methicillin and non-responsive to vancomycin was described. The resistance is connected to an increased synthesis of the cell wall, which thickens reducing the activity of vancomycin.     

Optimizing therapy for MRSA pneumonia

With its remarkable armamentarium of resistance and virulence factors, Staphylococcus aureus has emerged as a dominant pathogen causing pneumonia of all classifications. Rates of methicillin resistance are increasing as clinicians struggle to find ways to prevent the acquisition of methicillin-resistant Staphylococcus aureus (MRSA) and to effectively treat MRSA pneumonia. Community-associated MRSA has been identified as an important subset of MRSA with unique characteristics. Vancomycin remains a recommended first-line therapy for MRSA pneumonia, but resistance and therapeutic failures with vancomycin are being increasingly reported. Factors associated with vancomycin success or failure have been identified, including the genetics of the MRSA isolate, vancomycin lung penetration, minimum inhibitory concentration, and pharmacokinetic and pharmacodynamic variables. Retrospective analyses suggest that linezolid may provide improved outcomes compared with vancomycin for MRSA pneumonia, but validation in a prospective trial is currently lacking. Other treatment options are limited, but new prospects are being investigated. This paper reviews the epidemiology and pharmacotherapy of MRSA pneumonia.     

Prevention of MRSA pneumonia by oral vancomycin decontamination: a randomised trial.

This study was undertaken to assess whether oropharyngeal vancomycin may control oropharyngeal carriage and lower airway infection due to methicillin-resistant Staphylococcus aureus (MRSA) acquired in the intensive care unit (ICU). Secondary endpoints were the emergence of vancomycin-resistant enterococci, vancomycin-intermediate S. aureus and vancomycin consumption. A total of 84 patients, admitted to a medical/surgical ICU and mechanically ventilated for >72 h, were randomly assigned to control (n=42) or test (n=42) group. Both groups received the protocol of selective decontamination of the digestive tract, including polymyxin E, tobramycin and amphotericin B. Patients in the test group received 0.5 g of a 4% vancomycin gel at 6-h intervals in the oropharynx. Lower airway infections due to MRSA acquired on the ICU were reduced in the test group, as was oropharyngeal carriage. Neither vancomycin-resistant enterococci nor vancomycin-intermediate S. aureus were isolated from either surveillance or diagnostic samples during the study period. The vancomycin costs were lower in the test group. This study demonstrates that oropharyngeal vancomycin, which controls intensive care unit-acquired lower airway infections and secondary carriage due to methicillin-resistant Staphylococcus aureus, is cost-effective and safe in terms of vancomycin-resistant enterococci and vancomycin-intermediate Staphylococcus aureus.     

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.     

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.     

Desensitization to co-trimoxazole in a patient with fixed drug eruption

Although co-trimoxazole is a major cause of fixed drug eruption, there are no reports in the literature of desensitization protocols for co-trimoxazole in such patients. We present the case of an 85-year-old woman with a fixed drug eruption to co-trimoxazole. Since she needed co-trimoxazole therapy for treatment of infection of a prosthetic hip by Staphylococcus aureus, she underwent allergy testing with co-trimoxazole and its components sulfamethoxazole and trimethoprim. Allergy tests were all negative and a diagnosis of nonallergic hypersensitivity reaction to co-trimoxazole was made. Based on previous experience, we decided to attempt a desensitization protocol with co-trimoxazole. After 10 days, the patient could receive 800 mg of sulfamethoxazole and 160 mg of trimethoprim twice a day and no adverse reactions were observed. We suggest that desensitization protocols with co-trimoxazole be considered in patients with fixed drug eruption, especially when there are no alternative drugs.     

社区获得性耐甲氧西林金黄色葡萄球菌

社区获得性耐甲氧西林金黄色葡萄球菌是社区感染中重要的致病菌之一,以往由其所致感染多发生在医院环境,如今其引起的社区感染的比例不断上升.自1961年发现第1株耐甲氧西林金黄色葡萄球菌以来,耐甲氧西林金黄色葡萄球菌在世界各地流行并引起暴发流行,耐药程度不断加重.尤其1996年万古霉素不敏感金黄色葡萄球菌及2002年耐万古霉素金黄色葡萄球菌的出现,显示其对人类的威胁愈趋严重,已成为当今感染医学一个难题.本文介绍社区获得性耐甲氧西林金黄色葡萄球菌的流行情况及防治措施.     

Staphylococcus aureus endocarditis in a newborn with transposition of the great arteries: successful treatment

A newborn with transposition of the great arteries developed methicillin-resistant Staphylococcus aureus endocarditis a few days after cardiac catheterization and atrial septostomy performed through the umbilical vein. The association of vancomycin and rifampicin was successful after vancomycin alone proved insufficient.     

Rifampin resistance. Development during the therapy of methicillin-resistant Staphylococcus aureus infection

The incidence of methicillin-resistant staphylococcal infections, for which vancomycin hydrochloride remains the only active cell-wall antibiotic therapy, is rising. Some physicians have been combining other antibiotics with vancomycin in hopes of obtaining a more effective regimen for the therapy of these infections. Rifampin has been advocated as a concurrent second antibiotic because of its extraordinary potent bactericidal activity for Staphylococcus aureus. When rifampin is used in combination with a cell-wall antibiotic, suppression of the development of rifampin resistance has been thought possible. We report a case of infection caused by a methicillin-resistant S aureus in which the rifampin resistance occurred during therapy with vancomycin and rifampin. The rifampin resistance was stable and was present after ten serial broth and agar passages. Physicians are cautioned against the indiscriminant or routine use of rifampin as a second antibiotic in combination with vancomycin for the therapy of infections caused by S aureus.     

Evidence for a continuum of decreased vancomycin susceptibility in unselected Staphylococcus aureus clinical isolates

Some Staphylococcus aureus isolates have glycopeptide minimal inhibitory concentrations (MICs) in the susceptible range but have subpopulations that grow on >or=4 microg/mL vancomycin. Clinical laboratory methods for determining susceptibility have proven to be inadequate for detecting these strains. Among methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) clinical isolates, 149 (66.2%) of 225 and 17 (56.6%) of 30, respectively, grew on brain-heart infusion (BHI) medium containing 2 microg/mL vancomycin; 17 (7.5%) of the MRSA and 2 (6.6%) of the MSSA isolates grew on BHI screening plates containing 4 microg/mL vancomycin. One isolate grew on plates containing 6 microg/mL vancomycin. This isolate escaped detection by routine testing but had a vancomycin MIC of 6 microg/mL when tested in BHI medium. This isolate also had decreased Triton X-100-induced autolysis and killing when incubated in broth media containing vancomycin, properties accorded to glycopeptide-intermediate S. aureus isolates. These observations suggest that glycopeptide-intermediate-like S. aureus isolates are circulating undetected and that a continuum of decreased susceptibility exists in unselected isolates.     

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。     

The effects of salt concentration and growth phase on MRSA solar and germicidal ultraviolet radiation resistance

The extensive use of antimicrobial drugs has led to the widespread emergence of resistant bacterial strains. One such organism, methicillin-resistant Staphylococcus aureus, is now found extensively in both healthcare facilities and diverse community settings such as households, correctional facilities, and athletic teams. The importance of ultraviolet radiation as an adjunctive therapy to reduce bioburden and improve wound status in patients has been documented. An in vitro study to assess the effects of different types of ultraviolet radiation on antibiotic-resistant strains was conducted to provide information that will aid in the development of rational UV irradiation medical protocols. Methicillin-resistant Staphylococcus aureus was found to be sensitive to both germicidal (ultraviolet C) and solar (ultraviolet A and B) ultraviolet radiation (ultraviolet C substantially more lethal). For both types of ultraviolet radiation, as the medium concentration of sodium chloride increased, the methicillin-resistant Staphylococcus aureus cells exhibited increased sensitivity. It also was shown for both types of ultraviolet radiation that kill curves were comparable for log and stationary phase methicillin-resistant Staphylococcus aureus cells. Photoreactivation was observed for Pseudomonas aeruginosa PAO-1 but not for methicillin-resistant Staphylococcus aureus when ultraviolet C was applied to log phase cells. The Gram-negative Pseudomonas aeruginosa PAO-1 was considerably more sensitive than the Gram-positive methicillin-resistant Staphylococcus aureus to ultraviolet C radiation. The experiments reveal that medium composition exerts a substantial effect on methicillin-resistant Staphylococcus aureus ultraviolet resistance and that this species lacks photoreactivation capacity. This suggests that in a clinical setting, eradication of the bacterium may be achieved at far lower doses of ultraviolet radiation than would be indicated by treatment protocols that do not account for ionic conditions.     

Nosocomial infection caused by multidrug-resistant Staphylococcus aureus with reduced susceptibility to vancomycin and teicoplanin.--Yamagata Prefecture, Japan; May 2004-Jun 2005

Nosocomial infection caused by methicillin-resistant Staphylococcus aureus (MRSA) occurred at a major in Yamagata prefecture hospital between May 2004 and June 2005. We studied pulsed-field gel electrophoresis patterns, antimicrobial susceptibility patterns, and bacteriological features, such as coaglase type for eight isolates, including two of methicillin-resistant Staphylococcus epidermidis (MRSE). Our results suggest that this case was caused by a single strain of multidrug-resistant S. aureus. These 8 clinical isolates indicated reduced susceptibility to vancomycin and teicoplanin. PCR assay results for detection of the staphylococcal vanA, vanB, and vanC gene were all negative as all isolates. In transmission electron microscopy, cell walls appeared thicker than those of a susceptible strain from food poisoning. MRSA with reduced susceptibility to glycopeptide antibiotics may not be treated successfully with vancomycin or teicoplanin, making it important to closely observe MRSA with reduced susceptibility to glycopeptide antibiotics.     

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.     

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.     

Relationship between fluoroquinolone area under the curve: minimum inhibitory concentration ratio and the probability of eradication of the infecting pathogen, in patients with nosocomial pneumonia

Our objective was to prospectively determine the factors influencing the probability of a good microbiological or clinical outcome in patients with nosocomial pneumonia treated with a fluoroquinolone. Levofloxacin was administered as an infusion of 500 mg/h for 1.5 h (total dose, 750 mg). For patients with Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus, a second drug was added (ceftazidime or piperacillin/tazobactam for P. aeruginosa and vancomycin for methicillin-resistant S. aureus). Population pharmacokinetic studies of 58 patients demonstrated that this population handled the drug differently from populations of volunteers. Multivariate logistic regression analysis (n=47 patients) demonstrated that only the age of the patient and the achievement of an area under the curve: minimum inhibitory concentration ratio of > or =87 had a significant effect on eradication of the pathogen (P<.001). Achieving the breakpoint made the patient 4 times more likely to achieve eradication. The effect was greatest in patients > or =67 years old.     

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.     

Bacteremia caused by staphylococci with inducible vancomycin heteroresistance.

The clinical significance of bacteremia due to vancomycin-heteroresistant staphylococci and a rapid laboratory screening method were examined; 203 strains of staphylococci isolated from patients with clinically significant bacteremia were screened by the disk-agar method with use of vancomycin-salt agar to demonstrate satellitism around an aztreonam disk as well as by conventional population screening. Eighteen isolates (three Staphylococcus aureus and 15 coagulase-negative staphylococci) were shown to be heteroresistant to vancomycin. A case-control clinical study showed that the interval between admission and bacteremia, admission to the intensive care unit, prior use of vancomycin and/or beta-lactams, and isolation of methicillin-resistant staphylococci were significantly more common among patients with bacteremia due to staphylococci with heteroresistance to vancomycin; these patients had an overall mortality of 44.4%. The use of vancomycin and admission to the intensive care unit were independently significant risk factors on multivariate analysis. Vancomycin heteroresistance is inducible by salt and beta-lactams. Indiscriminate sequential use of beta-lactams and glycopeptides may facilitate the emergence of glycopeptide resistance.     

Treatment failure of methicillin-resistant Staphylococcus aureus endocarditis with linezolid

We report a case of methicillin-resistant Staphylococcus aureus endocarditis treated by vancomycin and cotrimoxazole switched to oral linezolid alone with a complete resolution of the vegetation. Two months after discontinuation of treatment, the patient presented a relapse confirmed by pulsed-field gel electrophoresis involving the same linezolid-susceptible strain and rapidly died.