Mupirocin Research Articles

Characterization of Isoleucyl-tRNA Synthetase from Staphylococcus aureus: II. MECHANISM OF INHIBITION BY REACTION INTERMEDIATE AND PSEUDOMONIC ACID ANALOGUES STUDIED USING TRANSIENT AND STEADY-STATE KINETICS

The interactions of isoleucyl-tRNA synthetase (IleRS, E) from Staphylococcus aureus with both intermediate analogues and pseudomonic acid (PS-A) have been investigated using transient and steady-state techniques. Non-hydrolyzable analogues of isoleucyl-AMP (I) were simple competitive inhibitors (Ile-ol-AMP, Ki = 50 nM and Ile-NHSO2-AMP, Ki = 1 nM;). PS-A (J) inhibits IleRS via a slow-tight binding competitive mechanism where E.J (Kj = approximately 2 nM), undergoes an isomerization to form a stabilized E*.J complex (K*j = 50 pM). To overcome tight-binding artifacts when K*j << [E], K*j values were estimated from PPi/ATP exchange where [S] >> Km, thus raising K*j,app well above [E]. Using [3H]PS-A, it was confirmed that binding occurs with 1:1 stoichiometry and is reversible. Formation of inhibitor complexes was monitored directly through changes in enzyme tryptophan fluorescence. For Ile-ol-AMP and Ile-NHSO2-AMP, the fluorescence intensity of E.I was identical to that when E.Ile-AMP forms catalytically. Binding of PS-A induced only a small change in IleRS fluorescence that was characterized using transient kinetic competition. SB-205952, a PS-A analogue, produced a 37% quenching of IleRS fluorescence upon binding as a result of radiationless energy transfer. Inhibitor reversal rates were obtained by measuring relaxation between spectroscopically different complexes. Together, these data represent a comprehensive solution to the kinetics of inhibition by these compounds.

In vitro susceptibility of S. aureus against mupirocin

In vitro susceptibility of S. aureus against mupirocin

Effect of mupirocin (MUP) nasal ointment on surgical site infection (SSI)-related hospital stay

Effect of mupirocin (MUP) nasal ointment on surgical site infection (SSI)-related hospital stay

New Drugs: New Formulations: Mupirocin

New Drugs: New Formulations: Mupirocin

Use of ion chromatography as an alternative method for the analysis of calcium in calcium mupirocin

Ion chromatography was investigated as an alternative technique to atomic absorption for the determination of calcium in calcium mupirocin drug substance (calcium pseudomonate dihydrate). The analytical method was evaluated by generating data on the parameters of specificity, linearity, precision, accuracy, sensitivity, robustness and stability of solution. The validation exercise shows that ion chromatography is a viable alternative to atomic absorption for the analysis of counter-ions in mupirocin.

Methicillin-resistant Staphylococcus aureus outbreak: A consensus panel's definition and management guidelines

To provide medical personnel with a definition of an outbreak of methicillin-resistant Staphylococcus aureus (MRSA) and guidelines for managing potential outbreaks. Eighteen panel members were chosen from different specialties, types of institutions, and geographic regions. Representatives from the American Society of Consultant Pharmacists, the American Society of Health-Systems Pharmacists, the Society for Healthcare Epidemiology of America, and the National Association of Directors of Nursing Administration participated. In preparation for the conference, panel members reviewed the literature and wrote abstracts outlining their personal opinions on the core issues, which were circulated to all participants. During a weekend conference, the panel summarized the reviewed literature, defined an MRSA outbreak, and developed management guidelines. Published literature, clinical experience, and expert opinion concerning the emergence and subsequent management of MRSA cases in health care institutions. An outbreak of MRSA was defined as either an increase in the rate of MRSA cases or a clustering of new cases due to the transmission of a single microbial strain in the health care institution. An increased rate of cases can be defined statistically or experientially and includes both infected and colonized patients. A potential outbreak should trigger stepwise, multidisciplinary actions consisting of basic epidemiologic procedures (phase I) to form an initial epidemiologic hypothesis of an outbreak (phase II) followed by a standard epidemiologic workup (phase III) and microbiologic studies (phase IV) to confirm the hypothesis. Mupirocin calcium treatments should be considered to decolonize health care workers during the fourth phase, even before typing is completed. Until studies can be conducted to delineate the effectiveness of different recommendations, the proposed guidelines may provide a useful starting point that can be adapted to meet an individual institution's specific needs.

Biosynthesis and regulation of coronatine, a non-host-specific phytotoxin produced by Pseudomonas syringae.

Many P. syringae pathovars are known to produce low-molecular-weight, diffusible toxins in infected host plants. These phytotoxins reproduce some of the symptoms of the relevant bacterial disease and are effective at very low concentrations. Phytotoxins generally enhance the virulence of the P. syringae pathovar which produces them, but are not required for pathogenesis. Genes encoding phytotoxin production have been identified and cloned from several P. syringae pathovars. With the exception of coronatine, toxin biosynthetic gene clusters are generally chromosomally encoded. In several pathovars, the toxin biosynthetic gene cluster also contains a resistance gene which functions to protect the producing strain from the biocidal effects of the toxin. In the case of phaseolotoxin, a resistance gene (argK) has been utilized to engineer phaseolotoxin-resistant tobacco plants. Although P. syringae phytotoxins can induce very similar effects in plants (chlorosis and necrosis), their biosynthesis and mode of action can be quite different. Knowledge of the biosynthetic pathways to these toxins and the cloning of the structural genes for their biosynthesis has relevance to the development of new bioactive compounds with altered specificity. For example, polyketides constitute a huge family of structurally diverse natural products including antibiotics, chemotherapeutic compounds, and antiparasitics. Most of the research on polyketide synthesis in bacteria has focused on compounds synthesized by Streptomyces or other actinomycetes. It is also important to note that it is now possible to utilize a genetic rather than synthetic approach to biosynthesize novel polyketides with altered biological properties (Hutchinson and Fujii, 1995; Kao et al., 1994; Donadio et al., 1993; Katz and Donadio, 1993). Most of the reprogramming or engineering of novel polyketides has been done using actinomycete PKSs, but much of this technology could also be applied to polyketides synthesized by Pseudomonas when sufficient sequence information is available. It is important to note that Pseudomonas produces a variety of antimicrobial compounds from the polyketide pathway, including mupirocin (pseudomonic acid) (Feline et al., 1977), pyoluteorin (Cuppels et al., 1986), and 2-4 diacetylphloroglucinol (Phl) (Bangera and Thomashow, 1996). Pseudomonic acid is valued for its pharmaceutical properties as an antibiotic (Aldridge, 1992), whereas pyoluteorin and Phl have antifungal properties (Howell and Stipanovic, 1980; Keel et al., 1992). A thorough understanding of the biosynthetic pathway to polyketide phytotoxins such as coronatine may ultimately lead to the development of novel compounds with altered biological properties. Thus, specific genes in the biosynthetic pathways of P. syringae phytotoxins could be deployed in other systems to develop new compounds with a wide range of activities.

New approaches to reduce Staphylococcus aureus nosocomial infection rates: treating S. aureus nasal carriage.

Nosocomial infections cause significant patient morbidity and mortality. The 2.5 million nosocomial infections that occur each year cost the US healthcare system $5 million to $10 million. Staphylococcus aureus has long been recognized as an important pathogen in human disease and is the most common cause of nosocomial infections. To describe the epidemiology of S. aureus nosocomial infections that are attributable to patients' endogenous colonization. Review of the English-language literature and a MEDLINE search (as of September 1997). The ecologic niche of S. aureus is the anterior nares. The prevalence of S. aureus nasal carriage is approximately 20-25%, but varies among different populations, and is influenced by age, underlying illness, race, certain behaviors, and the environment in which the person lives or works. The link between S. aureus nasal carriage and development of subsequent S. aureus infections has been established in patients on hemodialysis, on continuous ambulatory peritoneal dialysis, and those undergoing surgery. S. aureus nasal carriers have a two-to tenfold increased risk of developing S. aureus surgical site or intravenous catheter infections. Thirty percent of 100% of S. aureus infections are due to endogenous flora and infecting strains were genetically identical to nasal strains. Three treatment strategies may eliminate nasal carriage: locally applied antibiotics or disinfectants, systemic antibiotics, and bacterial interference. Among these strategies, locally applied or systemic antibiotics are most commonly used. Nasal ointments or sprays and oral antibiotics have variable efficacy and their use frequently results in antimicrobial resistance among S. aureus strains. Of the commonly used agents, mupirocin (pseudomonic acid) ointment has been shown to be 97% effective in reducing S. aureus nasal carriage. However, resistance occurs when the ointment has been applied for a prolonged period over large surface areas. Given the importance of S. aureus nosocomial infections and the increased risk of S. aureus nasal carriage in patients with nosocomial infections, investigators need to study cost-effective strategies to prevent certain types of nosocomial infections or nosocomial infections that occur in specific settings. One potential strategy is to decrease S. aureus nasal carriage among certain patient populations.

ChemInform Abstract: The Chemistry of Pseudomonic Acid. Part 18. Heterocyclic Replacement of the α,β‐Unsaturated Ester: Synthesis, Molecular Modeling, and Antibacterial Activity.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Novel derivatives of pseudomonic acid

Abstract The synthesis of a new series of pseudomonic acid analogs is described. The synthetic approach is based on replacement of the C9C14 sidechain of the parent molecule with a modified amino substituent. The most potent member of the compound series contains a 3-chloropropyl sulfonamide moiety at the C-8 position.

Intranasal mupirocin for outbreaks of methicillin-resistant Staphylococcus aureus.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of mupirocin are reviewed. Mupirocin is a naturally occurring antibiotic produced by submerged fermentation of Pseudomonas fluorescens. It inhibits bacterial protein synthesis by binding reversibly and specifically to isoleucyl-tRNA synthetase. Organisms resistant to other antimicrobials are not simultaneously resistant to mupirocin. Mupirocin is highly active against Staphylococcus aureus and other staphylococci and streptococci. When mupirocin ointment is applied topically, local concentrations exceed the inhibitory concentrations for staphylococci and remain detectable for up to 72 hours. Placebo-controlled studies demonstrate the ability of mupirocin to eliminate nasal carriage of S. aureus in health care workers. Observational studies suggest that mupirocin is efficacious in treating methicillin-resistant S. aureus (MRSA) outbreaks. Preliminary studies show that mupirocin might have a role in preventing infections in high-risk patients. Although mupirocin seems to be well tolerated, mild to moderate adverse events have been reported, including respiratory problems and effects confined to the nose--erythema, swelling, burning or stinging, pruritus, and dryness. Mupirocin calcium ointment has FDA-approved labeling for the eradication of nasal MRSA colonization in adult patients and health care workers as part of comprehensive infection-control programs to reduce the risk of infection during institutional outbreaks. The recommended dosage is 0.5 g inserted into each nostril twice daily for five days. Intranasal mupirocin ointment appears to be a useful addition to infection-control programs designed to reduce the risk of infection among patients during MRSA outbreaks.

The chemistry of pseudomonic acid. 18. Heterocyclic replacement of the alpha,beta-unsaturated ester: synthesis, molecular modeling, and antibacterial activity.

The electronic requirements around the C1-C3 region of pseudomonic acid analogues were investigated. Synthetic routes were developed to access a range of compounds where the alpha, beta-unsaturated ester moiety had been replaced by a 5-membered ring heterocycle. The inhibition of isoleucyl tRNA synthetase from Staphylococcus aureus NCTC 6571 was determined as was the minimum inhibitory concentration (MIC) of the test compounds against that organism. Compounds possessing a region of electrostatic potential corresponding to that of the carbonyl group in the alpha, beta-unsaturated ester, and a low-energy unoccupied molecular orbital in the region corresponding to the double bond, were found to have IC50 values of 0.7-5.3 ng mL-1. However the MIC values of these compounds were in the range 2.0-8.0 micrograms mL-1, reflecting their poorer penetration into the bacterial cell.

Characterization of the stringent and relaxed responses of Streptococcus equisimilis.

The 739-codon rel(Seq) gene of Streptococcus equisimilis H46A is bifunctional, encoding a strong guanosine 3',5'-bis(diphosphate) 3'-pyrophosphohydrolase (ppGppase) and a weaker ribosome-independent ATP:GTP 3'-pyrophosphoryltransferase [(p)ppGpp synthetase]. To analyze the function of this gene, (p)ppGpp accumulation patterns as well as protein and RNA synthesis were compared during amino acid deprivation and glucose exhaustion between the wild type and an insertion mutant carrying a rel(Seq) gene disrupted at codon 216. We found that under normal conditions, both strains contained basal levels of (p)ppGpp. Amino acid deprivation imposed by pseudomonic acid or isoleucine hydroxamate triggered a rel(Seq)-dependent stringent response characterized by rapid (p)ppGpp accumulation at the expense of GTP and abrupt cessation of net RNA accumulation in the wild type but not in the mutant. Tetracycline added to block (p)ppGpp synthesis caused the accumulated (p)ppGpp to degrade rapidly, with a concomitant increase of the GTP pool (decay constant of ppGpp, approximately 0.7 min(-1)). Simultaneous addition of pseudomonic acid and tetracycline to mimic a relaxed response caused wild-type RNA synthesis to proceed at rates approximating those seen under either condition in the mutant. Glucose exhaustion provoked the (p)ppGpp accumulation response in both the wild type and the rel(Seq) insertion mutant, consistent with the block of net RNA accumulation in both strains. Although the source of (p)ppGpp synthesis during glucose exhaustion remains to be determined, these findings reinforce the idea entertained previously that rel(Seq) fulfils functions that reside separately in the paralogous reL4 and spoT genes of Escherichia coli. Analysis of (p)ppGpp accumulation patterns was complicated by finding an unknown phosphorylated compound that comigrated with ppGpp under two standard thin-layer chromatography conditions. Unlike ppGpp, this compound did not adsorb to charcoal and did not accumulate appreciably during isoleucine deprivation. Like ppGpp, the unknown compound did accumulate during energy source starvation.

ChemInform Abstract: The Chemistry of Pseudomonic Acid. Part 17. Dual‐Action C‐1 Oxazole Derivatives of Pseudomonic Acid Having an Extended Spectrum of Antibacterial Activity.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Cost-Effectiveness of Perioperative Mupirocin Nasal Ointment in Cardiothoracic Surgery

AbstractObjective:To assess the cost-effectiveness of perioperative intranasal application of mupirocin calcium ointment in cardiothoracic surgery.Design:Cost-effectiveness analysis based on results of an intervention study with historical controls.Setting:University Hospital Rotterdam, a tertiary referral center for cardiac and pulmonary surgery.Patients:Consecutive patients undergoing cardiothoracic surgery between August 1, 1989, and February 1, 1991 (control group, n=928), and between March 1, 1991, and August 1, 1992 (intervention group, n=868).Intervention:Perioperative nasal application of mupirocin calcium ointment started on the day before surgery, continued for 5 days, twice daily.Results:Postoperative costs were increased significantly in patients with a surgical-site infection (SSI), compared with uninfected patients (P&lt;.001). Mean SSI-attributable costs were estimated at $16,878 (95% confidence interval, $15,575-$18,181). The incidence of SSIs was 7.3% in the control group and 2.8% in the intervention group, mupirocin effectiveness being 62%. The costs of mupirocin were $11 per patient. Thus, the savings per SSI prevented were $16,633. To validate this comparative estimate of SSI-attributable costs, a noncomparative analysis of the postoperative length of stay (POLS) was performed, according to the Appropriateness Evaluation Protocol. Approximately 50% of the comparative SSI-attributable POLS were judged SSI-attributable in the noncomparative analysis. Sensitivity analyses, testing for the robustness of our conclusions, indicated that the presented model is rather insensitive to variations in the incidence of SSIs and for the effectiveness and costs of mupirocin. SSI-attributable costs were shown to be the only variable with substantial effect on the cost-effectiveness ratio. Perioperative mupirocin would result in net costs instead of savings only if SSI-attributable costs were less than $245.Conclusions:SSIs in patients undergoing cardiothoracic surgery are associated with a substantial increase in postoperative costs. Provided that perioperative mupirocin reduces the SSI rate, this measure will be highly cost-effective in most centers providing cardiothoracic surgical services.

Patent Evaluation Anti-infectives: Derivatives of pseudomonic acid with antibacterial action

Patent Evaluation Anti-infectives: Derivatives of pseudomonic acid with antibacterial action

Nasal Mupirocin and Recurrent Staph Infections

While topical nasal mupirocin can effectively eradicate nasal Staphylococcus aureus, little is known of its value for preventing skin infections. This

ChemInform Abstract: Chemistry of Pseudomonic Acid (VIII). Part 15. Synthesis and Antibacterial Activity of a Series of 5‐Alkyl, 5‐Alkenyl, and 5‐ Heterosubstituted Oxazoles.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Clinical and economic effects of mupirocin calcium on preventing Staphylococcus aureus infection in hemodialysis patients: A decision analysis

This study was performed to determine the clinical and economic consequences of alternative strategies of preventing Staphylococcus aureus infection in chronic hemodialysis patients by use of intranasal mupirocin calcium to clear nasal carriage of S aureus. Decision analysis evaluated clinical outcomes and cost-effectiveness of three likely management strategies to address S aureus nasal carriage and prevent subsequent infection in chronic ambulatory hemodialysis patients: (1) screen for S aureus nasal carriage every 3 months and treat those with a positive test result with mupirocin calcium; (2) treat all patients weekly with mupirocin calcium; or (3) no prevention strategy, treat infection only. Rates of nasal carriage of S aureus, S aureus infection rates, proportion of infections attributable to nasal carriage, efficacy of mupirocin, natural history of infection, and patient management strategies were derived from the published literature and supplemented by a panel of experts. Actual payments for medical services were obtained from Medicare parts A and B. Incremental cost-effectiveness was calculated from the perspective of Medicare and subjected to sensitivity analyses. Assuming that 75% of S aureus infections are attributable to nasal carriage in hemodialysis patients, eliminating nasal carriage of S aureus with mupirocin calcium (with or without screening) markedly reduces the number of infections (45% to 55%) and also reduces health care expenditures relative to treating infections when they occur. Annual savings to Medicare are $784,000 to $1,117,000 per 1,000 hemodialysis patients, depending on the prevention strategy. Preventing S aureus infection by eradicating nasal carriage in chronic hemodialysis patients reduces morbidity while simultaneously reducing medical care costs. The decision to eliminate nasal carriage on a regular basis or use a screening test to guide antibiotic therapy is dependent on the tradeoff between improved short-term clinical and cost benefits and the potential for bacterial resistance that may arise from widespread use of mupirocin calcium.

A randomized trial of staphylococcus aureus prophylaxis in peritoneal dialysis patients: Mupirocin calcium ointment 2% applied to the exit site versus cyclic oral rifampin

The objective of this study was to compare prophylaxis for Staphylococcus aureus infections in peritoneal dialysis patients using 600 mg cyclic oral rifampin for 5 days every 3 months versus mupirocin calcium ointment 2% applied daily to the exit site. The study design was a prospective randomized trial, controlling for S aureus nasal carriage. Eighty-two continuous ambulatory and continuous cyclic peritoneal dialysis patients (54% male, 71% white, 34% insulin-dependent, mean prestudy time on peritoneal dialysis 1.2 years) were randomly assigned to cyclic rifampin (n = 41 patients) or daily exit site mupirocin prophylaxis (n = 41 patients). Mean follow-up was 1 year. S aureus catheter infection rates were 0.13/yr with mupirocin and 0.15/yr with rifampin ( P = NS). Both rates were significantly lower than the center's historical rate (the period between 1983 and 1992) of 0.46/yr prior to the study ( P < 0.001). S aureus peritonitis rates were 0.04/yr with mupirocin and 0.02/yr with rifampin ( P = NS), both significantly lower than the center's historical rate of 0.16/yr ( P < 0.02). Catheter loss due to S aureus infections was 0.02/yr with mupirocin and 0/yr with rifampin ( P = NS), both significantly lower than the center's historical rate of 0.12/yr ( P < 0.001). There were no side effects in patients using mupirocin, but 12% were unable to continue rifampin due to side effects. We conclude that mupirocin ointment at the exit site and cyclic oral rifampin are equally effective in reducing S aureus catheter infections. In addition, rifampin or mupirocin significantly reduced S aureus peritonitis and catheter loss due to S aureus infections. Mupirocin at the exit site provides an excellent alternative prophylaxis for S aureus infections, particularly in patients who cannot tolerate oral rifampin therapy.