Disproportionality Analysis of Safety with Nafcillin and Oxacillin with the FDA Adverse Event Reporting System (FAERS).

Antistaphylococcal penicillins such as nafcillin and oxacillin are among the first choices of treatment for severe invasive methicillin-susceptible Staphylococcus aureus (MSSA) infections, although there has been limited safety evaluations between individual agents. Using the FDA Adverse Event Reports System (FAERS), oxacillin was observed to have a lower proportion of reports of acute renal failure (reporting odds ratio [ROR], 5.3 [95% confidence interval {CI}, 3.1 to 9.3] versus 21.3 [95% CI, 15.8 to 28.6], respectively) and hypokalemia (ROR, 0.7 [95% CI, 0.1 to 4.8] versus 11.4 [95% CI, 7.1 to 18.3], respectively) than nafcillin.

Sub-inhibitory concentrations of oxacillin modify the expression of agr locus in Staphylococcus aureus clinical strains belonging to different clonal complexes.

BACKGROUND: The ability of Staphylococcus aureus to invade tissues and cause an infectious disease is the result of a multi-factorial process supported by the huge number of virulence factors inherent to this microorganism tightly regulated by the accessory gene regulator (agr). During antimicrobial therapy bacteria may be exposed to sub-inhibitory concentrations (subMICs) of antibiotics that may trigger transcriptional changes that may have an impact on the pathogenesis of infection. The objective of this study was to investigate the effect of oxacillin sub-MICs on agr system expression as the key component in the regulation of virulence in methicillin-susceptible (MSSA) and -resistant S. aureus (MRSA) strains. Furthermore, we studied the genetic basis of the agr locus and their potential association with the expression levels. METHODS: We have examined the expression of RNAIII and agrA mRNA as biomarkers for agr expression in the presence and absence of oxacillin subMICs in 10 MSSA and 4 MRSA clinical strains belonging to 5 clonal complexes (CC45-agrI, CC8-agrI, CC5-agrII, CC15-agrII and CC30-agrIII) causing endovascular complications. The DNA sequences of agr locus were obtained by whole genome sequencing. RESULTS: Our results revealed that exposure to subMICs of oxacillin had an impact on agr locus expression modifying the relative levels of expression with increases in 11 strains and with decreases in 3 strains. Thereby, the exposure to subMICs of oxacillin resulted in higher levels of expression of agr in CC15 and CC45 and lower levels in CC30. We also observed the presence of mutations in agrC and agrA in 13/14 strains with similar mutation profiles among strains within individual CCs except for strains of CC5. Although, agr expression levels differed among strains within CCs, the presence of these mutations was associated with differences in agr expression levels in most cases. CONCLUSIONS: Changes in agr expression induced by exposure to oxacillin subMICs should be considered because they could lead to changes in the virulence modulation and have an adverse effect on the course of infection, especially in certain clonal complexes.

Phenotypic and genotypic characterisation of multiple antibiotic-resistant Staphylococcus aureus exposed to subinhibitory levels of oxacillin and levofloxacin.

BACKGROUND: The emergence and spread of multidrug resistant methicillin-resistant Staphylococcus aureus (MDR-MRSA) has serious health consequences in the presence of sub-MIC antibiotics. Therefore, this study was designed to evaluate ß-lactamase activity, efflux activity, biofilm formation, and gene expression pattern in Staphylococcus aureus KACC 10778, S. aureus ATCC 15564, and S. aureus CCARM 3080 exposed to sublethal concentrations of levofloxacin and oxacillin. RESULTS: The decreased MICs were observed in S. aureus KACC and S. aureus ATCC when exposed to levofloxacin and oxacillin, while and S. aureus CCARM remained resistance to streptomycin (512 µg/mL) in the presence of levofloxacin and imipenem (>512 µg/mL) in the presence of oxacillin. The considerable increase in extracellular and membrane-bound ß-lactamase activities was observed in S. aureus ATCC exposed to oxacillin (>26 µmol/min/mL). The antibiotic susceptibility of all strains exposed to EPIs (CCCP and PAßN) varied depending on the classes of antibiotics. The relative expression levels of adhesion-related genes (clfA, clfB, fnbA, fnnB, and icaD), efflux-related genes (norB, norC, and qacA/B), and enterotoxin gene (sec) were increased more than 5-fold in S. aureus CCARM. The eno and qacA/B genes were highly overexpressed by more than 12- and 9-folds, respectively, in S. aureus CCARM exposed to levofloxacin. The antibiotic susceptibility, lactamase activity, biofilm-forming ability, efflux activity, and gene expression pattern varied with the intrinsic antibiotic resistance of S. aureus KACC, S. aureus ATCC, and S. aureus CCARM exposed to levofloxacin and oxacillin. CONCLUSIONS: This study would provide useful information for better understating of combination therapy related to antibiotic resistance mechanisms and open the door for designing effective antibiotic treatment protocols to prevent excessive use of antibiotics in clinical practice.

High-dose continuous oxacillin infusion results in achievement of pharmacokinetics targets in critically ill patients with deep sternal wound infections following cardiac surgery.

Knowledge regarding antimicrobial therapy strategies in deep sternal wound infections (DSWI) following cardiac surgery is limited. Therefore, we aimed to determine the steady-state plasma and mediastinal concentrations of oxacillin administered by continuous infusion in critically ill patients with DSWI and to compare these concentrations with the susceptibility of staphylococci recovered. A continuous infusion of oxacillin (150 to 200 mg/kg of body weight/24 h) was administered after a loading dose (50 mg/kg). Plasma and mediastinal concentrations of total and unbound oxacillin were determined 4 h after the loading dose (H4) and then at day 1 (H24) and day 2 (H48). Twelve patients were included. Nine patients exhibited bacteremia, 5 were in septic shock, 8 were positive for Staphylococcus aureus, and 4 were positive for coagulase-negative staphylococci. The median MIC (first to third interquartile range) was 0.25 (0.24 to 0.41) mg/liter. Median plasma concentrations of total and unbound oxacillin at H4, H24, and H48 were, respectively, 64.4 (41.4 to 78.5) and 20.4 (12.4 to 30.4) mg/liter, 56.9 (31.4 to 80.6) and 21.7 (6.5 to 27.3) mg/liter, and 57.5 (32.2 to 85.1) and 20 (14.3 to 35.7) mg/liter. The median mediastinal concentrations of total and unbound oxacillin at H4, H24, and H48 were, respectively, 2.3 (0.7 to 25.9) and 0.9 (<0.5 to 15) mg/liter, 29.1 (19.7 to 38.2) and 12.6 (5.9 to 19.8) mg/liter, and 31.6 (14.9 to 42.9) and 17.1 (6.7 to 26.7) mg/liter. High-dose oxacillin delivered by continuous infusion is a valuable strategy to achieve our pharmacokinetic target (4× MIC) at the site of action at H24. But concerns remain in cases of higher MICs, emphasizing the need for clinicians to obtain the MICs for the bacteria and to monitor oxacillin concentrations, especially the unbound forms, at the target site.

Bioluminescence and 19F magnetic resonance imaging visualize the efficacy of lysostaphin alone and in combination with oxacillin against Staphylococcus aureus in murine thigh and catheter-associated infection models.

Staphylococci are the leading cause of hospital-acquired infections worldwide. Increasingly, they resist antibiotic treatment owing to the development of multiple antibiotic resistance mechanisms in most strains. Therefore, the activity and efficacy of recombinant lysostaphin as a drug against this pathogen have been evaluated. Lysostaphin exerts high levels of activity against antibiotic-resistant strains of Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA). The therapeutic value of lysostaphin has been analyzed in two different clinically relevant in vivo models, a catheter-associated infection model and a thigh infection model. We infected mice with luciferase-expressing S. aureus Xen 29, and the efficacies of lysostaphin, vancomycin, oxacillin, and combined lysostaphin-oxacillin were investigated by determining numbers of CFU, detecting bioluminescent signals, and measuring the accumulation of perfluorocarbon emulsion at the site of infection by (19)F magnetic resonance imaging. Lysostaphin treatment significantly reduced the bacterial burden in infected thigh muscles and, after systemic spreading from the catheter, in inner organs. The efficiency of lysostaphin treatment was even more pronounced in combinatorial therapy with oxacillin. These results suggest that recombinant lysostaphin may have potential as an anti-S. aureus drug worthy of further clinical development. In addition, both imaging technologies demonstrated efficacy patterns similar to that of CFU determination, although they proved to be less sensitive. Nonetheless, they served as powerful tools to provide additional information about the course and gravity of infection in a noninvasive manner, possibly allowing a reduction in the number of animals needed for research evaluation of new antibiotics in future studies.

Simultaneous breakdown of multiple antibiotic resistance mechanisms in S. aureus.

In previous studies, the oligo-acyl-lysyl (OAK) C12(ω7)K-ß12 added to cultures of gram-positive bacteria exerted a bacteriostatic activity that was associated with membrane depolarization, even at high concentrations. Here, we report that multidrug-resistant Staphylococcus aureus strains, unlike other gram-positive species, have reverted to the sensitive phenotype when exposed to subminimal inhibitory concentrations (sub-MICs) of the OAK, thereby increasing antibiotics potency by up to 3 orders of magnitude. Such chemosensitization was achieved using either cytoplasm or cell-wall targeting antibiotics. Moreover, eventual emergence of resistance to antibiotics was significantly delayed. Using the mouse peritonitis-sepsis model, we show that on single-dose administration of oxacillin and OAK combinations, death induced by a lethal staphylococcal infection was prevented in a synergistic manner, thereby supporting the likelihood for synergism to persist under in vivo conditions. Toward illuminating the molecular basis for these observations, we present data arguing that sub-MIC OAK interactions with the plasma membrane can inhibit proton-dependent signal transduction responsible for expression and export of resistance factors, as demonstrated for ß-lactamase and PBP2a. Collectively, the data reveal a potentially useful approach for overcoming antibiotic resistance and for preventing resistance from emerging as readily as when bacteria are exposed to an antibiotic alone.

Prevention of orthopedic device-associated osteomyelitis using oxacillin-containing biomineral-binding liposomes.

PURPOSE: To develop novel biomineral-binding liposomes (BBL) for the prevention of orthopedic implant associated osteomyelitis. METHODS: A biomineral-binding lipid, alendronate-tri(ethyleneglycol)-cholesterol conjugate (ALN-TEG-Chol), was synthesized through Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (a versatile click reaction). Mixing with other excipients, the new lipid was used to develop BBL. Thermodynamic behavior was studied by differential scanning calorimetry (DSC). In vitro biomineral-binding potential and kinetics were evaluated on hydroxyapatite (HA, a widely used material for orthopedic implant devices) particles. Oxacillin was encapsulated into BBL and used for in vitro evaluation in preventing Staphylococcus aureus biofilm formation. RESULTS: DSC analysis showed that ALN-TEG-Chol could inhibit the phase transition of liposomes by reducing its cooperativity, yielding liposomes with thermodynamic stability similar to liposomes containing regular cholesterol. BBL showed fast and strong binding ability to HA. Oxacillin-loading BBL demonstrated significantly better preventive efficacy against bacteria colonization when challenged with S. aureus isolate, implying its potential in preventing orthopedic implant associated osteomyelitis. CONCLUSIONS: In this proof of concept study, novel BBL has been successfully developed and validated for reducing the frequency of implantable device-related infections.

Minimum inhibitory concentrations of Staphylococcus aureus recovered from clinical and subclinical cases of bovine mastitis.

Antimicrobials are often used for treatment of bovine mastitis and the possibility of selection for resistant bacteria must be considered. The objectives of this study were to determine the minimum inhibitory concentration of Staphylococcus aureus recovered from cases of clinical and subclinical bovine mastitis, and to determine the prevalence of multidrug resistance in this population. Milk samples were collected from cows on commercial dairy herds (n=13), including quarters (n=1,574) of cows with subclinical mastitis cases, and cows experiencing clinical mastitis cases (n=608). Selected Staph. aureus isolates, obtained from clinical (n=58) and subclinical (n=58) mastitis cases, were used to determine minimum inhibitory concentrations of 12 selected antimicrobials. Of Staph. aureus isolates tested, 87 (75%) did not exhibit resistance to any antimicrobial, 28 (24.1%) exhibited resistance to 1 (n=21) or 2 (n=7) classes of antimicrobials, and 1 (0.9%) exhibited multidrug resistance. All Staph. aureus (clinical and subclinical cases) were inhibited by the range of concentrations tested for ceftiofur and oxacillin. Moreover, no isolates obtained from clinical mastitis cases exhibited resistance to cephalothin, penicillin-novobiocin, or sulfadimethoxine. Of isolates, 3 exhibited resistance to enrofloxacin. Of isolates exhibiting resistance to more than 1 antimicrobial, independent of antimicrobial class, the combination of erythromycin and tetracycline, and ampicillin and penicillin accounted for the majority of resistance. Of isolates tested, 19% were resistant to tetracycline and 14% were resistant to penicillin. Survival curves of Staph. aureus relative to minimum inhibitory concentration demonstrated heterogeneity among case types for ceftiofur, cephalothin, and erythromycin. Multidrug resistance was identified in only 1 isolate obtained from a single farm.

Septic arthritis: monitoring with USPIO-enhanced macrophage MR imaging.

PURPOSE: To prospectively evaluate in vivo noninvasive monitoring of antibiotic therapy in experimental infectious arthritis by imaging macrophages by using magnetic resonance (MR) imaging enhanced with ultrasmall superparamagnetic iron oxide (USPIO) particles. MATERIALS AND METHODS: The institutional review committee on animal care approved the experimental protocol. Unilateral knee infection was induced by intra-articular injection of Staphylococcus aureus in 12 rabbits. Each rabbit underwent MR imaging before and after injection of USPIO particles, as well as before and after injection of gadoterate meglumine. All 12 of the animals were imaged during the acute phase of infection. Half were then sacrificed to obtain histopathologic samples, and the other half were imaged a second time after antibiotic treatment. MR imaging data were analyzed and compared with bacteriologic and histopathologic findings. RESULTS: In acute infections, intense synovitis with marked signal intensity increase of the synovium on gadoterate dimeglumine-enhanced fat-suppressed T1-weighted images was observed in all animals and was associated with areas of signal intensity loss within the infected synovium on USPIO-enhanced T2*-weighted gradient-echo images, reflecting an intense infiltration of USPIO-loaded macrophages. After antibiotic treatment and histologic evidence of healing infection, less synovial signal intensity loss was seen (P = .03). In contradistinction, the signal intensity increase on gadoterate dimeglumine-enhanced fat-suppressed T1-weighted images remained unchanged. CONCLUSION: In contrast to conventional MR imaging performed by using extracellular contrast agents, USPIO-enhanced macrophage MR imaging can demonstrate resolution of experimental bacterial joint infection.

In vitro potentiation of ampicillin, oxacillin, norfloxacin, ciprofloxacin, and vancomycin by sanguinarine against methicillin-resistant Staphylococcus aureus.

Few new drugs are available against methicillin-resistant Staphylococcus aureus (MRSA), because MRSA has the ability to acquire resistance to most antibiotics, which consequently increases the cost of medication. The objective of this study is to evaluate the potentiation of sanguinarine (SN) with selected antibiotics (ampicillin [AC], oxacillin [OX], norfloxacin [NR], ciprofloxacin [CP], and vancomycin [VC]) against MRSA. Minimum inhibitory concentration was determined by using the broth microdilution method and the synergistic effect of AC, OX, NR, CP, and VC in combination with SN was examined by the checkerboard dilution test. The results of the checkerboard test suggested that all combinations exhibited some synergy, partial synergy, or additivity. None of the combinations showed an antagonism effect. The combination of SN plus CP exhibited maximum synergistic effect in 11/13 strains, followed by SN plus NR in 9/13 strains, and AC and OX in 7/13 strains each. The combination of SN with VC, however, mostly showed partial synergy in 11/13 strains. The time-kill assay showed that SN in combination with other antibiotics reduced the bacterial count by 10(2)-10(3) colony forming units after 4 h and to less than the lowest detectable limit after 24 h. Although in vivo synergy and clinical efficacy of SN cannot be predicted, it can be concluded that SN has the potential to restore the effectiveness of the selected antibiotics, and it can be considered in an alternative MRSA treatment.

Antibiotic treatment schemes for very severe community-acquired pneumonia in children: a randomized clinical study.

OBJECTIVE: To compare clinical response to initial empiric treatment with oxacillin plus ceftriaxone and amoxicillin plus clavulanic acid in hospitalized children diagnosed with very severe community-acquired pneumonia (CAP). METHODS: A prospective randomized clinical study was conducted among children 2 months to 5 years old with a diagnosis of very severe CAP in the pediatric ward of São Paulo State University Hospital in Botucatu, São Paulo, Brazil, from April 2007 to May 2008. Patients were randomly divided into two groups by type of treatment: an oxacillin/ceftriaxone group (OCG, n = 48) and an amoxicillin/clavulanic acid group (ACG, n = 56). Analyzed outcomes were: time to clinical improvement (fever and tachypnea), time on oxygen therapy, length of stay in hospital, need to widen antimicrobial spectrum, and complications (including pleural effusion). RESULTS: The two groups did not differ statistically for age, sex, symptom duration before admission, or previous antibiotic treatment. Time to improve tachypnea was less among ACG patients than OCG patients (4.8 ± 2.2 versus 5.8 ± 2.4 days respectively; P = 0.028), as was length of hospital stay (11.0 ± 6.2 versus 14.4 ± 4.5 days respectively; P = 0.002). There were no statistically significant differences between the two groups for fever improvement time, time on oxygen therapy, need to widen antimicrobial spectrum, or frequency of pleural effusion. CONCLUSIONS: Both treatment plans are effective in treating very severe CAP in 2-month-to 5-year-old hospitalized children. The only analyzed outcome that favored amoxicillin/clavulanic acid treatment was time required to improve tachypnea. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01166932.

Treatment of a Large Multiloculated Liver Abscess with Intra-Abscess Antibiotic Instillation.

This report describes a 15-year-old with an 11.1 × 8.2 × 8.4 cm multiloculated liver abscess caused by methicillin-sensitive Staphylococcus aureus who failed extensive catheter drainage and intravenous antibiotics. Daily intra-abscess oxacillin was instilled for 7 days with rapid clinical improvement and sterilization of the abscess. One month later, an ultrasound of the abdomen revealed a normal liver.

Synergism between a novel chimeric lysin and oxacillin protects against infection by methicillin-resistant Staphylococcus aureus.

Staphylococcus aureus is the causative agent of several serious infectious diseases. The emergence of antibiotic-resistant S. aureus strains has resulted in significant treatment difficulties, intensifying the need for new antimicrobial agents. Toward this end, we have developed a novel chimeric bacteriophage (phage) lysin that is active against staphylococci, including methicillin-resistant S. aureus (MRSA). The chimeric lysin (called ClyS) was obtained by fusing the N-terminal catalytic domain of the S. aureus Twort phage lysin with the C-terminal cell wall-targeting domain from another S. aureus phage lysin (phiNM3), which displayed Staphylococcus-specific binding. ClyS was expressed in Escherichia coli, and the purified protein lysed MRSA, vancomycin-intermediate strains of S. aureus (VISA), and methicillin-sensitive (MSSA) strains of S. aureus in vitro. In a mouse nasal decolonization model, a 2-log reduction in the viability of MRSA cells was seen 1 h following a single treatment with ClyS. One intraperitoneal dose of ClyS also protected against death by MRSA in a mouse septicemia model. ClyS showed a typical pattern of synergistic interactions with both vancomycin and oxacillin in vitro. More importantly, ClyS and oxacillin at doses that were not protective individually protected synergistically against MRSA septic death in a mouse model. These results strongly support the development of ClyS as an attractive addition to the current treatment options of multidrug-resistant S. aureus infections and would allow for the reinstatement of antibiotics shelved because of mounting resistance.

In vitro and in vivo comparison of the anti-staphylococcal efficacy of generic products and the innovator of oxacillin.

BACKGROUND: Oxacillin continues to be an important agent in the treatment of staphylococcal infections; many generic products are available and the only requirement for their approval is demonstration of pharmaceutical equivalence. We tested the assumption that pharmaceutical equivalence predicts therapeutic equivalence by comparing 11 generics with the innovator product in terms of concentration of the active pharmaceutical ingredient (API), minimal inhibitory (MIC) and bactericidal concentrations (MBC), and antibacterial efficacy in the neutropenic mouse thigh infection model. METHODS: The API in each product was measured by a validated microbiological assay and compared by slope (potency) and intercept (concentration) analysis of linear regressions. MIC and MBC were determined by broth microdilution according to Clinical and Laboratory Standard Institute (CLSI) guidelines. For in vivo efficacy, neutropenic ICR mice were inoculated with a clinical strain of Staphylococcus aureus. The animals had 4.14 +/- 0.18 log10 CFU/thigh when treatment started. Groups of 10 mice per product received a total dose ranging from 2.93 to 750 mg/kg per day administered q1h. Sigmoidal dose-response curves were generated by nonlinear regression fitted to Hill equation to compute maximum effect (Emax), slope (N), and the effective dose reaching 50% of the Emax (ED50). Based on these results, bacteriostatic dose (BD) and dose needed to kill the first log of bacteria (1LKD) were also determined. RESULTS: 4 generic products failed pharmaceutical equivalence due to significant differences in potency; however, all products were undistinguishable from the innovator in terms of MIC and MBC. Independently of their status with respect to pharmaceutical equivalence or in vitro activity, all generics failed therapeutic equivalence in vivo, displaying significantly lower Emax and requiring greater BD and 1LKD, or fitting to a non-sigmoidal model. CONCLUSIONS: Pharmaceutical or in vitro equivalence did not entail therapeutic equivalence for oxacillin generic products, indicating that criteria for approval deserve review to include evaluation of in vivo efficacy.

Species distribution and antimicrobial susceptibility of staphylococci isolated from canine otitis externa.

The diversity of species of the genus Staphylococcus sp. and the antimicrobial resistance of isolates from 151 unmedicated dogs of both sexes with a clinical diagnosis of otitis were recorded. Ninety-one isolates of Staphylococcus spp. were identified by biochemical reactions and tested for susceptibility to 15 antimicrobials. Coagulase-positive species were most common; S. pseudintermedius (38.4%), S. schleiferi schleiferi (15.4%), S. aureus (14.3%), S. epidermidis (11%), S. simulans (11%), S. schleiferi coagulans (8.8%) and S. saprophyticus (1.1%). All the isolates showed resistance to at least one drug and 89% were multiresistant. Amoxicillin combined with clavulanic acid and oxacillin were the most effective, while resistance was widely observed for neomycin and erythromycin. The results highlight the recognition and the potential need for bacterial culture with species identification and antimicrobial susceptibility tests for appropriate antimicrobial therapy.

Evaluation of fosfomycin combined with vancomycin against vancomycin-resistant coagulase negative staphylococci.

The pathogenic potential of coagulase-negative staphylococci (CoNS) is increasingly recognized worldwide. The aim of the present study was to evaluate different combinations of fosfomycin (FOS) with vancomycin (VAN) or oxacillin (OXA) against vancomycin-resistant clinical isolates of CoNS. Characterization of VAN resistance in selected isolates was also sought. Antibiotic susceptibility of isolates was tested by disc diffusion method, MICs of antibiotics were determined by the agar dilution method, and fosfomycin combinations were evaluated by a time-kill assay according to the guidelines of the CLSI. Moreover, oxacillin and glycopeptides (vancomycin and teichoplanin) resistances were also characterized phenotypically and genotypically in this study. Out of 258 staphylococci, 52 were CoNS (20.2%). All isolates were multidrug resistant with 75% (n = 39) oxacillin-resistant, most of them with oxacillin MIC levels of >32 mg/L. Moreover, vancomycin non-susceptibility was observed in 46.2% (n = 24) of the tested isolates with MIC range of 4-32 mg/L. Identification of selected isolates revealed that S. epidermidis was the most abundant among tested CoNS, followed by S. hominis, S. saprophyticus, and interestingly S. caseolyticus. Furthermore, Synergistic and bactericidal effects of FOS + VAN combination were observed in 3 of 9 isolates after 6 h of treatment and in all studied isolates at 24 h. On the other hand, FOS + OXA combinations were ineffective. This study provides evidence that fosfomycin combination with vancomycin could be considered as a therapeutic alternative for CoNS infections. It also sheds some light on the possible emergence of the otherwise harmless bacterium S. caseolyticus as a human pathogen.

Synergistic anti-methicillin-resistant Staphylococcus aureus (MRSA) activity and absolute stereochemistry of 7,8-dideoxygriseorhodin C.

The emergence of antibiotic resistance necessitates not only the identification of new compounds with antimicrobial properties, but also new strategies and combination therapies to circumvent this growing problem. Here, we report synergistic activity against methicillin-resistant Staphylococcus aureus (MRSA) of the ß-lactam antibiotic oxacillin combined with 7,8-dideoxygriseorhodin C in vitro. Ongoing efforts to identify antibiotics from marine mollusk-associated bacteria resulted in the isolation of 7,8-dideoxygriseorhodin C from a Streptomyces sp. strain cultivated from a marine gastropod tissue homogenate. Despite the long history of 7,8-dideoxygriseorhodin C in the literature, the absolute configuration has never been previously reported. A comparison of measured and calculated ECD spectra resolved the configuration of the spiroketal carbon C6, and 2D ROESY NMR spectroscopy established the absolute configuration as 6s,6aS. The compound is selective against Gram-positive bacteria including MRSA and Enterococcus faecium with an MIC range of 0.125-0.5 µg ml-1. Moreover, the compound synergizes with oxacillin against MRSA as observed in the antimicrobial microdilution and time-kill assays. Simultaneous treatment of the compound with oxacillin resulted in an approximately tenfold decrease in MIC with a combination index of <0.5, indicating synergistic anti-MRSA activity.

Continuous versus intermittent infusion of oxacillin for treatment of infective endocarditis caused by methicillin-susceptible Staphylococcus aureus.

Infective endocarditis (IE) is the fourth leading cause of life-threatening infection in the United States and imposes significant morbidity and mortality. The American Heart Association guidelines for the diagnosis and treatment of IE do not address continuous-infusion (CI) oxacillin. This retrospective study compares outcomes between CI oxacillin and intermittent-infusion (II) oxacillin in the treatment of IE caused by methicillin-susceptible Staphylococcus aureus (MSSA). A total of 709 medical records were reviewed for inpatients with definitive IE treated between 1 January 2000 and 31 December 2007. Continuous data were analyzed by Student's t test or the Wilcoxon rank sum test. The chi-square test or Fisher's exact test was used to compare nominal data. A multivariate logistic model was constructed. One hundred seven patients met eligibility criteria for inclusion into the study. Seventy-eight patients received CI oxacillin, whereas 28 received II oxacillin. CI and II groups were similar with respect to 30-day mortality (8% versus 10%, P = 0.7) and length of stay (20 versus 25 days, P = 0.4) but differed in 30-day microbiological cure (94% versus 79%, P = 0.03). Sixty-three patients received synergistic gentamicin, whereas 44 did not. The gentamicin and no-gentamicin groups were similar with respect to 30-day mortality (11% versus 4%, P = 0.2) and 30-day microbiological cure (90% versus 89%, P = 0.8); however, times to defervescence (4 versus 2 days, P = 0.02) were significantly different. CI oxacillin is an effective alternative to II oxacillin for the treatment of IE caused by MSSA and may improve microbiological cure. This convenient and pharmacodynamically optimized dosing regimen for oxacillin deserves consideration for patients with IE caused by MSSA.

Continuous-infusion oxacillin for the treatment of burn wound cellulitis.

BACKGROUND: Burn cellulitis is an infection of the unburned skin at the margin of a burn wound or graft donor site, typically caused by group A beta-hemolytic streptococci and Staphylococcus aureus. beta-Lactam antibiotics exhibit time-dependent killing and, because of their narrow spectrum, minimize bacterial resistance. We therefore use continuous-infusion oxacillin in the treatment of burn cellulitis. METHODS: Patients at a regional burn center who were treated for burn cellulitis from January 2003 to December 2005 were included. Charts were reviewed for all pertinent data regarding the antibiotic treatment methods and outcomes. Successful treatment was defined as resolution of physical findings, fever, and leukocytosis and intravenous antibiotic cessation. RESULTS: Thirty-seven patients were treated for burn cellulitis, 26 (70%) of whom were treated initially with continuous-infusion oxacillin. Other initial antibiotics were chosen because of concomitant infections, penicillin allergy, or development of cellulitis during treatment with a beta-lactam antibiotic. Oxacillin treatment was successful in 19 patients (73%). Success required an average of 5.16 days, with 1.53 days required for fever resolution and 0.89 days for resolution of leukocytosis. Seven patients who did not respond rapidly were switched to intravenous vancomycin an average of 2.4 days after starting oxacillin, leading to a 100% success rate. There were no deaths, and only one suspected case of allergic reaction to oxacillin. In eleven patients treated with other antibiotics, the success rate was 75%. Success with these drugs required a longer treatment course of 6.45 days. Leukocytosis resolved significantly more slowly at 4.45 days (p = 0.02), and fever resolution was also slower at 3.18 days. CONCLUSIONS: Continuous-infusion oxacillin was successful in the treatment of 73% of patients, a success rate that might have been higher with clinical patience, and leukocytosis resolved faster than with other antibiotics. Failure of continuous-infusion oxacillin can be managed without clinical consequence by conversion to intravenous vancomycin.

[Staphylococcic necrotizing pneumopathy due to Panton-Valentine leukocidin toxin with good outcome]. / Pneumopathie nécrosante staphylococcique productrice de leucocidine de Panton-Valentine d'évolution favorable.

Panton-Valentine leukocidin (PLV) is a toxin produced by Staphylococcus aureus. Previously described as responsible for furunculoses and cutaneous abscesses, it was recently found to cause necrotizing pneumonia, generally lethal. We describe a case of necrotizing pneumonia caused by S. aureus containing PLV with an atypical form (bubble form), which had a good outcome despite several risk factors for death: hemoptysis, leukopenia, erythrodermia.