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.

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.

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.

Methicillin-sensible Staphylococcus aureus causing endocarditis, with cerebral and orthopaedic complications, in a 17-month-old child with no risk factor.

We report a case of Staphylococcus aureus endocarditis, with large vegetation, in a 17-month-old male infant, complicated with meningitis, ischaemic strokes and osteoarthritis leading to haemorrhagic stroke by aneurysm rupture. He did not present any risk factor for endocarditis. The final course was favourable through, after valve replacement. The strain was sensible to methicillin and belongs to complex clonal 398, with accessory gene regulator I. We did not found immunodeficiency.

Diffusion of antibiotics in intervertebral disc.

Delivering charged antibiotics to the intervertebral disc is challenging because of the avascular, negatively charged extracellular matrix (ECM) of the tissue. The purpose of this study was to measure the apparent diffusion coefficient of two clinically relevant, charged antibiotics, vancomycin (positively charged) and oxacillin (negatively charged) in IVD. A one-dimensional steady state diffusion experiment was employed to measure the apparent diffusion coefficient of the two antibiotics in bovine coccygeal annulus fibrosus (AF) tissue. The averaged apparent diffusion coefficient for vancomycin under 20% compressive strain was 7.94 ±â€¯2.00 × 10-12 m2/s (n = 10), while that of oxacillin was 2.26 ±â€¯0.68 × 10-10 m2/s (n = 10). A student's t-test showed that the diffusivity of vancomycin was significantly lower than that of oxacillin. This finding may be attributed to two factors: solute size and possible binding effects. Vancomycin is approximately 3 times larger in molecular weight than oxacillin, meaning that steric hindrance likely plays a role in the slower transport. Reversible binding between positive vancomycin and the negative ECM could also slow down the rate of diffusion. Therefore, more investigation is necessary to determine the specific relationship between net charge on antibiotic and diffusion coefficients in IVD. This study provides essential quantitative information regarding the transport rates of antibiotics in the IVD, which is critical in using computational modeling to design effective strategies to treat disc infection.

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.

Biofilm formation of methicillin-resistant coagulase negative staphylococci (MR-CoNS) isolated from community and hospital environments.

Methicillin-resistant coagulase negative staphylococci (MR-CoNS) are the major cause of infectious diseases because of their potential ability to form biofilm and colonize the community or hospital environments. This study was designed to investigate the biofilm producing ability, and the presence of mecA, icaAD, bap and fnbA genes in MR-CoNS isolates. The MR-CoNS used in this study were isolated from various samples of community environment and five wards of hospital environments, using mannitol salt agar (MSA) supplemented with 4 µg/ml of oxacillin. The specie level of Staphylococcus haemolyticus, Staphylococcus epidermidis, Staphylococcus hominis and Staphylococcus warneri was identified by specific primers of groESL (S. haemolyticus), rdr (S. epidermidis) and nuc (S. hominis and S. warneri). The remainder isolates were identified by tuf gene sequencing. Biofilm production was determined using Congo red agar (CRA) and Microtiter plate (MTP) assay. The mecA and biofilm associated genes (icaAD, fnbA and bap) were detected using PCR method. From the 558 samples from community and hospital environments, 292 MR-CoNS were isolated (41 from community environments, and 251 from hospital environments). S. haemolyticus (41.1%) and S. epidermidis (30.1%) were the predominant species in this study. Biofilm production was detected in 265 (90.7%) isolates by CRA, and 260 (88.6%) isolates were detected by MTP assay. The staphylococci isolates derived from hospital environments were more associated with biofilm production than the community-derived isolates. Overall, the icaAD and bap genes were detected in 74 (29.5%) and 14 (5.6%) of all isolates from hospital environments. When tested by MTP, the icaAD gene from hospital environment isolates was associated with biofilm biomass. No association was found between bap gene and biofilm formation. The MR-CoNS isolates obtained from community environments did not harbor the icaAD and bap genes. Conversely, fnbA gene presented in MR-CoNS isolated from both community and hospital environments. The high prevalence of biofilm producing MR-CoNS strains demonstrated in this study indicates the persisting ability in environments, and is useful in developing prevention strategies countering the spread of MR-CoNS.

Modified tunicamycins with reduced eukaryotic toxicity that enhance the antibacterial activity of ß-lactams.

Tunicamycins (TUN) are inhibitors of the UDP-HexNAc: polyprenol-P HexNAc-1-P transferase family of enzymes, which initiate the biosynthesis of bacterial peptidoglycan and catalyze the first step in eukaryotic protein N-glycosylation. The TUN are therefore general and potent toxins to both eukaryotes and prokaryotes. Screening a library of synthetic TUN against Bacillus and yeast identified TUN that are antibacterial, but have significantly reduced eukaryotic toxicity. One of these (Tun-15:0) differs from the native TUN control only by the lack of the conjugated double bond in the tunicaminyl N-acyl group. Tun-15:0 also showed reduced inhibition for protein N-glycosylation in a Pichia-based bioassay. Natural TUN was subsequently modified by chemically reducing the N-acyl double bond (TunR1) or both the N-acyl and uridyl double bonds (TunR2). TunR1 and TunR2 retain their antibacterial activity, but with considerably reduced eukaryotic toxicity. In protein N-glycosylation bioassays, TunR1 is a less potent inhibitor than native TUN and TunR2 is entirely inactive. Importantly, the less toxic TunR1 and TunR2 both enhance the antibacterial activity of ß-lactams: oxacillin by 32- to 64-fold, comparable with native TUN, and with similar enhancements for methicillin and penicillin G. Hence, the modified TUNs, TunR1 and TunR2, are potentially important as less-toxic synergistic enhancers of the ß-lactams.

Designed positively charged cyclodextrin hosts with enhanced binding of penicillins as carriers for the delivery of antibiotics: The case of oxacillin.

In an effort to identify the optimal cyclodextrin (CD) host for delivery of penicillins to mammalian cells that will also offer protection against ß-lactamase-induced hydrolysis, nuclear magnetic resonance (NMR) spectroscopy and isothermal titration calorimetry (ITC) have been employed to study the inclusion complexes formed in aqueous solution between designed CD derivatives and two aminopenicillins, ampicillin and amoxicillin, and two antistaphylococcal penicillins, methicillin and oxacillin. Anionic and cationic thioether-substituted-ß- and -γCD derivatives were thus synthesized and compared with the neutral, parent CDs for complexation with the penicillins. The synthesized derivatives were shown to present ∼20% elongated cavity space in solution. Moreover, the cationic ones are >98% protonated at physiological pH. The most efficient host was the positively charged octakis[6-(2-aminoethylthio)-6-deoxy]-γ-CD (γCys) that formed the strongest complex with oxacillin (Kb ∼1700M-1) in an enthalpically and entropically favorable process (ΔHb=-10.5kJ/mol,TΔSb=8.0kJ/mol). In vitro biological tests demonstrated that γCys reduces 2.3-fold the rate of hydrolysis of oxacillin in the presence of oxa-1 ß-lactamase while displaying cell crossing capability and efficient internalization into macrophages as well as a sufficiently safe cytotoxicity profile. Overall, γCys could be considered as a promising vehicle for protection and delivery of oxacillin.

Oxacillin magnetically targeted for the treatment of Methicillin-Resistant S. aureus infection in rats.

PURPOSE:: To evaluate the effect of oxacillin bonded to magnetic nanoparticles in local infection model in rat. METHODS:: Twelve Wistar rats weighing 290±18g were randomly divided into four groups (n=6, each) and all rats had a magnet ring sutured on their right thighs. In the biodistribution group rats 0.1mL of 99mTc-magnetite (0.66 MBq) was injected i.v and after 30 minutes, biodistribution of 99mTc-magnetite was evaluated in right and left thighs. The other groups were inoculated with MRSA in each thigh muscles. Group 1 rats were injected i.v. with magnetite, group 2 with Magnetite + Oxacillin, group 3 with saline twice a day. After 24 hours samples of muscle secretion were harvested for microbiological analysis; muscle, lungs and kidneys for histology. RESULTS:: 99mTc-magnetite uptake was three-fold higher in right thigh muscles (with external magnet) than in the left. In magnetite and oxacillin-magnetite groups, bacterial/CFU was significantly lower in thigh muscles than in saline-controls. The inflammatory reaction in muscles and lungs was significantly lower in oxacillin-magnetite group-rats than in other groups (p<0.001) . CONCLUSION:: This study confirms the potential antimicrobial activity of magnetic nanoparticles for Methicillin-Resistant S. aureus strains, which in addition to concentrate the antibiotic at the infection site, positively influenced the treatment.

Synergistic effects of vancomycin and ß-lactams against vancomycin highly resistant Staphylococcus aureus.

We previously reported isolating vancomycin (VAN) highly resistant Staphylococcus aureus (VRSA) strains from clinical methicillin-resistant S. aureus strains by repeating steps of in vitro mutagenesis and VAN selection. Here we describe that the in vitro susceptibility of these VRSA strains to VAN was markedly increased by combined treatment with ß-lactams such as ceftriaxone and oxacillin. Furthermore, in an in vivo silkworm infection model with VRSA, a combination of VAN and ceftriaxone exhibited therapeutic effects, whereas a combination of VAN and oxacillin did not. These findings suggest that combining VAN with an appropriate ß-lactam, such as ceftriaxone, is therapeutically effective against infectious diseases caused by VRSA.

Oxacillin magnetically targeted for the treatment of Methicillin-Resistant S. aureus infection in rats

Abstract Purpose: To evaluate the effect of oxacillin bonded to magnetic nanoparticles in local infection model in rat. Methods: Twelve Wistar rats weighing 290±18g were randomly divided into four groups (n=6, each) and all rats had a magnet ring sutured on their right thighs. In the biodistribution group rats 0.1mL of 99mTc-magnetite (0.66 MBq) was injected i.v and after 30 minutes, biodistribution of 99mTc-magnetite was evaluated in right and left thighs. The other groups were inoculated with MRSA in each thigh muscles. Group 1 rats were injected i.v. with magnetite, group 2 with Magnetite + Oxacillin, group 3 with saline twice a day. After 24 hours samples of muscle secretion were harvested for microbiological analysis; muscle, lungs and kidneys for histology. Results: 99mTc-magnetite uptake was three-fold higher in right thigh muscles (with external magnet) than in the left. In magnetite and oxacillin-magnetite groups, bacterial/CFU was significantly lower in thigh muscles than in saline-controls. The inflammatory reaction in muscles and lungs was significantly lower in oxacillin-magnetite group-rats than in other groups (p<0.001) . Conclusion: This study confirms the potential antimicrobial activity of magnetic nanoparticles for Methicillin-Resistant S. aureus strains, which in addition to concentrate the antibiotic at the infection site, positively influenced the treatment.

Oxacillin disk diffusion testing for the prediction of penicillin resistance in Streptococcus pneumoniae / Prueba de difusión con discos de oxacilina para predecir la resistencia a la penicilina de Streptococcus pneumoniae

ABSTRACT Objective To 1) describe the correlation between the zones of inhibition in 1-µg oxacillin disk diffusion (ODD) tests and penicillin and ceftriaxone minimum inhibitory concentrations (MICs) of meningeal and non-meningeal strains of Streptococcus pneumoniae and 2) evaluate the usefulness of the ODD test as a predictor of susceptibility to penicillin in S. pneumoniae and as a quick and cost-effective method easily implemented in a routine clinical laboratory setting. Methods S. pneumoniae isolates from healthy nasopharyngeal carriers less than 2 years old, obtained in a multicentric cross-sectional study conducted in various Peruvian hospitals and health centers from 2007 to 2009, were analyzed. Using Clinical and Laboratory Standards Institute (CLSI) breakpoints, the correlation between the zones of inhibition of the ODD test and the MICs of penicillin and ceftriaxone was determined. Results Of the 571 S. pneumoniae isolates, 314 (55%) showed resistance to penicillin (MIC ≥ 0.12 µg/mL) and 124 (21.7%) showed resistance to ceftriaxone (MIC ≥ 1 µg/mL). Comparison of the ODD test zones of inhibition and the penicillin MICs, using the CLSI meningeal breakpoints, showed good correlation (Cohen’s kappa coefficient = 0.8239). Conclusions There was good correlation between ODD zones of inhibition and penicillin meningeal breakpoints but weak correlation between the ODD results and non-meningeal breakpoints for both penicillin and ceftriaxone. Therefore, the ODD test appears to be a useful tool for predicting penicillin resistance in cases of meningeal strains of S. pneumoniae, particularly in low- and middle- income countries, where MIC determination is not routinely available.

RESUMEN Objetivo 1) Describir la correlación entre las zonas de inhibición observadas en la prueba de difusión con discos de oxacilina de 1 µg y la concentración inhibitoria mínima (CIM) de penicilina y ceftriaxona frente a cepas meníngeas y no meníngeas de Streptococcus pneumoniae y 2) evaluar si la prueba de difusión con discos de oxacilina permite predecir la sensibilidad de S. pneumoniae a la penicilina y sirve como método rápido y eficaz en función de los costos, y resulta fácil de aplicar en los laboratorios clínicos ordinarios. Métodos Se analizaron colonias de S. pneumoniae aisladas de la nasofaringe de portadores sanos menores de 2 años obtenidas en un estudio transversal multicéntrico realizado en diversos hospitales y centros de salud del Perú entre los años 2007 y 2009. Se determinó la correlación entre las zonas de inhibición observadas en la prueba de difusión con discos y la CIM de la penicilina y la ceftriaxona utilizando los valores críticos definidos por el Instituto de Estándares Clínicos y de Laboratorio. Resultados De las 571 colonias aisladas de S. pneumoniae, 314 (55 %) presentaron resistencia a la penicilina (CIM ≥ 0,12 µg/ml) y 124 (21,7%), resistencia a la ceftriaxona (CIM ≥ 1 µg/ml). Se observó una buena correlación (coeficiente κ de Cohen = 0,8239) entre las zonas de inhibición de la prueba de difusión con discos y la CIM de la penicilina utilizando los valores críticos del Instituto respecto de las cepas meníngeas. Conclusiones Se encontró una buena correlación entre las zonas de inhibición de la prueba de difusión con discos y los valores críticos de CIM de la penicilina respecto de las cepas meníngeas, pero una correlación débil entre los resultados de la prueba de difusión y los valores críticos tanto de la penicilina como de la ceftriaxona respecto de las cepas no meníngeas. Por consiguiente, la prueba de difusión con discos es un método de utilidad para predecir la resistencia a la penicilina de las cepas meníngeas de S. pneumoniae, en particular en los países de ingresos bajos y medianos, donde no suele ser posible determinar la CIM.

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.

Population Structure and Oxacillin Resistance of Staphylococcus aureus from Pigs and Pork Meat in South-West of Poland.

The genotypes and oxacillin resistance of 420 S. aureus isolates from pigs (n = 203) and pork (n = 217) were analyzed. Among 18 spa types detected in S. aureus from pig t011, t021, t034, t091, t318, t337, and t1334 were the most frequent. Among 30 spa types found in S. aureus isolates from pork t084, t091, t499, t4309, t12954, and t13074 were dominant. The animal S. aureus isolates were clustered into MLST clonal complexes CC7, CC9, CC15, CC30, and CC398 and meat-derived isolates to CC1, CC7, and CC15. Thirty-six MRSA were isolated exclusively from pigs. All MRSA were classified to spa t011 SCCmecV. BORSA phenotype was found in 14% S. aureus isolates from pigs and 10% isolates from pork meat. spa t034 dominated among BORSA from pigs and t091 among meat-derived BORSA. This is the first report on spa types and oxacillin resistance of S. aureus strains from pigs and pork meat in Poland. Besides S. aureus CC9, CC30, and CC398 known to be distributed in pigs, the occurrence of genotype belonging to CC7 in this species has been reported for the first time. To our knowledge it is also the first report concerning CC398 BORSA isolates from pigs and pork meat.

Adjunctive dexamethasone therapy improves lung injury by inhibiting inflammation and reducing RIP3 expression during Staphylococcus aureus pneumonia in mice.

Antibiotic-induced immunopathology associated with the release of bacterial cell wall components has been suggested to contribute to poor outcomes in bacterial pneumonia. Adjunctive systemic glucocorticoid steroid (GC) therapy for pneumonia has been a controversial issue. In the present study, we first found that dexamethasone (2.5 mg/kg/day) in combination with oxacillin was beneficial for improving lung injury in mice inoculated intratracheally with live Staphylococcus aureus, and did not interfere with bacterial clearance. Alleviation of lung injury was evidenced by attenuated lung pathology, reduced total protein levels, soluble receptor for advanced glycation end-products (sRAGE), tumor necrosis factor alpha (TNF-α), and keratinocyte chemoattractant (KC) and interleukin (IL)-6 in bronchoalveolar lavage fluid (BALF). It was further confirmed by inhibition of receptor interacting protein-3 (RIP3) expression in pulmonary tissues. As in the live S. aureus experiments, dexamethasone (2.5 mg/kg/day) improved lung injury in mice challenged with heat-killed S. aureus (HKSA). In conclusion, our results demonstrated that an appropriate dose of adjunctive dexamethasone (2.5 mg/kg/day) with oxacillin alleviated experimental S. aureus-induced lung injury via its inhibition of inflammatory cytokine release and RIP3 expression.

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.