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Supplementation of standard growth media (cation-adjusted Mueller-Hinton Broth [CAMHB]) with bicarbonate (NaHCO3) increases ß-lactam susceptibility of selected methicillin-resistant Staphylococcus aureus (MRSA) strains ("NaHCO3 responsive"). This "sensitization" phenomenon translated to enhanced ß-lactam efficacy in a rabbit model of endocarditis. The present study evaluated NaHCO3-mediated ß-lactam MRSA sensitization using an ex vivo pharmacodynamic model, featuring simulated endocardial vegetations (SEVs), to more closely mimic the host microenvironment. Four previously described MRSA strains were used: two each exhibiting in vitro NaHCO3-responsive or NaHCO3-nonresponsive phenotypes. Cefazolin (CFZ) and oxacillin (OXA) were evaluated in CAMHB with or without NaHCO3 Intra-SEV MRSA killing was determined over 72-h exposures. In both "responsive" strains, supplementation with 25 mM or 44 mM NaHCO3 significantly reduced ß-lactam MICs to below the OXA susceptibility breakpoint (≤4 mg/liter) and resulted in bactericidal activity (≥3-log killing) in the model for both OXA and CFZ. In contrast, neither in vitro-defined nonresponsive MRSA strain showed significant sensitization in the SEV model to either ß-lactam. At both NaHCO3 concentrations, the fractional time above MIC was >50% for both CFZ and OXA in the responsive MRSA strains. Also, in media containing RPMI plus 10% Luria-Bertani broth (proposed as a more host-mimicking microenvironment and containing 25 mM NaHCO3), both CFZ and OXA exhibited enhanced bactericidal activity against NaHCO3-responsive strains in the SEV model. Neither CFZ nor OXA exposures selected for emergence of high-level ß-lactam-resistant mutants within SEVs. Thus, in this ex vivo model of endocarditis, in the presence of NaHCO3 supplementation, both CFZ and OXA are highly active against MRSA strains that demonstrate similar enhanced susceptibility in NaHCO3-supplemented media in vitro.

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Gepotidacin (GSK2140944), a novel triazaacenaphthylene bacterial topoisomerase inhibitor, is currently in clinical development for the treatment of bacterial infections. This study examined in vitro its activity against intracellular Staphylococcus aureus (involved in the persistent character of skin and skin structure infections) by use of a pharmacodynamic model and in relation to cellular pharmacokinetics in phagocytic cells. Compared to oxacillin, vancomycin, linezolid, daptomycin, azithromycin, and moxifloxacin, gepotidacin was (i) more potent intracellularly (the apparent bacteriostatic concentration [Cs ] was reached at an extracellular concentration about 0.7× its MIC and was not affected by mechanisms of resistance to the comparators) and (ii) caused a maximal reduction of the intracellular burden (maximum effect) of about -1.6 log10 CFU (which was better than that caused by linezolid, macrolides, and daptomycin and similar to that caused by moxifloxacin). After 24 h of incubation of infected cells with antibiotics at 100× their MIC, the intracellular persisting fraction was <0.1% with moxifloxacin, 0.5% with gepotidacin, and >1% with the other drugs. The accumulation and efflux of gepotidacin in phagocytes were very fast (kin and kout, ∼0.3 min-1; the plateau was reached within 15 min) but modest (intracellular concentration-to-extracellular concentration ratio, ∼1.6). In cell fractionation studies, about 40 to 60% of the drug was recovered in the soluble fraction and ∼40% was associated with lysosomes in uninfected cells. In infected cells, about 20% of cell-associated gepotidacin was recovered in a sedimentable fraction that also contained bacteria. This study highlights the potential for further study of gepotidacin to fight infections where intracellular niches may play a determining role in bacterial persistence and relapses.

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Introducción. Los Staphylococcus coagulasa negativos (SCN) forman parte de la microbiota humana y están implicados en infecciones de materiales protésicos, dispositivos intravasculares o bacteriemias relacionadas con el catéter. Presentan mayor resistencia que Staphylococcus aureus frente a las diferentes familias de antimicrobianos, y existe un aumento de la morbi-mortalidad de los pacientes cuando se instaura un tratamiento inadecuado. Material y métodos. Analizar los resultados obtenidos mediante diferentes técnicas comerciales: dos sistemas de microdilución automática en placa (MicroScan y Vitek2 Compact), aglutinación de la PBP2a con y sin inducción previa con disco de oxacilina de 1 μg, y detección del gen mecA mediante técnicas de amplificación de ácidos nucleicos, para realizar el diagnóstico de resistencia a meticilina en 170 aislados de SCN provenientes de hemocultivos. Resultados. Se detectó la resistencia a meticilina en las 170 cepas mediante MicroScan, en 167 por Vitek 2 Compact, en 115 mediante PBP2a sin inducción con oxacilina de 1μg y en 168 tras la inducción. Finalmente, se detectó la presencia del gen mecA en 167 cepas mediante amplificación de ácidos nucleicos. Conclusiones. Es necesario realizar una inducción con oxacilina 1μg antes de realizar la detección de PBP2a para evitar falsos negativos. Existe una gran variabilidad fenotípica en la expresión de la resistencia a meticilina en SCN (AU)

Introduction. Coagulase-negative staphylococci (CoNS) take part of the human skin and mucous membranes, but they are also involving in infections with the increasing use of prosthetic, in-dwelling devices or intravascular catheter-related bacteraemia. They are more resistance than Staphylococcus aureus against a wide range of antimicrobial agents, and it have been observed an increase in morbidity and mortality of patients with incorrect treatment. Material and methods. To analyze the results obtained by different commercial techniques: two automatic microdilution systems (MicroScan and Vitek2 Compact), PBP2a agglutination test, with and without 1 μg oxacillin disk induction, and detection of mecA gene by nucleic acids amplification techniques, for the diagnosis of methicillin resistance staphylococci in 170 strains of CoNS isolated from blood cultures. Results. One hundred and seventy methicillin resistance staphylococci were detected by MicroScan, 167 strains by Vitek 2 Compact, 115 strains were PBP2a positive without oxacillin induction and 168 after oxacillin induction. Finally, 167 strains were mecA gene positive detected by nucleic acids amplification techniques. Conclusions. It is necessary to do oxacillin induction before PBP2a test to avoid false negatives. There are a great variability in the phenotypic expression of methicillin resistance in CoNS (AU)

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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.

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PURPOSE: The effects of stress-dose corticosteroid therapy were studied in a canine staphylococcal pneumonia model of septic shock. METHODS: Immediately following intrabronchial bacterial challenge, purpose-bred beagles were treated with stress doses of desoxycorticosterone (DOC), a mineralocorticoid agonist, and dexamethasone (DEX), a glucocorticoid agonist, or with placebo for 96 h. Oxacillin (30 mg/kg every 8 h) was started 4 h after infection onset. Bacterial dose was titrated to achieve 80-90 % lethality (n = 20) using an adaptive design; additional animals (n = 18) were investigated using the highest bacterial dose. RESULTS: Initial analysis of all animals (n = 38) demonstrated that the effects of DOC + DEX were significantly altered by bacterial dose (p = 0.04). The treatment effects of DOC + DEX were different in animals administered high or relatively lower bacterial doses in terms of survival (p = 0.05), shock reversal (p = 0.02), interleukin-6 levels (p = 0.02), and temperature (p = 0.01). DOC + DEX significantly improved the above parameters (p ≤ 0.03 for all) and lung injury scores (p = 0.02) after high-dose bacterial challenges, but not after lower challenges (p = not significant for all). Oxacillin trough levels were below the minimum inhibitory concentration of the infecting organism, and DOC + DEX increased the frequency of persistent staphylococcal bacteremia (odds ratio 3.09; 95 % confidence interval 1.05-9.11; p = 0.04). CONCLUSIONS: Stress-dose corticosteroids were only beneficial in cases of sepsis with high risk for death and even short courses may interfere with host mechanisms of bacterial clearance.

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Methicillin-resistant Staphylococcus aureus (MRSA) strains are major pathogens causing infections of the skin and soft tissues and more serious, life-threatening diseases, including sepsis and necrotizing pneumonia. The vraSR operon encodes the key regulatory system that modulates the stress response of S. aureus elicited upon exposure to cell wall antibiotics. Mutation of vraS and vraR results in decreased oxacillin resistance in vitro. We investigated the effect of oxacillin treatment in experimental models employing a clinical USA300 MRSA strain (strain 923) and an isogenic vraSR deletion mutant (strain 923-M23). In a murine model of S. aureus necrotizing pneumonia, animals were treated with oxacillin, beginning 15 min after inoculation. Among mice infected with mutant strain 923-M23, oxacillin treatment significantly improved survival compared with saline treatment, whereas oxacillin treatment had no effect in mice infected with strain 923. Similarly, treatment with oxacillin decreased the bacterial burden among animals infected with strain 923-M23 but not among animals infected with strain 923. In a murine skin infection model, oxacillin eliminated the development of dermonecrosis among 923-M23-infected mice and decreased the bacterial burden in the lesions, but not among strain 923-infected mice. We conclude that deletion of the vraSR operon allowed an oxacillin regimen to be effective in murine models of MRSA pneumonia and skin infection. These findings provide proof-of-principle for development of a new antibiotic that could restore the usefulness of oxacillin against MRSA by inhibiting VraS or VraR.

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With the current high prevalence of infection caused by methicillin-resistant Staphylococcus aureus (MRSA) strains but in light of the general belief that beta-lactam antibiotics are more effective than vancomycin against infections caused by methicillin-susceptible S. aureus (MSSA) isolates, clinicians may utilize antistaphylococcal penicillins in combination with vancomycin for the empirical treatment of S. aureus infections. Vancomycin is considered to kill MSSA more slowly than oxacillin. Thus, we sought to evaluate the interaction of the combination of oxacillin and vancomycin on bacterial killing in vitro. Ten clinical isolates of MSSA isolated in the year 2000 were investigated. The killing observed at 24 h by vancomycin at 20 microg/ml, oxacillin at 16 microg/ml, or the combination did not differ (approximately 2.5 to 3.5 log10 CFU/ml). In a separate experiment, we assessed bacterial killing in a dynamic model simulating the free plasma concentration profiles expected following the administration of a combination of vancomycin at 1 g every 12 h and oxacillin at 1 g every 6 h. The time-kill profiles of these regimens against S. aureus ATCC 29213 were comparable to those observed in the fixed-concentration experiments. Using these methods, we found no evidence that vancomycin antagonized the bactericidal effect of oxacillin or that there was any benefit from use of the combination.

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Human microsomal prostaglandin E synthase-1 (mPGES-1) is a membrane associated protein that catalyzes the conversion of prostaglandin H(2) (PGH(2)) into prostaglandin E(2) (PGE(2)). In this study, the expression of human mPGES-1 in E. coli was significantly enhanced by modifying the utility of specific codons and the recombinant mPGES-1 was efficiently purified to homogeneity. The K(m) and V(max) of the purified enzyme were determined and the trimeric state characterized by chemical cross-linking with glutaraldehyde. The purified mPGES-1 was used for the screening of a chemical library of bioactive or drug compounds to identify novel inhibitors, and oxacillin and dyphylline were identified as moderately inhibiting mPGES-1 with IC(50) values of 100 and 200 microM, respectively. As these compounds competitively inhibited the catalysis of PGH(2), their binding sites appeared to be located near the PGH2 binding pocket.

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INTRODUCCIÓN. Staphylococcus saprophyticus es una causa frecuente de infección del tracto urinario en mujeres, por lo que es necesario conocer su epidemiología y sensibilidad antibiótica. MÉTODOS. Estudio longitudinal retrospectivo de los urocultivos comunitarios procesados en el Laboratorio de Microbiología del C.E. Argüelles, durante 10 años (1997-2006). RESULTADOS. En 35.136 urocultivos con recuento significativo, se identificaron 331 S. saprophyticus (0,9%); 324 en mujeres y 7 en varones. La edad media de las pacientes infectadas fue 32,7 años. El 83,9% de las cepasse aislaron en mujeres con edades comprendidas entre 15 y 44 años (37 mujeres de este grupo eran gestantes) y en los meses de junio y noviembre se concentraron el mayor número de aislados. Todos los S. saprophyticus fueron sensibles a vancomicina, rifampicina, gentamicina y amoxicilina-ácido clavulánico. Destaca el elevado porcentaje de resistencia a eritromicina (37,7%) (el 96% compatible con fenotipo MSB), que ha ido aumentando desde 1997 de manera significativa (p de tendencia lineal< 0,05). El 1,5% también fue resistente a clindamicina. Únicamente el 0,9% no fue sensible afluorquinolonas. La resistencia a cloranfenicol, cotrimoxazol y penicilina supuso el 3,9, el 6 y el 55,6%, respectivamente. Siguiendo los criterios del Clinical and Laboratory Standards Institute (CLSI) de 2006, el 45% de S. saprophyticus se consideró resistente a oxacilina. CONCLUSIONES. Estos resultados sugieren: primero, debemos pensar en S. saprophyticus ante la infección del tracto urinario (ITU) de mujeres entre 15 y 44 años, incluidas las gestantes, especialmente en primavera y otoño. Segundo, cotrimoxazol puede ser una excelente opción para el tratamiento de estas cistitis en pacientes sin factores de riesgo. Tercero, prácticamente la mitad de S. saprophyticus son considerados resistentes a oxacilina, denegando el beneficio del tratamiento con betalactámicos orales en las ITU. Esta situación es especialmente importante en mujeres gestantes, en las que no se debe emplear cotrimoxazol y quinolonas (grupo C de la Food and Drug Administration [FDA]) y la fosfomicina es resistente in vitro (AU)

INTRODUCTION. Staphylococcus saprophyticus is frequent cause of urinary tract infection in women; hence, it is important to know the epidemiology and antibiotic susceptibility of this microorganism. METHOD. A retrospective longitudinal study was performed in urine specimens from outpatients in our health area cultured in the Microbiology Laboratory of C.E. Argüelles(Madrid, Spain) over a 10-year period (1997-2006). RESULTS. Among 35,136 urine cultures with a significant count, we identified 331 S. saprophyticus (0.9%); 324 in women and 7 in men. Mean age of the infected patients was 32.7 years. A total of 83.9% of the strains were in women aged 15 to 44 years (37 women in this group were pregnant) and the largest numbers of isolates were found during the months of June and November. AllS. saprophyticus strains were susceptible to vancomycin, rifampin, gentamicin and amoxicillin-clavulanic acid. Of note, there was a high percentage of resistance to erythromycin (37.7%) (96% consistent with the MSB phenotype) which has significantly increased since 1997 (P < 0.05); 1.5% were also resistant to clindamycin. Only 0.9% were resistant to fluorquinolones. Resistance tochloramphenicol, trimethoprim/sulfamethoxazole, and penicillin was 3.9%, 6%, and 55.6%, respectively. Based on the 2006 CLSI guidelines, 45% of S. saprophyticus isolates were considered oxacillin-resistant. CONCLUSION. These results suggest the following: First, S. saprophyticus should be considered among agents causing urinary tract infection in women 15 to 44 years old, including pregnant women, particularly during spring and autumn. Second, cotrimoxazole may be an excellent option for treating cystitis in patients without risk factors. Third, almost half of S. saprophyticus strains were considered oxacillin-resistant, there by denying the benefit of treatment with oral beta-lactams in urinary tract infections. This is especially important in pregnant women, who should avoid trimethoprim/sulfamethoxazole and quinolones (FDA Group C), as well as fosfomycin, with in vitro resistance (AU)

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O aumento importante do número de infecções causadas por bactérias Gram-positivas e o surgimento de resistência aos antibióticos destinados a tratar estas infecções são motivos de preocupação das autoridades internacionais em infecção hospitalar. O presente artigo tem como objetivo revisar os principais antibióticos utilizados para o tratamento destes agentes, como oxacilina, vancomicina, teicoplanina, linezolida, quinupristina-dalfopristina, daptomicina e tigeciclina.

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Las cepas de Staphylococcus aureus resistentes a meticilina (SARM) suponen un problema en el medio hospitalario. Conocer la prevalencia de estas cepas es importante para aplicar una terapia empírica adecuada cuando se sospeche la implicación de SARM en la infección. Se estudió todas las cepas de Staphylococcus aislados en La Rioja desde febrero de 2001 hasta Febrero de 2002, incluyendo un solo aislamiento por paciente. Tras su identificación fueron valoradas frente a 13 antibióticos, hallándose una elevada insensibilidad a la oxacilina (34.81 por ciento), observándose también elevada resistencia a otros antimicrobianos como el ciprofloxacino (36.12 por ciento) y la eritromicina (21.98 por ciento) . No se encontró ningún aislamiento de SARM resistente a vancomicina. Los aislamientos se produjeron de forma más frecuente en muestras de orina (63 por ciento). SARM es un problema grave en La Rioja y su prevalencia sigue aumentando progresivamente, así como la mutiresistencia, es necesario ampliar las medidas de vigilancia y control (AU)

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In vivo, tissue distribution of intra-mammarily administered antibiotics is mostly only assessed by sampling milk and blood. Therefore, the described study analysed whether measurement of tissue concentrations makes sense in vitro instead. Isolated bovine udders were perfused with gassed and warmed Tyrode solution. To four front and rear quarters each, 1000 mg oxacillin in 7.5 ml vehicle was administered intracisternally, completely formulated as sodium monohydrate in two lactation ointments (with or without sodium dodecylsulphate) or 80% as benzathine salt in a dry-off ointment. Over 3 h, perfusate and glandular tissue from different locations were sampled and analysed by high pressure liquid chromatography. With increasing vertical distance to the teat base, the tissue concentration of antibiotics decreased. With the lactation ointment containing sodium dodecylsulphate, lower oxacillin concentrations were reached in glandular tissue and lymph nodes compared to those without. The ointments led to a higher recovery of oxacillin in glandular tissue than in perfusate. Aluminium monostearate in the dry-off ointment caused an even poorer absorption of oxacillin into perfusate. The isolated perfused bovine udder is suitable to study the tissue distribution of antibiotics, since the results were mainly comparable with the few existing in vivo studies and show the influence of different formulations.

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OBJECTIVE: The aim of this study was to use the suction bullae technique to compare skin diffusion of 3 antibiotics commonly used for skin infections (fusidic acid, oxacillin, pristinamycin) and to estimate their potential activity at the site of skin infections. SUBJECTS AND METHODS: This comparative open study was conducted in 12 healthy volunteers using a repeated latin square experimental scheme. Antibiotic concentrations in serum and suction bullae fluid were measured by high performance liquid chromatography after 5.5 days of repeated oral administration of fusidic acid (1 g/d), oxacillin (2 g/d), and pristinamycin (2 g/d). RESULTS: Mean antibiotic concentrations in serum and interstitial fluid (suction bullae fluid) were highest for fusidic acid with a Cmax at 91.3 +/- 23.0 mg/l and 45.5 +/- 18.0 mg/l respectively (interstitial fluid/serum ratio=49 +/- 10 p. 100). For oxacillin, Cmax was 8.3 +/- 3.6 mg/l and 0.98 +/- 0.49 mg/l (ratio 13 +/- 5 p. 100). Pristinamycin concentrations were low with a Cmax at 0.51 +/- 0.40 and 0.26 +/- 0.15 mg/l (ratio 73 +/- 57 p. 100). Comparing the area under the interstitial fluid and the serum concentration-time curves showed that the best diffusion was obtained with pristinamycin (114 +/- 61 p. 100), followed by fusidic acid (57 +/- 13 p. 100) and oxacillin (48 +/- 25 p. 100). DISCUSSION: These data were used to calculate indicators of potential efficacy in the interstitial dermal fluid: inhibitor quotient (Cmax/MIC) and AUIC (ASC/MIC), indicator of the time antibiotic concentrations are maintained above the minimal inhibitor concentration (MIC). This showed that fusidic acid was potentially more active against all staphylococci. For streptococci, the observed interstitial concentrations of pristinamycin and of fusidic acid should theoretically inhibit streptococci A growth, but oxacillin was the most adapted antibiotic.

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The effects of anaesthesia on intestinal drug absorption and hepatic first-pass metabolism in rats were investigated by observing the difference in the drug concentration between portal and systemic bloods. Oxacillin and pentobarbital were selected as a model drug and as an anaesthetic, respectively. Rats were divided into a conscious control group and an anaesthetized group. All rats were cannulated simultaneously in the portal vein and in the femoral artery, and oxacillin was orally administered after its intra-arterial injection (double dosing). For the anaesthetized group, pentobarbital was intrasubcutaneously administered twice, first before intra-arterial injection and again before oral administration of oxacillin. The arterial blood alone was sampled from the cannula in the femoral artery before oral administration, whereas the arterial and portal bloods were simultaneously sampled from both cannulated sites after oral administration. Oxacillin concentrations in plasma were assayed by HPLC. The anaesthesia increased the absolute bioavailability (F), the mean absorption time (MAT) and the hepatic recovery ratio (F(H)), but caused little change in the local absorption ratio into the portal system (Fa) and the total clearance (CL). The hepatic clearance (CL(H)) was significantly decreased, resulting in an apparent small change in CL-CL(H) which is considered to be renal clearance. By this method, it was shown directly that an increase in F due to pentobarbital anaesthesia was attributable to the significant increase in F(H). It is expected that the method is useful not only to evaluate the effect of anaesthesia on the first-pass effect, but also to assess the effect of co-administration of drugs on first-pass metabolism.

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A curve-fitting program based on the Finite Element Method, MULTI(FEM), was developed to model nonlinear local disposition of a drug in the liver under non-steady-state conditions. The program was written in FORTRAN on an IBM-compatible personal computer. The validity of MULTI(FEM) was confirmed by analyzing the outflow kinetics of oxacillin (a model drug) following a pulse input to isolated, perfused rat livers, according to both linear and nonlinear dispersion models. Four dose levels (300, 1000, 3000, and 5000 microg) of oxacillin were administered to observe the dose-dependency in the hepatic local disposition. First, the individual outflow time-profiles at the same dose were averaged, and the average time-profile was analyzed by MULTI(FEM) based on linear dispersion models to yield a single curve fit. The fitted parameters at each dose level were compared with parameters estimated using MULTI(FILT), a program based on fast inverse Laplace transform, to analyze linear pharmacokinetics. The estimated parameters by MULTI(FEM) were in good agreement with those by MULTI(FILT). The apparent elimination rate constant (ke) decreased with an increase in dose, whereas other parameters showed no discernible dependency on an increase of dose. Second, the average outflow time-profiles at the four dose levels were simultaneously analyzed by MULTI(FEM) based on dispersion models featuring Michaelis-Menten elimination. The outflow time-profiles of oxacillin were well approximated by a two-compartment dispersion model with central Michaelis-Menten elimination. The maximum elimination rate constant (Vmax) and the Michaelis constant (Km) were estimated to be 1520 microg/mL/min and 41.3 microg/mL, respectively. Thus, the capability of MULTI(FEM) was demonstrated in evaluating capacity-limited local disposition in the liver.

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Se analizaron retrospectivamente 74 historias clínicas del Hospital de Niños Roberto del Río, con hemocultivos positivos para Estafilococo Dorado entre los años 1993 - 1996. Se observó que el grupo etario más afectado por bacteremia estafilocócica fue el de 0 - 23 meses (82,4 por ciento), al igual que lo descrito por la literatura. No hubo diferencia significativa con respecto al sexo y periodo estacional. Las manifestaciones clínicas fueron: fiebre (33.4 por ciento ), respiratoria (27 por ciento ). La principal complicación fue la neumopatía. El tratamiento antibiótico se inició durante la primera semana de evolución del cuadro clínico en un 77 por ciento , siendo la cloxacilína el más utilizado (55.4 por ciento). La evolución clínica fue tórpida en un 37.5 por ciento de los casos; con 8.1 por ciento de mortalidad. Seis lactantes menores de 4 meses fallecieron, destacando en este grupo la presencia de factores de riesgo asociados y la adquisición de la infección en el centro hospitalario. La sensibilidad del Estafilococo Dorado a la oxacilina fue de un 9.5 por ciento. El análisis estadístico mostró que la probabilidad de que el germen sea resistente al ser adquirido por infección intrahospitalaria es un OR 8,8 (P 0.00003). Al comparar la letalidad de los recién nacidos con el resto de los pacientes, letalidad con pacientes portadores de factores asociados, letalidad con desnutrición, y mortalidad con origen nosocomial de la infección estafilocócica no mostraron significación estadística

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A pharmacokinetic analysis program based on a tank-in-series model, MULTI(TIS), was developed for the evaluation of dose-dependency in the local disposition of a drug. The program written in FORTRAN was constructed by expanding MULTI(RUNGE). The reliability of MULTI(TIS) was verified by analyzing the experimental data based on linear and nonlinear tank-in-series models. Linear one- and two-compartment tank-in-series models were adopted to analyze outflow time profiles in single-pass hepatic perfusion following a pulse input of 5'-deoxy-5-fluorouridine (DFUR). The estimated parameters agreed well with those by MULTI(FILT) which is widely used for linear kinetic analysis. The nonlinear models adopted were one-compartment model with Michaelis-Menten elimination and two-compartment models with Michaelis-Menten elimination from central and peripheral compartments. Oxacillin was used as a model drug, because time courses of oxacillin show a capacity-limited hepatic disposition following a pulse input in high doses to the liver (300, 1000, 3000 and 5000 microg). The hepatic recovery ratio (F(H)) of oxacillin increased with dose, whereas the mean transit time (tH) was almost constant. The maximum elimination rate constant (Vmax) and Michaelis constant (Km) of oxacillin were estimated to be 1980 microg/ml/min and 54.1 microg/ml, respectively. Thus, the reliability of MULTI(TIS) was demonstrated for the analysis of nonlinear local disposition, especially, capacity-limited elimination in the liver.

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The effect of perfusate flow rate on hepatic structure and hepatic uptake kinetics was investigated using oxacillin as a model drug and bovine serum albumin (BSA) as a reference substance in the liver perfusion system from the standpoint of a dispersion model and moment characteristics. The estimated recovery ratio (FH) of oxacillin was about 40% which was independent of the change in perfusate flow rate. The mean transit time (tH) of oxacillin decreased with an increase in flow rate, while the relative variance (sigma 2/t2H) of oxacillin was independent of the flow rate. The tH of BSA decreased with an increase in the flow rate to the same extent as that of oxacillin, while sigma 2/t2H of BSA was independent of flow rate. When the dispersion model is adopted as a model system to analyze hepatic perfusion data following the pulse input, the moment characteristics (FH, tH and sigma 2/t2H) are given in complicated equations. It is demonstrated by the present investigation that these moment equations can be extensively simplified for a drug with a medium extraction ratio (FH > 50%), i.e., FH is independent of the distribution, both FH and tH are independent of the dispersion process in the hepatic blood space, and both tH and sigma 2/t2H are independent of the elimination. Thus, it is shown that FH and tH are exactly the indices of elimination and distribution, respectively, and sigma 2/t2H is the index of dispersion in the blood space plus nonequilibrium in the hepatic distribution.

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Antibiotics are frequently prophylactically administered in surgical procedures to reduce the incidence of infection. The penetration of antibiotics into lumbar discs has been studied with mixed results, but penetration into cervical discs has not been reviewed. In this study, we examined the penetration of two commonly used antibiotics, oxacillin and cefazolin, into cervical discs. Eighteen patients with a total of 30 discs removed were studied. Two groups, each consisting of four patients with five discs removed, received either 1 g of oxacillin or 1 g of cefazolin by a single, preoperative intravenous infusion. Two other groups, each consisting of five patients with 10 discs removed, received either 2 g of oxacillin or 2 g of cefazolin, also by a single, preoperative intravenous infusion. A blood specimen, from which serum antibiotic levels were determined, was obtained from each patient simultaneously with each discectomy. The time interval between the antibiotic infusion and discectomy/phlebotomy was also recorded. Antibiotic levels were detected in all discs removed but were quantifiable in only 12. Nine of these 12 had been exposed to cefazolin. Of these nine discs, one was from a patient who had received 1 g whereas the other eight were from patients who had received 2 g of cefazolin. This represents 80% of the removed discs exposed to 2 g of cefazolin (10 discs total) and 20% exposed to 1 g (5 discs total). The remaining three discs with quantifiable antibiotic levels had been exposed to 2 g of oxacillin, which represents 30% of the discs (10 total) exposed to that dose of oxacillin. Although cervical disc space infections are rare, they are serious.(ABSTRACT TRUNCATED AT 250 WORDS)

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