Emergence of Ceftriaxone Resistance during a Case of Pneumococcal Meningitis with Fatal Evolution.

We report a case of a 62-year-old man treated for Streptococcus pneumoniae meningitis by ceftriaxone and dexamethasone. After neurological improvement, neurological degradation by vasculitis occurred, despite effective concentrations of ceftriaxone in the serum and cerebrospinal fluid (CSF). S. pneumoniae with increased MICs to third-generation-cephalosporins (3GC) was isolated from the ventricular fluid 10 days after the isolation of the first strain. Isolate analysis showed that a mutation in the penicillin-binding protein 2X (PBP2X) has occurred under treatment.

Antibiotic Dosing in Continuous Renal Replacement Therapy.

Appropriate antibiotic dosing is critical to improve outcomes in critically ill patients with sepsis. The addition of continuous renal replacement therapy makes achieving appropriate antibiotic dosing more difficult. The lack of continuous renal replacement therapy standardization results in treatment variability between patients and may influence whether appropriate antibiotic exposure is achieved. The aim of this study was to determine if continuous renal replacement therapy effluent flow rate impacts attaining appropriate antibiotic concentrations when conventional continuous renal replacement therapy antibiotic doses were used. This study used Monte Carlo simulations to evaluate the effect of effluent flow rate variance on pharmacodynamic target attainment for cefepime, ceftazidime, levofloxacin, meropenem, piperacillin, and tazobactam. Published demographic and pharmacokinetic parameters for each antibiotic were used to develop a pharmacokinetic model. Monte Carlo simulations of 5000 patients were evaluated for each antibiotic dosing regimen at the extremes of Kidney Disease: Improving Global Outcomes guidelines recommended effluent flow rates (20 and 35 mL/kg/h). The probability of target attainment was calculated using antibiotic-specific pharmacodynamic targets assessed over the first 72 hours of therapy. Most conventional published antibiotic dosing recommendations, except for levofloxacin, reach acceptable probability of target attainment rates when effluent rates of 20 or 35 mL/kg/h are used.

Pharmacokinetics of ceftiofur sodium in equine pregnancy.

Eleven pregnant pony mares (D270-326) were administered ceftiofur sodium intramuscularly at 2.2 mg/kg (n = 6) or 4.4 mg/kg (n = 5), once daily. Plasma was obtained prior to ceftiofur administration and at 0.5, 1, 2, 4, 8, 12, and 24 hr after administration. Eight pony mares were re-enrolled in the study at least 3 days from expected foaling to ensure steady-state concentrations of drug at the time of foaling. Mares were administered ceftiofur sodium (4.4 mg/kg, IM) daily until foaling. Parturition was induced using oxytocin 1 hr after ceftiofur sodium administration. Allantoic and amniotic fluid, plasma, and colostrum samples were collected at time of foaling. Serial foal plasma samples were obtained. Placental tissues were collected. Desfuroylceftiofur acetamide (DCA) concentrations were measured in samples by high-performance liquid chromatography (HPLC). Mean (±SD) peak serum concentrations of DCA were 3.97 ± 0.50 µg/ml (low dose) and 7.45 ± 1.05 µg/ml (high dose). Terminal half-life was significantly (p = .014) shorter after administration of the low dose (2.91 ± 0.59 hr) than after administration of the high dose (4.10 ± 0.72 hr). The mean serum concentration of DCA from mares at time of foaling was 7.96 ± 1.39 µg/ml. The mean DCA concentration in colostrum was 1.39 ± 0.70 µg/ml. DCA concentrations in allantoic fluid, amniotic fluid, placental tissues, and foal plasma were below the limit of quantification (<0.1 µg/ml) and below the minimum inhibitory concentration of ceftiofur against relevant pathogens. These results infer incomplete passage of DCA across fetal membranes after administration of ceftiofur sodium to normal pony mares.

The pharmacokinetics change of cefepime after Shuanghuanglian injection administration in subjects with the renal damage.

Shuanghuanglian injection (SHLI) has been widely used for administration with cephalosporin in China for long time. The objective of this study was to evaluate the pharmacological properties and biochemical changes of cefepime combined with SHLI. The SD rats included were received either an intravenous (iv. 4 mL/kg) dose of normal saline, or intravenous (iv. 0.74, 0.37, 0.185 g/kg, respectively) doses of SHLI once daily for 7 days. After last administration, cefepime (0.41 g/kg) was intravenous injected to the animals. The serum and urine samples were acquired and stored at 4 °C. They were used for quantitative determination of urea nitrogen (BUN), creatinine (CRE), urine protein, alkaline phosphatase (ALP) and N-acetyl-B-d-glucosaminidase (NAG). At different time points, the levels of cefepime in rat plasma were estimated for pharmacokinetic measures by HPLC. Aspirin was selected as internal standard (IS). The results showed that there were positive effects by increasing the total amount of CRE, BUN, NAG and urine protein (p < 0.01 or <0.05) and decreasing the levels of ALP (especially the high dose group of SHLI with cefepime) (p < 0.01). Besides, the pharmacokinetic results indicated that cefepime was distributed as non-compartment model after intravenous administration. Compared with the corresponding values for the compounds given alone, the area under the blood drug concentration time curve (AUC0-t and AUC0-∞) was better increased in middle- and high-dose groups (pall < 0.01), the mean residence time (MRT) of cefepime was larger (pall < 0.01) and the total clearance (CL) was lower at different levels. The results mean that the duration and concentration of cefepime could be prolonged and the clearance reduced while in combination with SHLI. Furthermore, the cefepime in the three tested doses caused changes of renal tubular epithelial cells while the severity of changes mainly dependent on the specific doses. In conclusion, the results above-mentioned suggest a possible contribution of drug combination in the nephrotoxicity and biochemical alterations especially at high doses. Further, monitoring measures for the renal functions are warranted to evaluate during the combination of these two drugs.

In vivo activity of cefquinome against Riemerella anatipestifer using the pericarditis model in the duck.

Cefquinome is a fourth-generation cephalosporin with broad-spectrum antibacterial activity, including activity against enteric gram-negative bacilli such as Riemerella anatipestifer. The pericarditis model was used to examine the pharmacodynamic characteristics of cefquinome against R. anatipestifer. Serum levels of cefquinome following the administration of different doses were determined by LC-MS/MS. Ducks with ca. 10(6) CFU/mL at the initiation of therapy were treated with cefquinome at doses that ranged from 0.0156 to 2 mg/kg of body weight/day (in 3, 6, 12, or 24 divided doses) for 24 h. The percentage of a 24-h dosing interval that the unbound serum cefquinome concentrations exceeded the MIC (fT > MIC) were the pharmacokinetic (PK)-pharmacodynamic (PD) parameter that best correlated with efficacy (R(2) 86.3% for R. anatipestifer, compared with 58.9% for the area under the concentration-time curve/MIC and 10.6% for peak/MIC). A sigmoid Emax model was used to estimate the magnitudes of the %fT > MIC associated with net bacterial stasis, a 1-log10 CFU reduction from baseline, and a 2-log10 CFU reduction from baseline; the corresponding values were (22.5 ± 1.3) %, (35.2 ± 4.5) %, and (42.4 ± 2.7) %. These data showed that treatment with cefquinome results in marked antibacterial effects in vivo against R. anatipestifer and that the host's immunity may also play a key role in the anti-infective therapy process.

Effects of ceftiofur treatment on the susceptibility of commensal porcine E.coli--comparison between treated and untreated animals housed in the same stable.

BACKGROUND: Healthy farm animals have been found to act as a reservoir of extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli (E. coli). Therefore, the objective of the study was to determine the input of antimicrobial active ceftiofur metabolites in the stable via faeces and urine after intramuscular administration of the drug to pigs and the elucidation of the Escherichia coli ESBL resistance pattern of treated and untreated pigs housed in the same barn during therapy. METHODS: For determination of the minimal inhibitory concentration (MIC) the method of microdilutionaccording to the recommended procedure of the Clinical and Laboratory Standards Institute was used. Inaddition to that, a qualitative determination was performed by agar dilution. Unsusceptible E. coli speciesselected via agar dilution with cefotaxime were confirmed by MALDI-TOF and ESBL encoding genes wereidentified by PCR. The amounts of ceftiofur measured as desfuroylceftiofur (DFC) in the different probes (plasma, urine, faeces and dust) were analysed by UPLC-MS/MS. RESULTS: In a first experiment two groups of pigs (6 animals per group) were housed in the same barn in two separated boxes. One group (group B) were treated with ceftiofur according to the licence (3 mg/kg administered intramuscularly (i.m.) on three consecutive days, day 1-3). During a second treatment period (day 29-31) an increased rate of ESBL resistant E. coli was detectable in these treated pigs and in the air of the stable. Moreover, the second group of animals (group A) formerly untreated but housed for the whole period in the same stable as the treated animals revealed increased resistance rates during their first treatment (day 45-47) with ceftiofur. In order to investigate the environmental input of ceftiofur during therapy and to simulate oral uptake of ceftiofur residues from the air of the stable a second set of experiments were performed. Pigs (6 animals) were treated with an interval of 2 weeks for 3 days with different doses of ceftiofur (3 mg/kg, 1 mg/kg and 0.3 mg/kg i.m.) as well as with 3 mg/kg per os) and the renal and biliary excretion of ceftiofur as its active metabolite were measured in comparison to the plasma levels. In addition to that, probes of the sedimentation dust and the air of the stable were analysed for drug residues. CONCLUSION: The present study shows that treatment of several animals in a stable with ceftiofur influences the resistance pattern of intestinal Escherichia coli of the treated as well as untreated animals housed in the same stable. During therapy with the drug which was administered by injection according to the licence we detected nameable amounts of ceftiofur and its active metabolites in the dust and air of the stable.

Could ceftaroline be an alternative therapy for linezolid resistant Staphylococcus epidermidis infections in Intensive Care Medicine? / ¿Podría ceftarolina ser una alternativa terapéutica frente a las infecciones por Staphylococcus epidermidis en el paciente crítico?

Introduction. Staphylococcus coagulasa negativo sigue generando interés en los pacientes críticos, debido a sus infecciones en los ingresos prolongados, en pacientes instrumentados y, debido a su resistencia a múltiples fármacos descrito, que incluyen la heterorresistencia a glicopéptidos y el aumento de la resistencia oxazolidinonas. Ceftarolina es una nueva cefalosporina con actividad frente a grampositivos resistentes, que, por ser un betalactámico, podría proporcionar un perfil de seguridad adecuado en el paciente crítico. El objetivo de este estudio fue determinar la actividad de ceftarolina y otros agentes antimicrobianos frente a cepas de Staphylococcus epidermidis resistente a meticilina y linezolid. Material y métodos. Estudiamos la sensibilidad de ceftarolina, tigeciclina, daptomicina y vancomicina en un total de sesenta y ocho aislamientos con significación clínica de S. epidermidis resistente a meticilina y linezolid en una Unidad de Cuidados Intensivos, usando E-test. Resultados. Todas las cepas fueron sensibles a los cuatro agentes antimicrobianos, con independencia del nivel de resistencia a linezolid. Conclusión. Ceftarolina podría ser una alternativa en el tratamiento de infecciones por S. epidermidis resistente a meticilina y linezolid en el paciente crítico (AU)

Introduction. Coagulase negative Staphylococcus continues generating interest in critically ill patients, due to their infections in extended admissions, in instrumented patients and due to their described multidrug resistance, which include glycopeptide heterorresistance and the increase in oxazolidinone resistance. Ceftaroline is a new cephalosporin with activity against resistant gram-positives, which, being betalactam, may provide adequate safety profile in the critical ill patient. The aim of this study was to determine the activity of ceftaroline and other antimicrobial agents against methicillin and linezolid-resistant Staphylococcus epidermidis. Material and methods. We studied susceptibility of ceftaroline, tigecycline, daptomycin and vancomycin in a total of sixty-eight methicillin and linezolid-resistant S. epidermidis isolates with clinical significance from an Intensive Care Unit, using E-test. Results. All strains were susceptible to the four antimicrobial agents, regardless of the level of resistance to linezolid. Conclusion. Ceftaroline could be an alternative in the treatment of methicillin and linezolid-resistant S. epidermidis infections in critically ill patients (AU)

Pharmacokinetics, bioavailability and PK/PD relationship of cefquinome for Escherichia coli in Beagle dogs.

The pharmacokinetics and bioavailability of cefquinome in Beagle dogs were determined by intravenous (IV), intramuscular (IM) or subcutaneous (SC) injection at a single dose of 2 mg/kg body weight (BW). The minimum inhibitory concentrations (MIC) of cefquinome against 217 Escherichia coli isolated from dogs were also investigated. After IV injection, the plasma concentration-time curve of cefquinome was analyzed using a two-compartmental model, and the mean values of t1/2α (h), t1/2ß (h), Vss (L/kg), ClB (L/kg/h) and AUC (µg·h/mL) were 0.12, 0.98, 0.30, 0.24 and 8.51, respectively. After IM and SC administration, the PK data were best described by a one-compartmental model with first-order absorption. The mean values of t1/2Kel , t1/2Ka , tmax (h), Cmax (µg/mL) and AUC (µg·h/mL) were corresponding 0.85, 0.14, 0.43, 4.83 and 8.24 for IM administration, 0.99, 0.29, 0.72, 3.88 and 9.13 for SC injection. The duration of time that drug levels exceed the MIC (%T > MIC) were calculated using the determined MIC90 (0.125 µg/mL) and the PK data obtained in this study. The results indicated that the dosage regimen of cefquinome at 2 mg/kg BW with 12-h intervals could achieve %T > MIC above 50% that generally produced a satisfactory bactericidal effect against E. coli isolated from dogs in this study.

Treatment of multidrug-resistant pseudomonas aeruginosa using extended-infusion antimicrobial regimens.

In the management of multidrug-resistant infections in critically ill patients with multiorgan dysfunction, consideration must be given to the pharmacokinetics and pharmacodynamics of an antimicrobial agent to optimize dosing. We describe a 25-year-old woman who was undergoing thrice-weekly hemodialysis and developed multidrug-resistant Pseudomonas aeruginosa bacteremia secondary to infected left and right ventricular assist devices. After multiple courses of antibiotics, her blood cultures revealed that the infecting organism was becoming progressively more resistant to antibiotic options. Cefepime 2 g administered over 3 hours/day (in combination with colistimethate) provided adequate drug levels for multidrug-resistant, cefepime-intermediate P. aeruginosa bacteremia in this patient. We present the clinical case of this patient, followed by a discussion of possible therapeutic approaches to be considered, including illustration of the principles of using extended-infusion antimicrobial regimens, and present the patient's resulting clinical course.

Pharmacokinetics and ex-vivo pharmacodynamics of cefquinome against Klebsiella pneumonia in healthy dogs.

A two-period cross-over study was carried to investigate the pharmacokinetics (PK) and ex-vivo pharmacodynamics (PD) of cefquinome when administrated intravenously (IV) and intramuscularly (IM) in seven healthy dogs at a dose of 2 mg/kg of body weight. Serum concentrations were determined by HPLC-MS/MS assay and cefquinome concentration vs. time data after IV and IM were best fit to a two-compartment open model. Cefquinome mean values of area under concentration-time curve (AUC) were 5.15 µg · h/mL for IV dose and 4.59 µg · h/mL for IM dose. Distribution half-lives and elimination half-lives after IV dose and IM dose were 0.27 and 0.44 h, 1.53 and 1.94 h, respectively. Values of total body clearance (ClB ) and volume of distribution at steady-state (Vss ) were 0.49 L · kg/h and 0.81 L/kg, respectively. After IM dose, Cmax was 2.53 µg/mL and the bioavailability was 89.13%. For PD profile, the determined MIC and MBC values against K. pneumonia were 0.030 and 0.060 µg/mL in MHB and 0.032 and 0.064 µg/mL in serum. The ex vivo time-kill curves also were established in serum. In conjunction with the data on MIC, MBC values and the ex vivo bactericidal activity in serum, the present results allowed prediction that a single cefquinome dosage of 2 mg/kg may be effective in dogs against K. pneumonia infection.

Disposition of desfuroylceftiofur acetamide in serum, placental tissue, fetal fluids, and fetal tissues after administration of ceftiofur crystalline free acid (CCFA) to pony mares with placentitis.

The objective of this study was to determine the pharmacokinetics of CCFA in mares with placentitis and evaluate the disposition of the drug in fetal fluids, fetal membranes, colostrum, and serum of foals. A secondary objective was to obtain pilot data regarding the efficacy of CCFA for improving foal survival in mares with placentitis. Twelve pregnant pony mares were enrolled in the study, inoculated with Streptococcus zooepidemicus, intracervically and assigned to one of three groups: CEFT (n = 3; administered CCFA only; 6.6 mg/kg, i.m., q96h); COMBO (n = 6; administered combination therapy of CCFA, altrenogest, and pentoxifylline); UNTREAT (n = 3, no treatment). Treatment was initiated at the onset of clinical signs. Concentrations of desfuroylceftiofur acetamide (DCA), the acetamide derivative of ceftiofur and desfuroylceftiofur metabolites, were measured using high-performance liquid chromatography. Maximum and minimum serum concentrations of DCA at steady state in treated mares were 2.40±0.40 µg/mL and 1.06±0.29 µg/mL, respectively. Concentration of DCA in colostrum was 1.51±0.60 µg/mL. DCA concentrations in placenta and fetal tissues were very low (median = 0.03 µg/mL) and below the minimum inhibitory concentration of relevant pathogens. DCA was not detected in amniotic fluid or foal serum. Treatment did not appear to improve foal survival (CEFT: 0/3; COMBO: 2/6; UNTREAT: 2/3). Bacteria were recovered from the uterus of most mares postpartum and from blood cultures of most foals regardless of treatment.

[Effect of ceftiofur hydrochloride on pharmacokinetics of matrine in rats].

OBJECTIVE: To investigate the effect of ceftiofur hydrochloride on the pharmacokinetics of matrine in rats. METHOD: The rats were divided into two groups: one group was administrated with matrine only (control group) and the other was administrated with matrine in combination with ceftiofur hydrochloride. HPLC-UV method was used for determining the plasma concentration of matrine in both groups. The pharmacokinetic parameters were calculated from the plasma concentration-time data using the DAS 2. 1. 1 software program. RESULT: The main pharmacokinetic parameters for the control group were C(max) = 21.113 9 mg x L(-1), T(max) = 0.75 h, t1/2alpha = 1.34 h, t1/2beta = 3.509 h, AUC(0-t) = 90.984 mg x h(-1) x L(-1) and AUC(0-inifinity) = 100.346 mg x h(-1) x L(-1), and the data for the combination group were C(max) = 11.707 mg x L(-1), T(max) = 0.917 h, t1/2alpha = 1.598 h, t1/2beta = 3.247 h, AUC(0-t) = 53.28 mg x h(-1) x L(-1) and AUC(0-inifinity) = 60.035 mg x h(-1) x L(-1). CONCLUSION: The plasma concentration of matrine and bioavailability in combination group were significantly lower than those of the control group. In combination group, matrine had a higher clearance and volume of distribution in the central compartments, as well as a lower volume of distribution in the peripheral compartments.

Insufficient ß-lactam concentrations in the early phase of severe sepsis and septic shock.

INTRODUCTION: Altered pharmacokinetics (PK) in critically ill patients can result in insufficient serum ß-lactam concentrations when standard dosages are administered. Previous studies on ß-lactam PK have generally excluded the most severely ill patients, or were conducted during the steady-state period of treatment. The aim of our study was to determine whether the first dose of piperacillin-tazobactam, ceftazidime, cefepime, and meropenem would result in adequate serum drug concentrations in patients with severe sepsis and septic shock. METHODS: Open, prospective, multicenter study in four Belgian intensive care units. All consecutive patients with a diagnosis of severe sepsis or septic shock, in whom treatment with the study drugs was indicated, were included. Serum concentrations of the antibiotics were determined by high-pressure liquid chromatography (HPLC) before and 1, 1.5, 4.5 and 6 or 8 hours after administration. RESULTS: 80 patients were treated with piperacillin-tazobactam (n = 27), ceftazidime (n = 18), cefepime (n = 19) or meropenem (n = 16). Serum concentrations remained above 4 times the minimal inhibitory concentration (T > 4 × MIC), corresponding to the clinical breakpoint for Pseudomonas aeruginosa defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), for 57% of the dosage interval for meropenem (target MIC = 8 µg/mL), 45% for ceftazidime (MIC = 32 µg/mL), 34% for cefepime (MIC = 32 µg/mL), and 33% for piperacillin-tazobactam (MIC = 64 µg/mL). The number of patients who attained the target PK profile was 12/16 for meropenem (75%), 5/18 for ceftazidime (28%), 3/19 (16%) for cefepime, and 12/27 (44%) for piperacillin-tazobactam. CONCLUSIONS: Serum concentrations of the antibiotic after the first dose were acceptable only for meropenem. Standard dosage regimens for piperacillin-tazobactam, ceftazidime and cefepime may, therefore, be insufficient to empirically cover less susceptible pathogens in the early phase of severe sepsis and septic shock.

Real-time therapeutic drug monitoring of cefozopran in plasma using high-performance liquid chromatography with ultraviolet detection.

A simple, rapid, and precise HPLC method using ultrafiltration to remove plasma protein was developed to determine cefozopran concentrations in human plasma for real-time therapeutic drug monitoring. Plasma was separated by centrifugation at 4 degrees C from blood collected in heparinized vacuum tubes. Cefozopran and an internal standard were detected by ultraviolet absorbances at 235 nm with no interfering plasma peak. The calibration curve of cefozopran in human plasma was linear from 0.2 to 200 microg/ml. The limit of detection was 0.05 microg/ml. The assay was applied to febrile neutropenia patients in a clinical setting.

Effect of L-phenylalanine supplementation and a high-protein diet on pharmacokinetics of cefdinir in healthy volunteers: an exploratory study.

BACKGROUND: Upregulation of oligopeptide transport activity by dietary protein, certain dipeptides and amino acids has been reported in the rat intestine and a human intestinal cell line. OBJECTIVE: In this study, the pharmacokinetics of cefdinir were investigated after L-phenylalanine supplementation and a high-protein diet (HPD) in humans to explore changes in the activities of intestinal and renal oligopeptide transporters. METHODS: A normal-protein diet (NPD, 73.2 +/- 2.6 g/day), NPD + l-phenylalanine (7.5 g/day), or HPD (141.3 +/- 3.7 g/day) was given to six male healthy volunteers for 12 days followed by a single dose of cefdinir after an overnight fast in a randomized three-way crossover study with a 22-day washout. Blood and urine were collected over a 12-h period after administration of cefdinir. Concentrations of cefdinir in plasma and/or urine were measured by high-performance liquid chromatography. RESULTS: Plasma concentrations and urinary excretion of the drug did not change throughout the study. Physiological variables and laboratory values did not reveal any differences between the three periods except for serum and urinary nitrogen levels and serum triglyceride. DISCUSSION: A reason for the unchanged pharmacokinetics of cefdinir may be due to lower doses of L-phenylalanine and protein in humans than in animals when converting animal effective doses to humans. CONCLUSION: In humans, L-phenylalanine supplementation and HPD do not seem to upregulate intestinal and renal oligopeptide transport in the ranges of duration and dose examined.

Evaluation of ceftobiprole in a rabbit model of aortic valve endocarditis due to methicillin-resistant and vancomycin-intermediate Staphylococcus aureus.

Ceftobiprole is a novel broad-spectrum cephalosporin that binds with high affinity to PBP 2a, the methicillin-resistance determinant of staphylococci, and is active against methicillin- and vancomycin-resistant Staphylococcus aureus. Ceftobiprole was compared to vancomycin in a rabbit model of methicillin-resistant S. aureus aortic valve endocarditis. Ceftobiprole and vancomycin were equally effective against endocarditis caused by methicillin-resistant S. aureus strain 76, whereas ceftobiprole was more effective than vancomycin against the vancomycin-intermediate S. aureus strain HIP5836. The activity of ceftobiprole against drug-resistant strains of S. aureus warrants its further clinical development.

Comparison of in vivo intrinsic activity of cefepime and imipenem in a Pseudomonas aeruginosa rabbit endocarditis model: effect of combination with tobramycin simulating human serum pharmacokinetics.

OBJECTIVES: The purpose of this experimental study was first to compare the in vivo intrinsic activity of imipenem and cefepime administered as a continuous infusion and to determine their lowest effective serum steady-state concentration (LESSC). Secondly, we studied the effect of combining therapy with tobramycin. METHODS: In a Pseudomonas aeruginosa (ATCC 27853) rabbit endocarditis model, beta-lactam antibiotics were administered by continuous infusion over a 24 h treatment period at different doses until the LESSC was reached, i.e. able to achieve a 2-log drop of cfu/g of vegetations versus untreated animals. The effect of adding tobramycin (3 mg/kg once daily) was then studied. RESULTS: The LESSC was between 3 x and 4 x MIC of cefepime for P. aeruginosa and about 0.2 5x MIC of imipenem. Combination of tobramycin with each of the two beta-lactams did not result in any further significant killing. CONCLUSION: The optimal Css/MIC ratio might differ from one molecule to another. The LESSC of imipenem is lower than that of cefepime, giving a better intrinsic activity in vivo, despite a higher MIC in vitro.

BAL9141, a novel extended-spectrum cephalosporin active against methicillin-resistant Staphylococcus aureus in treatment of experimental endocarditis.

The therapeutic efficacy of BAL9141 (formerly Ro 63-9141), a novel cephalosporin with broad in vitro activity that also has activity against methicillin-resistant Staphylococcus aureus (MRSA), was investigated in rats with experimental endocarditis. The test organisms were homogeneously methicillin-resistant S. aureus strain COL transformed with the penicillinase-encoding plasmid pI524 (COL Bla+) and homogeneously methicillin-resistant, penicillinase-producing isolate P8-Hom, selected by serial exposure of parent strain P8 to methicillin. The MICs of BAL9141 for these organisms (2 mg/liter) were low, and BAL9141was bactericidal in time-kill curve studies after 24 h of exposure to either two, four, or eight times the MIC. Rats with experimental endocarditis were treated in a three-arm study with a continuous infusion of BAL5788 (formerly Ro 65-5788), a carbamate prodrug of BAL9141, or with amoxicillin-clavulanate or vancomycin. The rats were administered BAL9141 to obtain steady-state target levels of 20, 10, and 5 mg of per liter or were administered either 1.2 g of amoxicillin-clavulanate (ratio 5:1) every 6 h or 1 g of vancomycin every 12 h at changing flow rates to simulate the pharmacokinetics produced in humans by intermittent intravenous treatment. Treatment was started 12 h after bacterial challenge and lasted for 3 days. BAL9141 was successful in the treatment of experimental endocarditis due to either MRSA isolate COL Bla+ or MRSA isolate P8-Hom at the three targeted steady-state concentrations and sterilized >90% of cardiac vegetations (P < 0.005 versus controls; P < 0.05 versus amoxicillin-clavulanate and vancomycin treatment groups). These promising in vivo results with BAL9141 correlated with the high affinity of the drug for PBP 2a and its stability to penicillinase hydrolysis observed in vitro.