Pharmacokinetics of Cefazolin and Vancomycin in Infants Undergoing Open-Heart Surgery With Cardiopulmonary Bypass.

BACKGROUND: Gram-positive bacteria account for nearly three-quarters of all surgical site infections. Antibiotic prophylaxis against these bacteria with cephalosporins or, in select circumstances, with vancomycin is considered standard of care for prevention of surgical site infections. There is little evidence to describe the optimal dosing regimen for surgical site infection prophylaxis in infants undergoing cardiac surgery, and a great deal of institutional variability exists in dosing prophylactic antibiotics. We designed this study to describe an optimal dose regimen for cephalosporin and vancomycin based on pharmacokinetic evidence for infant open-heart surgery on cardiopulmonary bypass. METHODS: Two separate cohorts of infants undergoing cardiac surgery with cardiopulmonary bypass were evaluated. Plasma concentrations of vancomycin (cohort 1, N = 10) and cefazolin (cohort 2, N = 10) were measured, and mixed-effects pharmacokinetic models were constructed for each drug. Simulations of various dosing regimens were performed to describe an appropriate dosing regimen necessary to maintain antibiotic concentrations above the susceptibility cutoff for staphylococci. RESULTS: Both cefazolin and vancomycin plasma concentration versus time profiles were characterized by a 2-compartment model. Subject weight was a significant covariate for V1 for vancomycin. Subject age was a significant covariate for V1 for cefazolin. Cardiopulmonary bypass did not influence concentration versus time profiles. Simulations demonstrated that a 1-hour vancomycin infusion (15 mg·kg), repeated every 12 hours and a 10-minute infusion of cefazolin (30 mg·kg), repeated every 4 hours maintained plasma concentrations above 4 µg·mL and 16 µg·mL, for vancomycin and cefazolin, respectively. Both concentrations are above the minimum inhibitory concentration 90 for most susceptible staphylococci. CONCLUSIONS: Prophylactic treatment of vancomycin 15 mg·kg infused >1 hour with 12-hour redosing and cefazolin 30 mg·kg infused >10 minutes with 4-hour redosing will maintain serum levels of each antibiotic above the susceptibility cut-offs for susceptible staphylococci in infants undergoing cardiac surgery. Cefazolin levels may be adequate for some, but not all, Gram-negative bacteria. The effect of cardiopulmonary bypass on pharmacokinetics is negligible.

Subcutaneous cefazolin to reduce surgical site infections in a porcine model.

BACKGROUND: Surgical site infections (SSIs) pose a significant health and financial burden. A key aspect of appropriate prophylaxis is the administration of antibiotics intravenously (IV). However, subcutaneous administration of antibiotics is not well described in the literature. During surgery, we hypothesize that subcutaneous injection may provide better protection against SSIs. To better understand the kinetics after subcutaneous injection, we describe the serum concentrations of cefazolin in a porcine model. MATERIALS AND METHODS: Juvenile mini-Yucatan pigs were administered 20 mL of 25 mg/kg cefazolin subcutaneously, and serial blood samples were taken for 3 h. Blood samples were analyzed for cefazolin concentration using chromatography. Pharmacokinetic data were calculated based on the blood serum concentrations. RESULTS: Maximum serum concentrations of cefazolin were achieved 42.6 ± 2.0 min after the time of injection and were found to be 18.8 ± 7.4 µg/mL. The elimination rate constant was 0.0033 ± 0.0016 min-1 and the half-life was 266 ± 149 min. The area under the curve was 4940 ± 1030 µg × min/mL. The relative bioavailability of subcutaneous injection was 95% +5%/-20%. CONCLUSIONS: Subcutaneous administration of cefazolin achieves a significantly lower maximum serum concentration than IV injection. As a result, higher doses of antibiotic can be injected locally without incurring systemic toxicity. Subcutaneous administration will therefore result in higher concentrations of antibiotic for a longer time at the incision site compared with standard IV administration. This strategy of antibiotic delivery may be more effective in preventing SSIs. Further studies are needed to detail the exact effect of subcutaneous antibiotic injection on SSI rates.

In vitro potency of amikacin and comparators against E. coli, K. pneumoniae and P. aeruginosa respiratory and blood isolates.

BACKGROUND: The purpose of this study was to define the potency of amikacin and comparator agents against a collection of blood and respiratory nosocomial isolates implicated in ICU based pulmonary infections gathered from US hospitals. METHODS: Minimum inhibitory concentrations of amikacin, aztreonam, cefepime, ceftazidime, ceftolozane/tazobactam, ceftriaxone, ciprofloxacin, imipenem, meropenem, piperacillin/tazobactam and tobramycin were tested against 2460 Gram-negative isolates. Amikacin had 96 % susceptibility against the combined E. coli and K. pneumoniae isolates and 95 % susceptibility against P. aeruginosa. RESULTS: Ninety-six percent of all of isolates tested were susceptible (i.e., MICs ≤16 mg/L) to amikacin by current laboratory standards which demonstrates a high level of activity to combat infections caused by these organisms including ESBL, MDR, ß-lactam and fluoroquinolone resistant strains. Moreover, 99 % of all organisms had amikacin MICs ≤64 mg/L. CONCLUSIONS: Overall, these data highlight the continued potency of amikacin and suggest that the achievable lung concentrations of approximately 5000 mg/L with the administration of the amikacin by inhalation (Amikacin Inhale, BAY41-6551) will exceed the MICs typically observed for P. aeruginosa, E. coli and K. pneumoniae in the hospital setting.

Impact of revised cefepime CLSI breakpoints on Escherichia coli and Klebsiella pneumoniae susceptibility and potential impact if applied to Pseudomonas aeruginosa.

The CLSI reduced the cefepime Enterobacteriaceae susceptibility breakpoint and introduced the susceptible-dose-dependent (S-DD) category. In this study, MICs were determined for a Gram-negative collection to assess the impact of this change. For Enterobacteriaceae, this resulted in <2% reduction in susceptibility, with 1% being S-DD. If applied to Pseudomonas aeruginosa, the % susceptibility (%S) dropped from 77% to 43%, with 34% being S-DD. The new breakpoints did little to the Enterobacteriaceae %S, but for P. aeruginosa, a profound reduction was seen in %S. The recognition of a S-DD response to cefepime should alert clinicians to the possible need for higher doses.

To add or not to add polysorbate 80: impact on colistin MICs for clinical strains of Enterobacteriaceae and Pseudomonas aeruginosa and quality controls.

Colistin adherence to plastics can be diminished by adding a surfactant, i.e., polysorbate 80. Incorporating polysorbate 80 resulted in 3 twofold and 2 twofold modal MIC decreases for Enterobacteriaceae and Pseudomonas aeruginosa, respectively. The reproducibility of the quality controls (QCs) with and without polysorbate 80 supports the use of Escherichia coli strain 25922 and P. aeruginosa strain 27853.

In vivo comparison of CXA-101 (FR264205) with and without tazobactam versus piperacillin-tazobactam using human simulated exposures against phenotypically diverse gram-negative organisms.

CXA-101 is a novel antipseudomonal cephalosporin with enhanced activity against Gram-negative organisms displaying various resistance mechanisms. This study evaluates the efficacy of exposures approximating human percent free time above the MIC (%fT > MIC) of CXA-101 with or without tazobactam and piperacillin-tazobactam (TZP) against target Gram-negative organisms, including those expressing extended-spectrum ß-lactamases (ESBLs). Sixteen clinical Gram-negative isolates (6 Pseudomonas aeruginosa isolates [piperacillin-tazobactam MIC range, 8 to 64 µg/ml], 4 Escherichia coli isolates (2 ESBL and 2 non-ESBL expressing), and 4 Klebsiella pneumoniae isolates (3 ESBL and 1 non-ESBL expressing) were used in an immunocompetent murine thigh infection model. After infection, groups of mice were administered doses of CXA-101 with or without tazobactam (2:1) designed to approximate the %fT > MIC observed in humans given 1 g of CXA-101 with or without tazobactam every 8 h as a 1-h infusion. As a comparison, groups of mice were administered piperacillin-tazobactam doses designed to approximate the %fT > MIC observed in humans given 4.5 g piperacillin-tazobactam every 6 h as a 30-min infusion. Predicted piperacillin-tazobactam %fT > MIC exposures of greater than 40% resulted in static to >1 log decreases in CFU in non-ESBL-expressing organisms with MICs of ≤32 µg/ml after 24 h of therapy. Predicted CXA-101 with or without tazobactam %fT > MIC exposures of ≥37.5% resulted in 1- to 3-log-unit decreases in CFU in non-ESBL-expressing organisms, with MICs of ≤16 µg/ml after 24 h of therapy. With regard to the ESBL-expressing organisms, the inhibitor combinations showed enhanced CFU decreases versus CXA-101 alone. Due to enhanced in vitro potency and resultant increased in vivo exposure, CXA-101 produced statistically significant reductions in CFU in 9 isolates compared with piperacillin-tazobactam. The addition of tazobactam to CXA-101 produced significant reductions in CFU for 7 isolates compared with piperacillin-tazobactam. Overall, human simulated exposures of CXA-101 with or without tazobactam demonstrated improved efficacy versus piperacillin-tazobactam.

Comparison of the activity of a human simulated, high-dose, prolonged infusion of meropenem against Klebsiella pneumoniae producing the KPC carbapenemase versus that against Pseudomonas aeruginosa in an in vitro pharmacodynamic model.

We have previously demonstrated that a high-dose, prolonged-infusion meropenem regimen (2 g every 8 h [q8h]; 3-hour infusion) can achieve 40% free drug concentration above the MIC against Pseudomonas aeruginosa with MICs of or=3 log CFU reduction against all KPC isolates within 6 h, followed by regrowth in all but two isolates. The targeted %fT>MIC (percent time that free drug concentrations remain above the MIC) exposure was achieved against both of these KPC isolates (100% fT>MIC versus MIC=2 microg/ml, 75% fT>MIC versus MIC=8 microg/ml). Against KPC isolates with MICs of 8 and 16 microg/ml that did regrow, actual meropenem exposures were significantly lower than targeted due to rapid in vitro hydrolysis, whereby targeted %fT>MIC was reduced with each subsequent dosing. In contrast, a >or=3 log CFU reduction was maintained over 24 h for all Pseudomonas isolates with meropenem MICs of 8 and 16 microg/ml. Although KPC and P. aeruginosa isolates may share similar meropenem MICs, the differing resistance mechanisms produce discordant responses to a high-dose, prolonged infusion of meropenem. Thus, predicting the efficacy of an antimicrobial regimen based on MIC may not be a valid assumption for KPC-producing organisms.

Tissue penetration and pharmacokinetics of tigecycline in diabetic patients with chronic wound infections described by using in vivo microdialysis.

Tissue penetration of systemic antibiotics is an important consideration for positive outcomes in diabetic patients. Herein we describe the exposure profile and penetration of tigecycline in the interstitial fluid of wound margins versus that of uninfected thigh tissue in 8 adult diabetic patients intravenously (IV) administered 100 mg and then 50 mg of tigecycline twice daily for 3 to 5 doses. Prior to administration of the first dose, 2 microdialysis catheters were inserted into the subcutaneous tissue, the first within 10 cm of the wound margin and the second in the thigh of the same extremity. Samples for determination of plasma and tissue concentrations were simultaneously collected over 12 h under steady-state conditions. Tissue concentrations were corrected for percent in vivo recovery by the retrodialysis technique. Plasma samples were also collected for determination of protein binding at 1, 6, and 12 h postdose for each patient. Protein binding data were corrected using a fitted polynomial equation. The mean patient weight was 95.1 kg (range, 63.6 to 149.2 kg), the mean patient age was 63.5 ± 9.4 years, and 75% of the patients were males. The mean values for the plasma, thigh, and wound free area under the concentration-time curve from 0 to 24 h (fAUC(0-24)) were 2.65 ± 0.33, 2.52 ± 1.15, and 2.60 ± 1.02 µg·h/ml, respectively. Protein binding was nonlinear, with the percentage of free drug increasing with decreasing serum concentrations. Exposure values for thigh tissue and wound tissue were similar (P = 0.986). Mean steady-state tissue concentrations for the thigh and wound were similar at 0.12 ± 0.02 µg/ml, and clearance from the tissues appeared similar to that from plasma. Tissue penetration ratios (tissue fAUC/plasma fAUC) were 99% in the thigh and 100% in the wound (P = 0.964). Tigecycline penetrated equally well into wound and uninfected tissue of the same extremity.

Development of an HPLC Method for the Determination of Meropenem/Vaborbactam in Biological and Aqueous Matrixes.

A HPLC method was developed and validated to analyze meropenem and vaborbactam simultaneously in murine plasma and saline matrixes. A 60-µL volume of extracted sample was injected onto a 5-µm BDS Phenyl-Hypersil C18 reversed-phase column and analyzed with a UV detector set at 298 nm for the first 4.9 min and switched to 240 nm. The mobile phase contained a mixture of methanol and 25-mM sodium phosphate buffer set at a flow rate of 1.0 mL/min for the 16 min run time. Cefuroxime was used as the internal standard. The standard curves were linear over a range of 0.25-50 µg/mL. The precision and accuracy for 0.25 µg/mL (LLQ) in plasma for both compounds were <4.8% and >98.9%, respectively. Interday and intraday precision and accuracy for all QC plasma samples for both compounds were <6.2% and >95.7%, respectively. This methodology details a reproducible assay for both compounds using a single extraction with good accuracy and precision.

Single ß-lactams versus combinations as empiric therapy for infections with Pseudomonas aeruginosa: assessing the in vitro susceptibility.

Background: While the value of combination versus monotherapy of infections with Pseudomonas aeruginosa infection is a subject of debate, increasing antimicrobial resistance of this pathogen makes it difficult to select appropriate empiric regimens. We evaluated the probability that P. aeruginosa would be susceptible to ß-lactams either as monotherapy or as part of a combination regimen.Methods: Contemporary non-duplicate isolates of P. aeruginosa derived from blood or the respiratory tract of patients hospitalized in the United States were investigated. Minimum inhibitory concentrations were determined using broth microdilution methods for amikacin (AMK), cefepime (FEP), ceftazidime (CAZ), ceftolozane/tazobactam (C/T), ciprofloxacin (CIP), fosfomycin (FOF), meropenem (MEM), piperacillin/tazobactam (TZP) and tobramycin (TOB). Susceptibility to a regimen was derived from the minimum inhibitory concentrations value of the beta-lactam plus the minimum inhibitory concentrations value of the additional agent.Results: In 1209 P. aeruginosa, susceptibility to C/T exceeded 90%, while susceptibility to FEP, CAZ, MEM and TZP ranged from 73 to 78%. For antibiotic combinations, the addition of the 2nd agent AMK, TOB, CIP or FOF raised the susceptibility to FEP, CAZ, MEM and TZP, whereas very little added activity was noted for C/T due to the intrinsic potency of this compound alone.Conclusions: While the addition of AMK, TOB, CIP or FOF markedly increased the probability that an active regimen would be selected for empirical therapy with FEP, CAZ, MEM and TZP, C/T alone had higher activity than the combinations.

Elevated vancomycin minimum inhibitory concentrations among methicillin-resistant Staphylococcus aureus isolated from patients with ventilator-associated pneumonia at a Connecticut hospital.

Emerging evidence suggests that vancomycin minimum inhibitory concentrations (MICs) within methicillin-resistant Staphylococcus aureus (MRSA) are increasing. The objective of this surveillance study was to determine vancomycin MIC distributions for MRSA isolates collected from the respiratory tract of patients with ventilator-associated pneumonia (VAP) at a large community hospital in Hartford, Connecticut. The frequency of heteroresistant vancomycin intermediate S. aureus (hVISA) was also assessed for select isolates. Vancomycin MICs and hVISA screening were conducted using standard inoculum and macromethod Etest methodology, respectively, for isolates collected between November 2005 and August 2007. Fifty-eight isolates of MRSA were collected over the two-year period. The MIC50 and MIC90 were both 2 microg/ml; 31.0% and 58.6% of isolates had vancomycin MICs of 1.5 microg/ml and 2 microg/ml, respectively. None of the isolates tested were positive for hVISA; four isolates were VISA. Vancomycin MICs for respiratory MRSA at this Connecticut hospital are elevated. Institution-specific surveillance in the state is warranted.

In vitro investigation of synergy among fosfomycin and parenteral antimicrobials against carbapenemase-producing Enterobacteriaceae.

Intravenous fosfomycin is undergoing clinical development in the United States for treatment of complicated urinary tract infections (cUTIs) and may be prescribed as a component of dual antibiotic regimens against carbapenemase-producing Enterobacteriaceae (CPE). Fosfomycin, aztreonam, cefepime, ceftazidime, ceftazidime/avibactam, ceftolozane/tazobactam, meropenem, piperacillin/tazobactam, and tobramycin minimum inhibitory concentrations (MICs) were determined by gradient diffusion strip (GDS) against CPE isolates (N = 49). The GDS cross method was used to assess antibiotic interactions between fosfomycin and the aforementioned parenteral antibiotics. The resultant fractional inhibitory concentration index was used to classify interactions. Fosfomycin-containing combinations were evaluated only if nonsusceptible to the second agent. The fosfomycin MIC50 was ≥1024 mg/L by GDS. Synergy or additivity was detected in 80 (22%) fosfomycin-containing combinations. Antagonism was not observed. Ceftolozane/tazobactam most frequently displayed synergy [8 (16.3%) isolates]. When CPE are isolated, clinical laboratories should consider performing GDS synergy tests to identify favorable antibiotic interactions.

In vitro potency of antipseudomonal ß-lactams against blood and respiratory isolates of P. aeruginosa collected from US hospitals.

BACKGROUND: Challenges due to multidrug resistant (MDR) Gram-negative bacterial pathogens such as P. aeruginosa (PSA) are increasing globally. Suboptimal antimicrobial therapy of infections caused by PSA is associated with increased morbidity and mortality. As a result, antimicrobial susceptibility (%S) studies are pivotal to identifying trends in antimicrobial resistance that inform decisions regarding choice of antimicrobial therapy. This study assessed the in vitro potency of 7 antipseudomonal agents including ceftolozane/tazobactam (C/T) against PSA collected from numerous sites across the US. METHODS: Multiple US hospitals provided non-duplicate respiratory and blood isolates of PSA for potency testing. MICs against PSA were determined using broth microdilution methods according to CLSI for 7 antimicrobials with antipseudomonal activity: aztreonam (ATM), cefepime (FEP), ceftazidime (CAZ), C/T, imipenem (IPM), meropenem (MEM) and piperacillin/tazobactam (TZP). %S was defined per CLSI or FDA breakpoint criteria. RESULTS: Thirty-five hospitals geographically spread across the US provided a total of 1,209 PSA isolates. Of the antibiotics assessed, %S to C/T was the highest at 95% with an MIC50 of 0.5 mg/L and MIC90 of 2 mg/L. In comparison, other %S (MIC50/MIC90) was as follows: ATM 66% (8/32); FEP 76% (4/32); CAZ 78% (4/64); IPM 68% (2/16); MEM 74% (0.5/16); and TZP 73% (8/128). CONCLUSIONS: For this geographically diverse PSA population, C/T demonstrated the highest overall susceptibility (95%). Other antipseudomonal agents inclusive of the carbapenems displayed susceptibilities of 66-78%. In the era of escalating PSA resistance to the ß-lactams, the potency of C/T may represent an important clinical option.

Prevalence of in vitro synergistic antibiotic interaction between fosfomycin and nonsusceptible antimicrobials in carbapenem-resistant Pseudomonas aeruginosa.

PURPOSE: We assessed the synergistic potential of fosfomycin and parenteral antibiotics among carbapenem-resistant Pseudomonas aeruginosa (CRP). METHODOLOGY: Minimum inhibitory concentrations (MICs) were determined by broth microdilution for all antibiotics except fosfomycin, for which the gradient diffusion strip (GDS) method was used. The GDS cross method was performed to assess interactions between fosfomycin and: aztreonam, cefepime, ceftazidime, ceftazidime/avibactam, ceftolozane/tazobactam, meropenem, piperacillin/tazobactam and tobramycin. Only organisms that were nonsusceptible to the second drug were assessed. RESULTS: Among 153 clinical isolates, the fosfomycin MIC50/90 was 48/≥1024 mg l-1 . Synergy was detected in 131/604 (21.7 %) fosfomycin-antibiotic combinations among 76 (49.7 %) isolates. Ceftazidime (42/81, 51.9%) and ceftolozane/tazobactam (7/14, 50.0%) displayed synergy most frequently. Meropenem susceptibility was restored in 21 (13.7 %) isolates. Antagonism was not observed. CONCLUSION: Fosfomycin synergy was commonly observed in vitro among CRP. These data may guide the selection of combination antibiotic therapy. The susceptibility to other antibiotics was restored in combination with fosfomycin, warranting further in vivo evaluation.

Development of an HPLC-MS/MS method for the determination of ceftolozane/tazobactam in bronchoalveolar lavage fluid.

AIM: We describe the validation of an HPLC-MS/MS method to analyze ceftolozane and tazobactam simultaneously in saline matrixes. MATERIALS & METHODS: An Agilent 1260 HPLC interfaced to an Agilent 6470 triple-quadrupole mass spectrometer was used for quantification. A reverse-phase column running a gradient of water and acetonitrile containing 0.1% formic acid mobile phase at a flow rate of 1.0 ml/min provided chromatographic fractionation. Tazobactam15N3 was used as the internal standard. The standard curves were linear over a range of 0.02-0.5 µg/ml. CONCLUSION: This methodology represents a simple, reproducible approach to the determination of drug concentrations with accuracy and precision for pharmacokinetic studies undertaken with this recently US FDA-approved antimicrobial therapy.

In vivo microdialysis study of the penetration of daptomycin into soft tissues in diabetic versus healthy volunteers.

Daptomycin is approved for the treatment of complicated skin and soft tissue infections, including diabetic wounds of the lower extremities, at a dose of 4 mg/kg of body weight once daily. For such localized tissue infections, drug concentrations in the interstitial space are an important determinant of successful therapy. In the diabetic population, peripheral arterial disease may limit antibiotic penetration into the target tissue. The objective of this study was to describe and compare the pharmacokinetic profiles of daptomycin in the interstitial fluid of soft tissues in diabetic and healthy volunteers by using in vivo microdialysis. Twelve subjects (six diabetic and six healthy) received a single 4-mg/kg dose of daptomycin intravenously. Samples of plasma and tissue were simultaneously collected over 24 h. Diabetic and healthy groups were matched in mean age (+/-10 years), gender ratio, mean weight (+/-10 kg), and creatinine clearance rate (+/-20 ml/min/1.73 m(2)). Pharmacokinetic parameters for plasma were similar between groups (P > 0.05). The mean peak drug concentrations +/- standard deviations in tissue were 4.3 +/- 3.3 microg/ml and 3.8 +/- 1.4 microg/ml for diabetic and healthy subjects, respectively. The degree of tissue penetration, defined as the ratio of the area under the free drug concentration-time curve for tissue to that for plasma, was 0.93 +/- 0.61 for diabetic subjects and 0.74 +/- 0.09 for healthy subjects (P = 0.46). Daptomycin at 4 mg/kg penetrated well into the soft tissue, reaching concentrations approximately 70 to 90% of those of the free drug in plasma. Moreover, these free, bioactive concentrations in tissue exceeded the MICs for staphylococci and streptococci over the 24-h dosing interval.

Optimal dosing of piperacillin-tazobactam for the treatment of Pseudomonas aeruginosa infections: prolonged or continuous infusion?

STUDY OBJECTIVE: To compare conventional intermittent dosing regimens of piperacillin-tazobactam with prolonged and continuous infusions to determine the optimal dosing scheme against a local Pseudomonas aeruginosa population. DESIGN: Pharmacodynamic Monte Carlo simulation model. DATA SOURCE: Microbiologic data from 470 consecutive non duplicate P. aeruginosa isolates collected from a single institution over 6 months in 2006. PATIENTS: Five thousand simulated surgical patients and patients with neutropenia. MEASUREMENTS AND MAIN RESULTS: We simulated serum concentration-time profiles at steady state for several piperacillin-tazobactam dosing regimens, including intermittent, prolonged, and continuous infusions. The probability of achieving 50% free time above the MIC against 470 P. aeruginosa isolates was calculated. The cumulative fractions of response for the intermittent-infusion regimens were 74.7% (3.375 g every 6 hrs), 79.9% (4.5 g every 6 hrs), and 85.6% (3.375 g every 4 hrs). For prolonged infusion regimens, the cumulative fractions of response were 83.3% (3.375 g every 8 hrs, 4-hr infusion), 87.1% (4.5 g every 8 hrs, 4-hr infusion), and 89.6% (4.5 g every 6 hrs, 3-hr infusion). For continuous-infusion regimens, the cumulative fractions of response were 82.3% (10.125 g), 86.5% (13.5 g), 89.2% (18 g), 90.0% (20.25 g), and 90.6% (22.5 g). CONCLUSION: Both prolonged- and continuous-infusion strategies improved the pharmacodynamics of piperacillin-tazobactam over those of traditional 30-minute intermittent-infusion regimens. Prolonged- and continuous infusion regimens that contained the same daily doses of piperacillin had similar likelihoods of bactericidal exposure. Thus, the selection of dosing strategy depends on the availability of intravenous access versus the convenience of once-daily administration.

Pharmacokinetics of cefprozil in plasma and middle ear fluid: in children undergoing treatment for acute otitis media.

BACKGROUND: Despite the wide-scale use of cefprozil for acute otitis media (AOM), there are only limited data available regarding the pharmacokinetic profile of this agent in the pediatric population. OBJECTIVE: To characterize the plasma and middle ear fluid (MEF) pharmacokinetic profile of cefprozil in pediatric patients with AOM. METHODS: Pharmacokinetic sampling was obtained as part of a phase IV, multicenter, open-label study of children with AOM receiving cefprozil suspension 15 mg/kg twice daily. A single blood sample was obtained 4-6 days after the initiation of cefprozil therapy and a simultaneous MEF sample was obtained by tympanocentesis when clinically indicated. Cefprozil concentrations in both matrices were determined using a validated high-performance liquid chromatography methodology. A composite profile of cefprozil concentration data in each matrix was constructed and values for the pharmacokinetic parameters were obtained using conventional modeling techniques. RESULTS: Plasma concentrations were obtained in 53 children aged 6-48 months. In this population the maximum concentration (C(max)) in plasma was 9.18 microg/mL, the time to C(max) (t(max)) was 1.5 hours, and the terminal elimination half-life (t((1/2))(beta)) was 0.98 hours. Simultaneous plasma and MEF concentration data were available in 22 children. In this subset the C(max) in plasma was 8.2 microg/mL, the t(max) was 1.9 hours, and the t((1/2))(beta) was 1.02 hours; the corresponding MEF C(max) was 2.4 microg/mL, the t(max) was 3.5 hours, and the t((1/2))(beta) was 1.23 hours. Cefprozil MEF penetration as assessed using the ratio of the area under the concentration-time curves from the two matrices was 28%. Moreover, concentrations in MEF approximated 1 microg/mL 6 hours' post-dose. CONCLUSIONS: The plasma profile of cefprozil in the current analysis is consistent with previously reported values in children receiving the 15 mg/kg twice daily dose. MEF penetration and the duration of drug exposure at the site of infection support the clinical utility of this agent for organisms with minimum inhibitory concentrations (MIC) of < or =1 microg/mL. However, these results also predict higher clinical failure when using this dose of cefprozil against penicillin-non-susceptible Streptococcus pneumoniae or Haemophilus influenzae because of typically higher MIC values for these organisms.

Potency of parenteral antimicrobials including ceftolozane/tazobactam against nosocomial respiratory tract pathogens: considerations for empiric and directed therapy.

BACKGROUND: Empiric therapy decisions are predicated on knowledge of both the epidemiology and antimicrobial susceptibility of the probable infecting pathogen(s). The objective of this study was to evaluate the microbial distribution and phenotypic profiles of nosocomial respiratory isolates collected from multiple US hospitals and assess the clinical utility of various monotherapy and combination regimens. METHODS: Hospitals provided consecutive non-duplicate adult inpatients Gram-negative nosocomial respiratory isolates from cultures received ≥48 h after hospital admission. Minimum inhibitory concentrations (MICs) for 12 antimicrobials were determined using broth microdilution methods. An antibiogram was constructed for monotherapy regimens as well as combinations inclusive of either tobramycin (TOB) or ciprofloxacin (CIP). RESULTS: Six hospitals provided 518 nosocomial respiratory isolates. P. aeruginosa (PSA) comprised 28% of the population followed by Klebsiella pneumoniae (13%), Enterobacter spp. (13%), S. maltophilia (9%), S. marcesens (6%), A. baumannii (6%), and others (18%). When considering monotherapy for the Enterobacteriaceae & PSA ceftolozane/tazobactam (C/T) provided the highest (87%) percent susceptibility (%S) followed by meropenem (MEM), CIP, cefepime (FEP), ceftazidime (CAZ) and piperacillin-tazobactam (TZP) at 71-85%S. The addition of TOB > CIP improved the probability that the antimicrobial combination would provide ≥1 active agent. CONCLUSIONS: PSA was the predominant nosocomial respiratory pathogen; however, the Enterobacteriaceae comprised an additional 53% in this survey. When considering empiric ß-lactam monotherapy therapy for the entire spectrum of pathogens C/T provided the highest (78%) %S followed by MEM, FEP and TZP. The addition of either TOB > CIP to these ß-lactams enhances the likelihood that an active agent would be selected when considering empirical therapy choices for nosocomial respiratory tract infections.

Development of an HPLC Method for the Determination of Ceftolozane/Tazobactam in Biological and Aqueous Matrixes.

Herein, we report the development and validation of an HPLC method to analyze ceftolozane and tazobactam simultaneously in human plasma, human serum, swine serum and saline matrixes. A reversed-phase column was used with a UV detector set at 260 nm and switched to 218 nm. The mobile phase consisted of methanol and sodium phosphate buffer at a flow rate of 1.1 mL/min. Cefepime was used as the internal standard. The standard curves were linear over a range of 0.4-50 µg/mL. This methodology represents a simple, reproducible approach to the determination of drug concentrations with sufficient accuracy and precision for pharmacokinetic studies undertaken with this recently FDA-approved antimicrobial therapy.