Prolonged Infusion Regimens Research Articles

Defining standard and high dosages for β-lactam agents administered by intermittent, prolonged or continuous infusion: a PK/PD simulation study.

The new definitions of antimicrobial susceptibility categories proposed by EUCAST in 2020 require the definition of standard and high dosages of antibiotic. For injectable β-lactams, standard and high dosages have been proposed for short-infusion regimens only. To evaluate dosages for β-lactams administered by prolonged infusion (PI) and continuous infusion (CI). Monte Carlo simulations were performed for seven injectable β-lactams: aztreonam, cefepime, cefotaxime, cefoxitin, ceftazidime, piperacillin and temocillin. Various dosage regimens based on short infusion, PI or CI were simulated in virtual patients. Pharmacokinetic (PK) profiles and PTAs were obtained based on reference population PK models, as well as PK/pharmacodynamic targets and MIC breakpoints proposed by EUCAST. Alternative dosage regimens associated with PTA values similar to those of recommended dosages up to the breakpoints were considered acceptable. Adequate PTAs were confirmed for most EUCAST short-infusion dosage regimens. A total of 9 standard and 14 high dosages based on PI (3 to 4 h) or CI were identified as alternatives. For cefepime and aztreonam, only PI and CI regimens could achieve acceptable PTAs for infections caused by Pseudomonas spp.: 2 g q8h as PI of 4 h or 6 g/24 h CI for cefepime; 2 g q6h as PI of 3 h or 6 g/24 h CI for aztreonam. These alternative standard and high dosage regimens are expected to provide antibiotic exposure compatible with new EUCAST definitions of susceptibility categories and associated MIC breakpoints. However, further clinical evaluation is necessary.

Pharmacokinetic/Pharmacodynamic Determination of Systemic MIC Breakpoints for Intermittent, Extended, and Continuous Infusion Dosage Regimens of Mecillinam.

Intravenous mecillinam has been used for the treatment of urosepsis at several dosing regimens, including a dose of 1,000 mg three times a day (TID). In the current pharmacokinetic/pharmacodynamic (PK/PD) study, we analyzed intermittent, extended, and continuous infusion regimens of mecillinam to provide dosage recommendations to treat infections caused by Enterobacterales exhibiting relatively higher mecillinam MICs than the wild-type strains. Monte Carlo simulation studies indicated that regimens of 1,000 mg TID and 1,000 to 1,200 mg four times a day (QID) are efficacious against wild-type and extended-spectrum β-lactamase-producing Enterobacterales, respectively. Prolonged infusion regimens (extended and continuous) could cover carbapenemase producers with a higher range of MICs (2 to 8 mg/L). IMPORTANCE Previous studies have shown that intravenous mecillinam might be suitable for treatment of urosepsis. Since multidrug-resistant Enterobacterales are common pathogens in such infections, an effort was made to delineate intermittent, extended, and continuous infusion regimens that could cover pathogens exhibiting relatively higher mecillinam MICs than the wild-type strains. Our PK/PD analysis has shown that mecillinam might be considered a valuable therapeutic option for the treatment of systemic infections caused by extended-spectrum β-lactamase- and carbapenemase-producing Enterobacterales exhibiting mecillinam MICs up to 8 mg/L.

Parameters influencing the pharmacokinetics/pharmacodynamics of piperacillin/tazobactam in patients with febrile neutropenia and haematological malignancy: a prospective study.

To assess population pharmacokinetics (PK) and pharmacodynamics (PD) of both piperacillin and tazobactam in neutropenia patients and examine dosage requirements related to the MIC distribution for Gram-negative bacteria involved in bloodstream infections (BSIs). We conducted a prospective study including adult haematological malignancy patients with febrile neutropenia receiving piperacillin/tazobactam as short (30 min) or prolonged (4 h) intravenous infusions. Concentration data were analysed using a population approach. Dosing simulations with the final model investigated factors influencing the PK/PD of piperacillin/tazobactam quantified by fT>MIC or PTA for piperacillin and tazobactam, respectively. In parallel, the local MIC distribution of β-lactams was documented for Gram-negative bacteria involved in BSIs. Over 10 months, 31 patients were enrolled, with 11 (35.5%) short and 20 (64.5%) prolonged infusion regimens. A one-compartment model adequately described the data for both drugs. Prolonged infusion, increased serum alkaline phosphatase (ALP) values and renal function impairment were associated with increased piperacillin fT>MIC. For patients with normal or augmented renal CL, dosing regimens q8h or q6h with 30 min of infusion were insufficient to achieve acceptable PTA for piperacillin/tazobactam at the median MIC value of 8 mg/L. Prolonged infusion of large doses was associated with the best PTA for both piperacillin and tazobactam. In a population of haematological malignancy patients with neutropenia, renal function and ALP influenced the PK of piperacillin/tazobactam. Prolonged intravenous infusion would optimize the PK of piperacillin/tazobactam, especially in the case of augmented renal CL and/or low-range bacterial susceptibility.

A Review of Wound Infusion With Local Anesthetics in Plastic Surgery.

Suboptimal pain management is a common, yet largely unrecognized, problem in the postsurgical patient population. Current treatment protocols heavily rely on opioid use and, though generally effective in providing pain relief, are associated with multiple side effects. The present systematic review aims to offer plastic surgeons insight into the current state of literature on prolonged local anesthetic wound infusion regimens, evaluating both their efficacy in lowering pain scores and the potential opioid-sparing effect. A comprehensive literature search of the Medline, Embase, and Cochrane Library databases was performed to identify relevant studies published between 1980 and December 2017 evaluating the use of prolonged local anesthetic wound infusion for postoperative pain management in plastic surgery. A total of 28 articles were selected, including 3904 patients. The overall infection rate in all patients treated with postsurgical local anesthetic wound infiltration was 0.28% (7/2536). There were no reported cases of systemic toxicity. An opioid-sparing effect was found in 92% (12/13) of studies when compared to an active comparator and 88% (7/8) of those comparing to placebo. Pain scores were decreased in 90% (9/10) of studies comparing wound infiltration to narcotic-based regimens and in 67% (6/9) of those comparing to placebo. Continuous or intermittent wound infusion is safe and effective in reducing pain scores and opioid consumption in plastic surgery. Though the overall pain-lowering effect appears to be modest, ease of catheter insertion and patient satisfaction make this technique an alluring alternative to more validated approaches such as neuraxial or peripheral nerve blocks.

Population Pharmacokinetics and Pharmacodynamic Target Attainment of Meropenem in Critically Ill Young Children.

This study aims to describe the population pharmacokinetics and pharmacodynamic target attainment of meropenem in critically ill children. The study involved a retrospective medical record review from a 189-bed, freestanding children's tertiary care teaching hospital of patients ages 1 to 9 years who received meropenem with concurrent therapeutic drug monitoring. There were 9 patients ages 1 to 9 years (mean age, 3.1 ± 2.9 years) with a mean weight of 17.1 ± 11.9 kg who met the inclusion/exclusion criteria and were included in the pharmacokinetic analysis. Meropenem concentrations were best described by a 2-compartment model with first-order elimination, with an R2 and bias of 0.91 and 13.2 mg/L, respectively, for the observed versus population predicted concentrations, and an R2, bias, and imprecision of 1, 0.0675, and 1 mg/L, respectively, for the observed versus individual predicted concentrations. The mean total body drug clearance for the population was 6.99 ± 2.5 mL/min/kg, and Vc was 0.57 ± 0.47 L/kg. The calculated population estimate for the total volume of distribution was 0.78 ± 0.73 L/kg. Standard 0.5-hour meropenem infusions did not provide for appropriate pharmacodynamic exposures of 40% free time > minimum inhibitory concentration (40% fT > MIC) for Gram-negative organisms with susceptible MICs. Dosage regimens employing prolonged and continuous infusion regimens did provide appropriate pharmacodynamic exposures of 40% fT > MIC for Gram-negative organisms up to the break point for Pseudomonas aeruginosa of 4 mg/L. These data suggest the reference dosage regimens for meropenem (20-40 mg/kg per dose every 8 hours) do not meet an appropriate pharmacodynamic target attainment in critically ill children ages 1 to 9 years. Based on these data, only the 3- to 4-hour prolonged infusion and 24-hour continuous infusion regimens were able to achieve an optimal probability of target attainment against all susceptible Gram-negative bacteria in critically ill children for 40% fT > MIC. Dosage regimens of 120 and 160 mg/kg/day as continuous infusion regimens may be necessary to achieve an optimal probability of target attainment against all susceptible Gram-negative bacteria in critically ill children for 80% fT > MIC. Based on these findings, confirmation with a larger, prospective investigation in critically ill children is warranted.

The Effect of Clinical Concentrations of Meropenem (MEM), Ceftolozane/tazobactam (C/T), and Ceftazidime/avaibactam (CZA) on Time to Detection (TTD) and Growth of Pseudomonas aeruginosa (PSA) in bioMerieux BacT/ALERT®FA Plus Blood Culture (BC) Bottles

BackgroundAntimicrobial binding agents (ABA) are added to BC bottle media to reduce TTD and prevent false negatives that may result when BCs are obtained in patients receiving antibiotics. Sparse data are available on the effectiveness of ABA containing BacT/ALERT®FA Plus BC bottles against MEM, C/T and CZA, which are often administered as high dose and/or prolonged infusion regimens for suspected PSA infections.MethodsBC bottles were inoculated with 10ml of fresh whole blood collected from healthy volunteers. The blood was spiked to achieve mean peak, midpoint, and trough concentrations of MEM (40, 20 and 5 µg/mL), C/T (150, 50, and 8 µg/mL), and CZA (90, 25, and 10 µg/mL), respectively. A control bottle containing no antibiotic was included. BC bottles were then inoculated with 7–30 colony forming units (CFU)/bottle of either a MEM susceptible (MEM-S) (MIC = 0.5 µg/mL, C/T = 0.5 µg/mL, CZA = 2 µg/mL) or MEM resistant (MEM-R) PSA (MIC = 8 µg/mL, C/T = 4 µg/mL, CZA = 8 µg/mL) isolate. Matching bottles were entered into a BacT/ALERT®-3D detection instrument and a standard incubator at 37° C for up to 72h. Each series was conducted in duplicate. TTD was measured in the detection instrument, and CFUs were counted at 0, 4, 12, 24, 36, 48, 60, and 72h in incubated bottles.ResultsControl PSA grew to 7.4 × 108/mL with a TTD of 15.5–19.5 hours. Both PSA grew in the presence of MEM trough concentrations with TTD of 21.3 ± 3.3 hours. However, midpoint and peak concentrations inhibited growth of the MEM-S PSA. The MEM-R PSA grew in the presence of all MEM concentrations, with a TTD of 18.6 ± 0.5 hours. Both PSA grew in the presence of C/T trough concentrations with TTD of 23.0 ± 2.6 hours, but were inhibited by midpoint and peak C/T concentrations. For CZA, both PSA grew in the presence of trough concentrations with TTD of 20.1 ± 1.9 hours. Peak CZA concentrations inhibited growth of both PSA, while midpoint concentrations inhibited growth of the MEM-S isolate.ConclusionThese are the first data to show that BacT/ALERT BC bottles containing ABA may not sufficiently inactivate achievable concentrations of MEM, C/T or CZA, which could result in false negatives. In patients already receiving one of these antibiotics, BCs should be collected just prior to the next dose to increase the probability of PSA detection.Disclosures All authors: No reported disclosures.

Simplifying Piperacillin/Tazobactam Dosing: Pharmacodynamics of Utilizing Only 4.5 or 3.375 g Doses for Patients With Normal and Impaired Renal Function

Objectives: To evaluate the pharmacodynamic exposure of piperacillin/tazobactam across the renal function range using 4.5 or 3.375 g dosing regimens. Methods: A 5000-patient Monte Carlo simulation was conducted to determine the probability of achieving 50% free time above the minimum inhibitory concentration (fT > MIC) for piperacillin. Proposed regimens, using solely 4.5 or 3.375 g strengths, were compared with regimens listed in piperacillin/tazobactam prescribing information over creatinine clearance (CrCl) ranges of 120 mL/min to hemodialysis. The probability of target attainment (PTA) at MICs ≤ 16 μg/mL was compared between proposed and standard regimens. Results: At CrCl 41 to 120 mL/min, prolonged infusions of 4.5 g (3 hours) and 3.375 g (4 hours) every 6 hours resulted in ≥95% PTA versus ≥76% for standard regimens (0.5 hour). At CrCl 20 to 40 mL/min, 4.5 and 3.375 g every 8 hours as prolonged infusions achieved slightly higher PTA (≥98%) versus standard regimens (≥93%). Similarly, PTA achieved with prolonged infusions of 4.5 and 3.375 g every 12 hours (≥93%) was comparable with those of standard regimens (≥91%) at CrCl 1 to 19 mL/min. In hemodialysis, 100% PTA was achieved with prolonged infusion regimens. Conclusion: Piperacillin/tazobactam regimens designed around the 4.5 or 3.375 g dose and prolonged infusions provided similar or better PTA at MICs ≤ 16 μg/mL compared with standard regimens. These observations may support the stocking and use of a single piperacillin/tazobactam strength to simplify dosing.

Optimizing beta-lactam pharmacodynamics against Pseudomonas aeruginosa in adult cystic fibrosis patients

BackgroundPatients with cystic fibrosis (CF) exhibit increased clearance of beta-lactams. The purpose of this study was to predict the probability of beta-lactam target attainment (PTA) against Pseudomonas aeruginosa in adult CF patients based on local microbiological data. MethodsCF-specific pharmacokinetic parameters were obtained from published data for aztreonam, cefepime, ceftazidime, meropenem and piperacillin–tazobactam. Pharmacodynamic modeling was used to determine the PTA for bolus, prolonged infusion, and continuous infusion regimens. ResultsProlonged infusion of meropenem 2g every 8h performed the best among all regimens tested, with a PTA of 83%. The PTA was increased with both prolonged and continuous infusion; however, no regimen reached the target PTA of >90% against P. aeruginosa in CF patients at our institution. ConclusionsProlonged and continuous infusion provided higher PTA than bolus for all regimens. Further investigation of novel regimens in CF patients is needed.

Pharmacodynamic Evaluation of the Potential Clinical Utility of Fosfomycin and Meropenem in Combination Therapy against KPC-2-Producing Klebsiella pneumoniae

KPC-producing Klebsiella pneumoniae causes serious infections associated with high death rates worldwide. Combination therapy consisting of fosfomycin and a carbapenem is better than monotherapy to combat multidrug-resistant microorganisms, but no dosages for the combination have been defined. The MICs of meropenem and fosfomycin were evaluated against 18 clinical isolates of KPC-2-producing K. pneumoniae The activities of combination antimicrobials were also determined by the checkerboard method. The MIC50 and MIC90 of each agent alone and in combination were challenged against short (1.5-h) or prolonged (3-h) infusion regimens of meropenem (1 g every 8 h [q8h], 1.5 g q6h, 2 g q8h) and fosfomycin (4 g q8h, 6 g q6h, 8 g q8h) by Monte Carlo simulation to evaluate the time above the MIC of the free drug concentration as a percentage of the dosing interval (fT>MIC). The monotherapy MIC50s and MIC90s were 32 and 256 mg/liter for meropenem and 64 and 512 mg/liter for fosfomycin, respectively. Antimicrobial combination increased bacterial susceptibility to 1/4 the MIC50s and to 1/8 to 1/16 the MIC90s of monotherapy. The antimicrobial combination demonstrated a synergistic effect for at least two-thirds of the isolates. In combination therapy, fosfomycin regimens of 6 g q6h and 8 g q8h as a 3-h infusion against the MIC50 and MIC90 had better chances of achieving ≥90% probability of target attainment (PTA) of 70% fT>MIC. Meropenem regimens of 1.5 g q6h and 2 g q8h in prolonged infusion can achieve close to 90% PTA of 40% fT>MIC for MIC50 but not MIC90 The significant reduction in the MIC values and the achievement of appropriate PTA demonstrated that regimens containing fosfomycin with meropenem can be effective against KPC-2-producing K. pneumoniae.

Comparison of Short Versus Prolonged Infusion of Standard Dose of Meropenem Against Carbapenemase-Producing Klebsiella pneumoniae Isolates in Different Patient Groups: A Pharmacokinetic–Pharmacodynamic Approach

Dose optimization is required to increase carbapenem's efficacy against carbapenemase-producing isolates. Four clinical Klebsiella pneumoniae isolates were used: one susceptible to meropenem with minimum inhibitory concentration (MIC) 0.031 mg/L and 3 verona integron-borne metallo bete-lactamase-1–producing isolates with MICs 8, 16, and 128 mg/L. The human pharmacokinetics of short (0.5-h) and prolonged (3-h) infusion regimens of 1 g meropenem every 8 h were simulated in an in vitro pharmacokinetic–pharmacodynamic model. Time-kill curves were constructed for each isolate and dosing regimen, and the %T > MIC associated with maximal bactericidal activity was estimated. The percentage of pharmacodynamic target attainment for isolates with different MICs was calculated for 350 ICU, surgical, and internal medicine patients. The isolates with MIC ≤8 mg/L were killed with both dosing regimens. The %T > MIC corresponding to maximal bactericidal activity was ∼40%. The percentages of target attainment were >90%, 61%-83%, 23%-33%, and <3% with the short infusion regimen and >90%, 98%-99%, 55%-79%, and <5% with the prolonged infusion regimen for isolates with MIC ≤2, 4, 8, and ≥16 mg/L, respectively. The lowest target attainment rates were observed for the ICU patients and the highest for internal medicine patients. The prolonged infusion regimen was more effective than the short infusion regimen against isolates with MIC 4-8 mg/L.

Pharmacokinetic-pharmacodynamic modelling of meropenem against VIM-producing Klebsiella pneumoniae isolates: clinical implications.

VIM-producing Klebsiella pneumoniae isolates are usually associated with high MICs to carbapenems. Preclinical studies investigating the pharmacokinetic-pharmacodynamic (PK-PD) characteristics of carbapenems against these isolates are lacking. The in vitro antibacterial activity of meropenem against one WT and three VIM-producing K. pneumoniae clinical isolates (median MICs 0.031, 8, 16 and 128 mg l- 1) was studied in a dialysis-diffusion PK-PD model and verified in a thigh infection neutropenic animal model by testing selected strains and exposures. The in vitro PK-PD target associated with bactericidal activity was estimated and the target attainment for different dosing regimens was calculated with Monte Carlo analysis. The in vitro model was correlated with the in vivo data, with log10CFU/ml reduction of < 1 for the VIM-producing (MIC 16 mg l- 1) and >2 for the WT (MIC 0.031 mg l- 1) isolates, with %f T >MIC 25 and 100%, respectively. The in vitro bactericidal activity for all isolates was associated with 40 % f T>MIC and attained in >90% of cases with the standard 1 g q8 0.5 h infusion dosing regimen only for isolates with MICs up to 1 mg l- 1. For isolates with MICs of 2-8 mg l- 1, prolonged infusion regimens (4 h infusion q8 or 2 h infusion q4) of standard (1 g) and higher (2 g) doses or continuous infusion regimens (3-6 g) are required. For isolates with a MIC of 16 mg l- 1 the unconventional dosing regimen of 2 g as 2 h infusion q4 or 12 g continuous infusion will be required. Prolonged and continuous infusion regimens of meropenem may increase efficacy against VIM-producing K. pneumoniae isolates.

Steady‐state pharmacokinetics and pharmacodynamics of meropenem in morbidly obese patients hospitalized in an intensive care unit

The study objective was to evaluate meropenem pharmacokinetics and pharmacodynamics in morbid obesity. Nine patients hospitalized in an intensive care unit with a body mass index ≥40 kg/m(2) received meropenem 500 mg or 1 g q6h, infused over 0.5 hours. Pharmacokinetic parameters were estimated, and Monte Carlo simulations were performed for 5 dosing regimens (500 mg q8h, 1 g q8h, 2 g q8h, 500 mg q6h, 1 g q6h) infused over 0.5 and 3 hours. Probability of target attainment (PTA) was calculated using fT > MIC of 40% and 54%. Total body weight and body mass index were 152.3 ± 31.0 kg and 54.7 ± 8.6 kg/m(2) , respectively. Volume of distribution of the central compartment was 13.3 ± 6.7 L, volume of distribution at steady-state was 37.4 ± 14.7 L, and systemic clearance was 10.2 ± 5.0 L/h. At an MIC of 2 µg/mL, PTA was ≥90% for 4/5 and 2/5 regimens infused over 0.5 hours and for 5/5 and 4/5 regimens infused over 3 hours at 40% and 54% fT > MIC, respectively. Standard doses achieve adequate exposures for susceptible bacteria at a pharmacodynamic target of 40% fT > MIC. Higher doses or prolonged infusion regimens are needed at the higher pharmacodynamic target.

Pharmacokinetics and pharmacodynamics of extended-infusion piperacillin/tazobactam in adult patients with cystic fibrosis-related acute pulmonary exacerbations

Given the high frequency of acute pulmonary exacerbations due to Pseudomonas aeruginosa in patients with cystic fibrosis (CF), piperacillin/tazobactam is commonly used in empirical regimens. While extended-infusion piperacillin/tazobactam has been employed as one strategy to optimize this agent's pharmacodynamics, this approach has not been well characterized in patients with CF. The objectives of this study were to characterize the pharmacokinetics and pharmacodynamics of extended-infusion piperacillin/tazobactam in adult patients with CF and derive optimized piperacillin/tazobactam dosing recommendations. Six serum samples were collected from nine adult patients with CF hospitalized for acute pulmonary exacerbations who received 3/0.375 g of piperacillin/tazobactam intravenously for 4 h every 8 h. Population pharmacokinetic models were fitted to the data utilizing first-order, Michaelis-Menten (MM) and parallel first-order/MM clearance. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) for regimens where free piperacillin concentrations were above the MIC for at least 50% of the dosing interval. The model incorporating MM clearance best described the data. Results of our simulation revealed that piperacillin/tazobactam dosed at 3-4 g for 30 min every 6-8 h led to <90% PTA against MIC values >4 mg/L. More intensive prolonged infusion regimens than are commonly used in practice, such as continuous infusions or 3 h infusions every 6 h, were needed to maximize the PTA for MICs ≥ 8 mg/L. Intensive prolonged infusion regimens are the best option to ensure optimal exposures against most susceptible isolates in adult patients with CF.

Pharmacodynamic Profiling of Antimicrobials against Gram-negative Respiratory Isolates from Canadian Hospitals

With diminishing antimicrobial potency, the choice of effective empirical therapy has become more challenging. Thus, the pharmacodynamic evaluation of potential therapies is essential to identify optimal agents, doses and administration strategies. Monte Carlo simulation was conducted for standard and/or prolonged infusion regimens of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, doripenem, ertapenem, meropenem and piperacillin/tazobactam. Minimum inhibitory concentrations were obtained for Escherichia coli (n=64 respiratory isolates), Enterobacter cloacae (n=53), Klebsiella pneumoniae (n=75) and Pseudomonas aeruginosa (n=273) throughout Canada. The cumulative fraction of response (CFR) was calculated using bactericidal targets for each regimen against each species. A CFR ≥90% was defined as optimal. All cefepime, doripenem, ertapenem and meropenem regimens achieved optimal exposures against Enterobacteriaceae, whereas target attainment was organism and dose dependent for the other agents. Prolonged infusion doripenem and meropenem 1 g and 2 g every 8 h, along with standard infusion doripenem and meropenem 2 g every 8 h, were the only regimens to attain optimal exposures against P aeruginosa. Ciprofloxacin had the lowest CFR against P aeruginosa, followed by cefepime. Among the P aeruginosa isolates collected in the intensive care unit (ICU) compared with the wards, differences of 0.5% to 10% were noted in favour of non-ICU isolates for all agents; however, marked differences (10% to 15%) in CFR were observed for ciprofloxacin in favour of ICU isolates. Standard dosing of cefepime, doripenem, ertapenem and meropenem has a high likelihood of obtaining optimal pharmacodynamic indexes against these Enterobacteriaceae. For P aeruginosa, aggressive treatment with high-dose and/or prolonged infusion regimens are likely required to address the elevated resistance rates of respiratory isolates from Canada.

Pharmacodynamic profiling of intravenous antibiotics against prevalent Gram-negative organisms across the globe: the PASSPORT Program—Asia-Pacific Region

Due to escalating antimicrobial resistance amongst Gram-negative organisms, the choice of effective empirical antimicrobial regimens has become challenging. Monte Carlo simulations were conducted for conventional and prolonged infusion regimens of doripenem, imipenem and meropenem using pharmacokinetic data from adult patients with conserved renal function. Minimum inhibitory concentration data against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii were incorporated from the COMPACT surveillance programme in the Asia-Pacific region of the world. The cumulative fraction of response (CFR) was determined for each regimen against each bacterial population. All simulated carbapenem regimens achieved an optimal CFR against E. coli and K. pneumoniae (94.5–100% CFR). Against P. aeruginosa, doripenem achieved 78.7–92.6% CFR, imipenem achieved 60.4–79.0% CFR and meropenem achieved 73.0–85.1% CFR. The only dosing regimen to achieve ≥90% CFR against P. aeruginosa was doripenem 1000mg and 2000mg every 8h (4-h infusion). Carbapenem CFRs against A. baumannii were much lower (29.2–54.4% CFR). CFRs for non-fermenting isolates were ca. 10% lower for isolates collected in the Intensive Care Unit. Carbapenem resistance amongst Enterobacteriaceae remains low in the Asia-Pacific region and thus standard carbapenem dosing regimens had a high likelihood of achieving pharmacodynamic exposures. However, larger doses combined with prolonged infusion will be required to increase the CFR for these carbapenems against resistant non-fermenting Gram-negatives that are common in these countries. The safety and efficacy of these high dosing regimens will need to be confirmed in the clinical setting.

Appropriate Billing for Infusion Pumps Used in Prolonged Chemotherapy Provided in the Office Setting.

Appropriate Billing for Infusion Pumps Used in Prolonged Chemotherapy Provided in the Office Setting.

Phase I–II trial of prolonged gemcitabine infusion plus paclitaxel as a biweekly schedule for advanced breast cancer patients pretreated with anthracyclines

Paclitaxel (PACL) plus gemcitabine (GEM) is an effective regimen for advanced breast cancer patients pretreated with anthracyclines. A prolonged GEM infusion at a fixed dose rate (FDR) of 10 mg/m²/min produces higher levels of intracellular active metabolites of GEM when compared with a standard 30-min infusion. In the present phase I/II trial, we investigated the association of FDR GEM plus PACL. 1,200 mg/m² was the dose of GEM recommended for the phase II study, in which patients received PACL at 150 mg/m², followed by FDR GEM at 1,200 mg/m² (total GEM infusion time = 120 min), both drugs administered biweekly. Forty-two anthracycline-pretreated advanced breast cancer patients with disease recurrence following at least one line of chemotherapy were enrolled. Two (4.8%) and 12 (33.3%) patients experienced a complete and partial response, respectively, for an overall response rate of 38.1% (95% CI 23.4-52.8%). Median progression free survival and overall survival were 5 and 19.9 months, respectively. No statistically significant association was noted between in situ protein expression of RRM1 and BRCA1 (as assessed by immunofluorescence combined with automated quantitative analysis) and response to treatment in 15 patients with tissue available for analysis. Toxicity was mostly mild to moderate, mainly consisting of G3-G4 neutropenia (9.6%) and hypertransaminasemia (9.5%). Biweekly FDR GEM in combination with PACL is an active and safe regimen for advanced breast cancer patients pretreated with anthracyclines. A prolonged infusion regimen of GEM does not seem to improve the efficacy of a standard 30-min infusion.

Pharmacodynamic modeling of intravenous antibiotics against gram-negative bacteria collected in the United States

Background: In the era of escalating antimicrobial resistance, the choice of effective empiric antimicrobial therapy has become considerably more difficult. In an attempt to improve antimicrobial selection, pharmacodynamic modeling that considers the drug, dose, dosing interval, and duration of infusion is increasingly used as a tool to assist in the clinical decision-making process. Objective: The aim of the PASSPORT (Probability of target attainment of Antibacterial agents Studied for Susceptibility and Pharmacodynamic Optimization in Regional Trials) study was to compare the probabilities of achieving requisite pharmacodynamic exposure (eg, T>MIC, AUC/MIC) of common intravenous antibiotics against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Methods: Using a 5000-patient Monte Carlo simulation, pharmacodynamic analyses were conducted for standard and high-dose, prolonged (ie, 3-to 4-hour) infusions of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, doripenem, ertapenem, imipenem, levofloxacin, meropenem, and piperacillin/tazobactam in adult patients with normal renal function (≥50 mL/min). MIC data were incorporated from the 2008 TRUST (Tracking Resistance in the United States Today)-12 surveillance program, a long-running resistance study in 56 participating US hospitals. The cumulative fraction of response (CFR) was determined for each regimen against each population of E coli, K pneumoniae, A baumannii, and P aeruginosa. Optimal CFR was defined a priori as ≥90%. Results: All of the β-lactam regimens had optimal CFRs against E coli, and all but piperacillin/tazobactam 3.375 g q6h had optimal CFRs against K pneumoniae. The fluoroquinolones had the lowest CFRs against all of the pathogen populations tested (73.2%–88.9% against E coli and K pneumortfae; 44.5 %–61.9 % against A baumannii and P aeruginosa). Optimal CFR against A baumannii was not achieved with any of the regimens. Against P aeruginosa, high-dose, prolonged-infusion doripenem and meropenem had CFRs of 97.2% to 98.8%, followed by high-dose, prolonged-infusion ceftazidime (93.3%) and cefepime (93.2%). High-dose, prolonged-infusion regimens were associated with increased CFRs for all (β-lactams by ~10% over that of standard 0.5-hour infusion regimens against the nonfermenting gram-negative bacilli. Conclusions: Based on this model, standard doses of most intravenous (β-lactam regimens had high probabilities of achieving optimal exposure against Enterobacteriaceae. For nonfermenting gram-negative bacilli such as A baumannii and P aeruginosa, high-dose, prolonged infusions of cefepime, ceftazidime, doripenem, and meropenem had the highest probabilities of achieving bactericidal exposure.

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=16 microg/ml. The objective of this experiment was to compare the efficacy of this high-dose, prolonged-infusion regimen against carbapenemase-producing Klebsiella pneumoniae isolates with the efficacy against P. aeruginosa isolates having similar meropenem MICs. An in vitro pharmacodynamic model was used to simulate human serum concentrations. Eleven genotypically confirmed K. pneumoniae carbapenemase (KPC)-producing isolates and six clinical P. aeruginosa isolates were tested for 24 h, and time-kill curves were constructed. High-performance liquid chromatography (HPLC) was used to verify meropenem concentrations in each experiment. Meropenem achieved a rapid >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.

Probability of pharmacodynamic target attainment with standard and prolonged-infusion antibiotic regimens for empiric therapy in adults with hospital-acquired pneumonia

Background: The pharmacodynamic characteristics of antibiotics should be considered when choosing empiric dosage regimens for the treatment of pneumonia. Objective: This study compared the probabilities of achieving requisite pharmacodynamic exposure (ie, f T > MIC, AUC/MIC) for antibiotics given for the empiric treatment of hospital-acquired pneumonia (HAP) as recommended by the 2005 guidelines of the American Thoracic Society and the Infectious Diseases Society of America. Methods: In a 5000-patient Monte Carlo simulation, pharmacodynamic analyses were performed for standard doses of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, ertapenem, imipenem, levofloxacin, meropenem, and piperacillin/tazobactam. Prolonged 3-hour infusion regimens were also evaluated for anti-pseudomonal β-lactams. MIC data were incorporated from the 2007 Meropenem Yearly Susceptibility Test Information Collection, a national surveillance study. The weighted cumulative fraction of response (wCFR) against common pneumonia pathogens was determined for each regimen. A second scenario was conducted by altering the pathogen prevalence to assess wCFR for late-onset pneumonia (ie, HAP in patients with prolonged mechanical ventilation). Optimal wCFR was defined a priori as ≥90%. Results: Among the 0.5-hour infusions, cefepime, ceftazidime, and meropenem had the highest wCFRs (≥90%) against pathogens that cause HAP (cefepime, 1 g q8h, 92.8%; 2 g q8h, 97.2%; 2 g q12h, 94.3%; ceftazidime, 2 g q8h, 93.2%; meropenem, 1 g q8h, 90.9%; 2 g q8h, 93.9%). Imipenem (500 mg q6h, 85.5%; 1 g q8h, 88.1%) and piperacillin/tazobactam (4.5 g q6h, 80.5%) as 0.5-hour infusions were nearly optimal, whereas ceftriaxone, ertapenem, and the fluoroquinolones had the lowest wCFR values. All regimens showed lower wCFRs for late-onset pneumonia than for HAP. Optimal wCFRs were found only with prolonged (3-hour) infusions of 2 g q8h for ceftazidime (94.5%) and meropenem (90.1%), whereas cefepime 2 g q8h achieved optimal wCFR with both a 0.5-hour infusion (93.1%) and a 3-hour infusion (95.3%). Conclusions: Results of this model suggest that standard doses of most antipseudomonal β-lactams (cefepime, ceftazidime, and meropenem) had high probabilities of achieving optimal pharmacodynamic exposure as empiric therapy for HAP, whereas the low probabilities predicted from ceftriaxone, ertapenem, and the fluoroquinolones suggest that these agents would be inappropriate as monotherapy. For late-onset HAP, prolonged infusions of cefepime, ceftazidime, and meropenem offered the highest probabilities of achieving bactericidal exposure.