Relative bioavailability of crushed tebipenem administered through a nasogastric tube with and without enteral feeding.

OBJECTIVE: Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem prodrug of the active agent tebipenem with broad-spectrum activity against drug-resistant Enterobacterales. This study aimed to evaluate the relative bioavailability of crushed tebipenem tablets administered via nasogastric tube (NGT) with or without concomitant enteral feeds. METHODS: This Phase 1, open label study randomized 12 healthy subjects to receive a crushed tebipenem tablet via NGT (n = 6) or via NGT with concomitant Osmolite® enteral feeds (n = 6) on Study Day 1, followed by oral administration of tebipenem whole tablet (reference formulation) on Study Day 2. Tebipenem plasma concentrations were measured by LC with mass spectrometry. Bioequivalence was determined using pharmacokinetic parameters derived through non-compartmental analyses. RESULTS: Mean ±â€ŠSD tebipenem pharmacokinetic parameters in plasma for subjects who received a crushed tablet via NGT (relative to whole tablet) and a crushed tablet with enteral feeds (relative to whole tablet) were as follows: maximum total plasma concentration (Cmax), 11.1 ±â€Š3.9 (12 ±â€Š3.4) and 10.2 ±â€Š1.9 (10 ±â€Š4) mg/L; area under the curve (AUC0-8), 17.5 ±â€Š3.5 (17.9 ±â€Š2.3) and 15 ±â€Š4.3 (13.4 ±â€Š5.3) mg•h/L. Using the 90% CI criteria, Cmaxand AUC0-8 values for tebipenem were found to be bioequivalent following alternative methods of administration compared with oral dosing of the whole tablet. The three methods of administration were well tolerated. CONCLUSION: Results demonstrate that tebipenem maintained bioequivalence when crushed and administered via NGT with and without accompanying enteral feeds in healthy subjects, relative to whole tablet oral administration. Data therefore support alternative methods of tebipenem administration depending on patient condition.

Assessment of Clostridium difficile Burden in Patients Over Time With First Episode Infection Following Fidaxomicin or Vancomycin.

In patients with first episode Clostridium difficile infection treated with vancomycin or fidaxomicin, more patients receiving fidaxomicin achieved at least 2 log10 colony-forming units/g reduction in spores at the follow-up visit (P=.02). Similar to published literature, a higher proportion of patients receiving fidaxomicin demonstrated sustained clinical response.

Pharmacokinetics of doripenem in infected patients treated within and outside the intensive care unit.

BACKGROUND: Doripenem often is used in the intensive care unit (ICU) to treat serious infections. However, pharmacokinetics in this population often are altered by various physiologic changes. Current pharmacokinetic data in critically ill patients receiving doripenem are limited. OBJECTIVE: To determine the pharmacokinetics of doripenem in patients treated in the ICU versus outside the ICU. METHODS: A total of 3-4 serum samples were collected from 25 infected patients receiving doripenem. A 2-compartment model was fit to serum pharmacokinetic data with nonparametric adaptive grid with adaptive γ. In the structural pharmacokinetic model, clearance (Cl) was made proportional to creatinine clearance (CrCl) and an intercept term. Bayesian pharmacokinetic parameters were compared between the 2 populations. A 5000-patient Monte Carlo simulation was performed for various CrCl ranges. The probability of pharmacodynamic target attainment was calculated over a range of minimum inhibitory concentrations (MICs), assuming a target of 35% of the dosing interval that unbound drug concentrations remain above the MIC. RESULTS: Mean (range) age, body mass index, and CrCl were 61 (31-90) years, 31.2 (15.1-55.5) kg/m(2), and 86 (15-221) mL/min, respectively. After the Bayesian step, r(2), bias, and precision were 0.97, 0.04, and 1.44 µg/mL, respectively. Mean (SD) parameters for ICU (n = 13) and non-ICU (n = 12) patients were not significantly different (p > 0.05): volume of central compartment (17.3 [11.2] vs 18.5 [11.7] L), Cl (10.1 [10.2] vs 15.5 [16.9] L/h), k12 (4.7 [4.7] vs 4.7 [4.8] h(-1)), and k21 (7.1 [5.5] vs 5.7 [5.3] h(-1)), respectively. Optimal target attainments were obtained for patients with normal renal function up to MICs of 2 µg/mL with a dose of 500 mg every 8 hours as 1-hour and 4-hour infusions. CONCLUSIONS: Doripenem pharmacokinetics were similar between ICU and non-ICU patients in this population. Optimal dosing regimens should be selected based on underlying renal function and suspected MIC of the infecting pathogen.

Comparative pharmacokinetics, pharmacodynamics, and tolerability of ertapenem 1 gram/day administered as a rapid 5-minute infusion versus the standard 30-minute infusion in healthy adult volunteers.

STUDY OBJECTIVE: To compare ertapenem pharmacokinetics, pharmacodynamics, and tolerability when administered as a rapid 5-minute infusion to the standard 30-minute infusion. DESIGN: Prospective, randomized, crossover pharmacokinetic study. SETTING: Clinical research center. SUBJECTS: Twelve healthy adult volunteers. INTERVENTION: Each subject received ertapenem 1 g intravenously, administered either as a rapid 5-minute infusion or the standard 30-minute infusion, every 24 hours for 3 days (first phase); after a 4-day washout period, each subject then received the other infusion every 24 hours for 3 days (second phase). MEASUREMENTS AND MAIN RESULTS: Plasma samples were collected after the first and third (steady-state) doses of each study phase, and protein binding was assessed by use of ultrafiltration. Pharmacokinetic analyses were conducted using noncompartmental and compartmental methods. A 5000-subject Monte Carlo simulation was used to assess the probability of target attainment for free drug concentration remaining above the minimum inhibitory concentration (MIC) for 40% or greater of the dosing interval (40% fT > MIC) over an MIC range. Ertapenem was well tolerated and adverse events were similar for both infusions. The ertapenem steady-state mean ± SD maximum concentrations were 193.3 ± 43.3 and 165.7 ± 20.4 mg/L for the 5- and 30-minute infusions, respectively; the mean ± SD areas under the concentration-time curves from 0-24 hours were 561.2 ± 77.0 and 531.3 ± 56.9 µg · hr/ml (geometric mean ratio 1.008, 90% confidence interval 0.999-1.017), respectively. Protein binding was concentration dependent (range 87.9-98.9%). A two-compartment model best described ertapenem pharmacokinetics with the following parameter estimates: clearance 1.89 ± 0.19 L/hr, volume of central compartment 5.04 ± 0.56 L, and transfer constants k12 0.43 ± 0.08/hr and k21 0.44 ± 0.07/hr. The probabilities of target attainment for 5- and 30-minute infusions were 97.0% and 97.9% at an MIC of 0.25 mg/L and 1.7% and 2.8% at an MIC of 0.5 mg/L, respectively. CONCLUSION: Ertapenem administered as a rapid 5-minute infusion provides a well tolerated, bioequivalent, and pharmacodynamically equivalent regimen to the 30-minute infusion at clinically relevant MICs.

Pneumonia due to Pseudomonas aeruginosa: part II: antimicrobial resistance, pharmacodynamic concepts, and antibiotic therapy.

Pseudomonas aeruginosa carries a notably higher mortality rate than other pneumonia pathogens. Because of its multiple mechanisms of antibiotic resistance, therapy has always been challenging. This problem has been magnified in recent years with the emergence of multidrug-resistant (MDR) pathogens often unharmed by almost all classes of antimicrobials. The objective of this article is to assess optimal antimicrobial therapy based on in vitro activity, animal studies, and pharmacokinetic/pharmacodynamic (PK/PD) observations so that evidence-based recommendations can be developed to maximize favorable clinical outcomes. Mechanisms of antimicrobial resistance of P aeruginosa are reviewed. A selective literature review of laboratory studies, PK/PD concepts, and controlled clinical trials of antibiotic therapy directed at P aeruginosa pneumonia was performed. P aeruginosa possesses multiple mechanisms for inducing antibiotic resistance to antimicrobial agents. Continuous infusion of antipseudomonal ß-lactam antibiotics enhances bacterial killing. Although the advantages of combination therapy remain contentious, in vitro and animal model studies plus selected meta-analyses of clinical trials support its use, especially in the era of MDR. Colistin use and the role of antibiotic aerosolization are reviewed. An evidence-based algorithmic approach based on severity of illness, Clinical Pulmonary Infection Score, and combination antibiotic therapy is presented; clinical outcomes may be improved, and the emergence of MDR pathogens should be minimized with this approach.

Pharmacokinetics/Pharmacodynamics for critical care clinicians.

For appropriate antibiotic therapy and selection, the clinician must be familiar with pharmacodynamic concepts that integrate an antibiotic's microbiologic activity, pharmacokinetic properties, and mode of bacterial killing. Much of the traditional dosing methods that continue to this day are based more on habit rather than science. This article addresses these issues and explains the basis for the new scientific ways to administer antibiotics to optimize patient outcomes.

Treatment of Serratia marcescens meningitis with prolonged infusion of meropenem.

OBJECTIVE: To describe the use of and cerebral spinal fluid (CSF) penetration of a prolonged infusion meropenem regimen in a patient with Serratia marcescens meningitis. CASE SUMMARY: A 54-year-old female was diagnosed with S. marcescens meningitis associated with an epidural abscess 57 days after surgery for a herniated spinal disk. Meropenem 2000 mg every 8 hours was administered as a prolonged (3 h) infusion for the purpose of optimizing pharmacodynamic exposure. Meropenem concentrations were measured from the patient's blood and CSF (via a lumbar drain). The prolonged infusion regimen resulted in concentrations in both serum and CSF above the meropenem minimum inhibitory concentration (MIC) of 0.047 microg/mL for 100% of the dosing interval. After 6 days of therapy, the patient showed no further signs of infection and was subsequently discharged to a rehabilitation facility. At follow-up, she had completed a 4 week course of the prolonged infused therapy without relapse or adverse events. DISCUSSION: Gram-negative infections of the central nervous system result in high morbidity and mortality. These infections are often difficult to treat because of poor antibiotic penetration coupled with increasing antibiotic resistance. Although there are 2 other case reports that describe the use of prolonged infusion of meropenem, our patient had a lumbar drain in place, thereby allowing us to collect multiple CSF samples and more accurately assess meropenem exposure at the site of infection. CSF penetration was 6.4% in this patient, resulting in 100% time above the MIC throughout the dosing interval. CONCLUSIONS: In this patient with meropenem-susceptible S. marcescens meningitis, the use of a high-dose prolonged infusion of meropenem resulted in adequate exposure at the site of infection and a successful clinical response.

Acute exacerbation of chronic bronchitis: a primary care consensus guideline.

OBJECTIVE: To develop consensus on appropriate treatment for acute exacerbation of chronic bronchitis (AECB). CHARACTERISTICS AND ETIOLOGY: Patients with chronic bronchitis have an irreversible reduction in maximal airflow velocity and a productive cough on most days of the month for 3 months over 2 consecutive years. An AECB is characterized by a period of unstable lung function with worsening airflow and other symptoms. Most (80%) cases of AECB are due to infection, with half due to aerobic bacteria. The remaining 20% are due to noninfectious causes such as environmental factors or medication nonadherence. MANAGEMENT: Supportive care should be provided to all patients, which might include removal of irritants, use of a bronchodilator, oxygen, hydration, use of a systemic corticosteroid, and chest physical therapy. Antibacterial treatment should be reserved for patients with at least 1 key symptom (ie, increased dyspnea, sputum production, sputum purulence) and 1 risk factor (ie, age > or = 65 years, forced expiratory volume in 1 second < 50% of the predicted value, > or = 4 AECBs in 12 months, 1 or more comorbidities). A newer macrolide, extended-spectrum cephalosporin, or doxycycline is appropriate for an exacerbation of moderate severity, and high-dose amoxicillin/clavulanate or a respiratory fluoroquinolone should be used for a severe exacerbation. There has been increasing antibacterial resistance by the 3 most prevalent pathogens (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis). CONCLUSION: Although all AECB patients should receive supportive care, only patients with at least 1 key symptom and 1 risk factor should receive antibiotic therapy.

Pharmacodynamic study of beta-lactams alone and in combination with beta-lactamase inhibitors against Pseudomonas aeruginosa possessing an inducible beta-lactamase.

OBJECTIVES: The antimicrobial efficacies of beta-lactams alone and in combination with beta-lactamase inhibitors were investigated by applying a rabbit tissue cage model against a strain of Pseudomonas aeruginosa with an inducible AmpC (iAmpC) beta-lactamase. METHODS: Two sterilized golf Wiffle balls were surgically implanted in the rabbit dorsal cervical area. After 4 weeks, Wiffle balls had filled with tissue cage fluid (TCF), in which 2 mL of 10(6) cfu/mL of the test isolate were inoculated. To achieve the same T > MIC as in humans, 400 mg/kg of the beta-lactams alone and in combination was administered twice a day via subcutaneous injection. The dosing regimens were as follows: piperacillin alone, 4 g piperacillin/0.5 g tazobactam; ticarcillin alone, 3 g ticarcillin/0.1 g clavulanate; and 3 g ticarcillin/ 0.3 g clavulanate. RESULTS: The changes in bacterial counts (log cfu/mL) after the 3 day treatments were as follows: 1.03 +/- 0.97 (control), -1.31 +/- 0.61 (piperacillin), -2.81 +/- 0.53 (4 g piperacillin/0.5 g tazobactam), -1.61 +/- 0.68 (ticarcillin), -3.42 +/- 0.75 (3 g ticarcillin/0.1 g clavulanate) and -1.65 +/- 1.47 log cfu/mL (3 g ticarcillin/0.3 g clavulanate). AmpC induction by high-dose clavulanate was observed in rabbit TCF, and was confirmed by the in vitro induction study. CONCLUSIONS: The study indicated that tazobactam significantly enhanced the antibacterial activity of piperacillin against iAmpC P. aeruginosa; clavulanate had synergy with the antibacterial activity of ticarcillin at low concentration, but had no effect on ticarcillin at high concentration due to AmpC induction by clavulanate.

The CroRS two-component regulatory system is required for intrinsic beta-lactam resistance in Enterococcus faecalis.

Enterococcus faecalis produces a specific penicillin-binding protein (PBP5) that mediates high-level resistance to the cephalosporin class of beta-lactam antibiotics. Deletion of a locus encoding a previously uncharacterized two-component regulatory system of E. faecalis (croRS) led to a 4,000-fold reduction in the MIC of the expanded-spectrum cephalosporin ceftriaxone. The cytoplasmic domain of the sensor kinase (CroS) was purified and shown to catalyze ATP-dependent autophosphorylation followed by transfer of the phosphate to the mated response regulator (CroR). The croR and croS genes were cotranscribed from a promoter (croRp) located in the rrnC-croR intergenic region. A putative seryl-tRNA synthetase gene (serS) located immediately downstream from croS did not appear to be a target of CroRS regulation or to play a role in ceftriaxone resistance. A plasmid-borne croRp-lacZ fusion was trans-activated by the CroRS system in response to the presence of ceftriaxone in the culture medium. The fusion was also induced by representatives of other classes of beta-lactam antibiotics and by inhibitors of early and late steps of peptidoglycan synthesis. The croRS null mutant produced PBP5, and expression of an additional copy of pbp5 under the control of a heterologous promoter did not restore ceftriaxone resistance. Deletion of croRS was not associated with any defect in the synthesis of the nucleotide precursor UDP-MurNAc-pentapeptide or of the D-Ala(4)-->L-Ala-L-Ala-Lys(3) peptidoglycan cross-bridge. Thus, the croRS mutant was susceptible to ceftriaxone despite the production of PBP5 and the synthesis of wild-type peptidoglycan precursors. These observations constitute the first description of regulatory genes essential for PBP5-mediated beta-lactam resistance in enterococci.

Inhalational anthrax and bioterrorism.

Until recently, inhalational anthrax was considered an infectious disease curiosity for medical specialists and veterinarians. This attitude abruptly changed following the intentional release of Bacillus anthracis spores via the US Postal Service in October 2001. Because of its rarity, few physicians were familiar with its clinical manifestations, treatment and prophylaxis. In this report, we try to fill this informational gap by reviewing these issues based on additional data culled from this recent bioterrorism-related epidemic. Moreover, we have purposely emphasized its clinical manifestations, searching for common findings that may alert the physician to suspect and rapidly diagnose this infection. To improve survival rates, prompt diagnosis of inhalational anthrax is crucial, since even a brief delay in therapy of this fulminating infection almost uniformly results in death.

Pharmacoeconomics of a pharmacist-managed program for automatically converting levofloxacin route from i.v. to oral.

The economic and clinical outcomes of a pharmacist-managed proactive program that used predetermined clinical criteria for converting levofloxacin therapy from i.v. to oral without physician approval were examined. A prospective observational study (POS) assessing the standard of care was conducted over two months and was compared with a proactive conversion program (PCP). A cost-minimization analysis was performed from the provider's perspective. The analysis was divided into cost levels 1, 2, and 3. During the POS and PCP, 49 and 82 patients were evaluated, respectively. The percentage of patients meeting conversion criteria in each group was similar (61% POS versus 65% PCP) (p = 0.827). Candidates met criteria for conversion on day 2 in both groups. The average days that conversion occurred during the POS and PCP were days 7 and 3, respectively (p = 0.010). In those patients, the length of stay was significantly shorter for the PCP (6 versus 9.5 days) (p = 0.031). Level-1, level-2, and level-3 costs were significantly less during the PCP than during the POS for patients who met conversion criteria ($77 versus $133, $91 versus $151, and $13,931 versus $17,198, respectively). Two patients in the PCP were switched back to i.v. levofloxacin due to noninfection-related complications. The overall clinical success rate for evaluable conversion candidates was 100% during the PCP. A pharmacist-managed proactive program that used predetermined clinical criteria for converting levofloxacin therapy from i.v. to p.o. without physician approval reduced length of stay and institutional health care costs without compromising clinical outcomes.

Pharmacodynamic profiling of continuously infused piperacillin/tazobactam against Pseudomonas aeruginosa using Monte Carlo analysis.

Standard doses of piperacillin/tazobactam (9-13.5 g over 24 h) administered by continuous infusion (CI) routinely provide serum concentrations in excess of the susceptibility breakpoint (< or =16/4 micro g/ml) for most Enterobacteriaceae. Since the breakpoint of this agent for Pseudomonas aeruginosa is considerably higher (< or=64/4 micro g/ml), the likelihood of obtaining adequate drug exposures with these doses against this bacterium is currently unknown. Monte Carlo simulation was utilized to determine the probability of obtaining adequate piperacillin concentrations above its MICs for P. aeruginosa in patients receiving CI. MICs of 557 P. aeruginosa isolates were determined by E-test and a distribution was constructed for the 496 susceptible isolates. Using a previously validated population pharmacokinetic equation, steady-state serum concentrations were estimated for 210 patients who received piperacillin/tazobactam via CI. A Monte Carlo simulation was performed to predict the probability of obtaining concentrations at the MIC, 2 x MIC, 4 x MIC, 5 x MIC, and 6 x MIC for patients infected with susceptible P. aeruginosa isolates. MICs ranged from 0.09 to 64 micro g/ml with modal and median values of 3 and 4 micro g/ml, respectively. Steady-state concentrations of 51.14 +/- 17.52 micro g/ml were estimated in our patient population. The simulation resulted in a median level of exposure 12.62 times the MIC. The level of certainty of obtaining concentrations at the MIC, 2 x MIC, 4 x MIC, 5 x MIC, and 6 x MIC for piperacillin administered by CI was 97, 93, 85, 81, and 77%, respectively. Despite concern for the place of CI piperacillin/tazobactam in the management of P. aeruginosa infections due to the higher established breakpoint, these data suggest a high probability of achieving adequate drug exposure against susceptible isolates with this dosing regimen.

Minimal interaction between gatifloxacin and oxycodone.

Previous studies have demonstrated a significant reduction in the oral bioavailability of trovafloxacin and ciprofloxacin when administered concomitantly with an intravenous opiate, such as morphine. This decrease in absorption results in a 36% and 50% lower AUC for trovafloxacin and ciprofloxacin, respectively, which could cause clinical failures. The authors investigated the possibility of a similar interaction between oxycodone and gatifloxacin. Twelve healthy volunteers were randomized in an open-label, two-way crossover study to receive oxycodone (5 mgpo Q4H) andgatifloxacin (400 mg po 1 h) after starting the oxycodone or gatifloxacin 400 mg po alone. Blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours postdosing. No significant difference was noted (p > 0.05) in AUC (31.6 +/- 7.3 vs. 31.7 +/- 7.1) and Cmax (3.2 +/- 0.6 vs. 3.0 +/- 0.6) for gatifloxacin versus gatifloxacin/oxycodone regimens; however, the tmax (1.8 +/- 0.8 vs. 4.3 +/- 1.5) was significantly delayed (p < 0.001). It was concluded that oral oxycodone and gatifloxacin can be administered concomitantly without a significant decrease in bioavailability.

Fatal case of inhalational anthrax mimicking intra-abdominal sepsis.

In this report, we discuss the second fatal case of inhalational anthrax related to the use of Bacillus anthracis spores as a biological weapon in the United States. This case highlights two of the major characteristics of inhalational anthrax: the fulminating nature of the infection and the difficulty of promptly establishing a diagnosis. In the patient discussed here, gastrointestinal symptoms and findings were so impressive that the patient was thought to have a primary intra-abdominal condition. In the current situation, in which bioterrorism is a real threat, any patient presenting with a flulike or gastrointestinal illness should be queried about their occupation. Anyone with evidence of systemic disease who resides or works in a geographical region where anthrax cases are occurring should be treated until the diagnosis of anthrax is excluded. In the United States, the group that is at high risk for anthrax has shifted from rural farm workers to city dwellers, especially postal workers and public figures.

Comparative pharmacokinetic and pharmacodynamic profile of piperacillin/tazobactam 3.375G Q4H and 4.5G Q6H.

When piperacillin/tazobactam has been used to treat hospitalized patients with serious infections, including nosocomial pneumonia caused by Pseudomonas aeruginosa, it has usually been dosed at 3.375 g q4h to provide serum concentrations above commonly encountered organisms' MICs (T > MIC) for at least 40-50% of the dosing interval. Pharmacodynamic principles suggest that a similar efficacy can be realized with extended dosing intervals when a larger dose (e.g. 4.5 g q6h) is administered, which was the objective of this study. Twelve healthy volunteers, 29.4 +/- 8.9 years of age, were enrolled in this multiple-dose, open-labeled, randomized, two-period crossover study. Blood samples were collected after the third dose and concentrations of piperacillin/tazobactam were determined with a validated HPLC method. Pharmacokinetic profiles were determined by noncompartment analysis. T > MIC of piperacillin was calculated for a range of MIC values. Piperacillin/tazobactam was well tolerated in 11 subjects who completed both regimens. The C(max), T(1/2), K, and AUC of P were significantly different according to a paired t test (p < 0.05) between two study regimens. Significant differences (p < 0.05) in tazobactam regimens were noted for C(max), and AUC. The piperacillin/tazobactam regimen of 4.5 g q6h achieved a 44% T > MIC for MIC values of < or = 16 microg/ml, while the 3.375-gram q4h regimen achieved 42% T > MIC, for MIC values of < or = 32 microg/ml. Dosage regimens for treating serious infections can be extended safely and effectively to 4.5 g q6h and obtain at least 40-50% T > MIC in the coverage of pathogens implicated with serious infections, including P. aeruginosa.

Pharmacokinetic and pharmacodynamic evaluation of two dosing regimens for piperacillin-tazobactam.

STUDY OBJECTIVE: To compare the pharmacokinetic and pharmacodynamic profiles of two dosing regimens for piperacillin-tazobactam against commonly encountered pathogens. The regimens compared were piperacillin 4.0 g-tazobactam 0.5 g administered every 8 hours, and piperacillin 3.0 g-tazobactam 0.375 g administered every 6 hours. DESIGN: Multiple-dose, open-label, randomized, crossover study. SETTING: Clinical research center at Hartford Hospital. SUBJECTS: Twelve healthy volunteers. INTERVENTION: The two dosing regimens for piperacillin-tazobactam were administered intravenously in crossover design. Blood was sampled after the third dose. MEASUREMENTS AND MAIN RESULTS: Drug concentrations were determined by a validated high-performance liquid chromatography assay. The percentage of time above minimum inhibitory concentration (%T>MIC) for piperacillin was calculated for a range of MIC values. The maximum concentration (Cmax), area under the concentration-time curve (AUC0-tau), and total clearance of piperacillin differed significantly between the two study regimens, as did the Cmax, AUC0-tau, volume of distribution, and total clearance of tazobactam (p<0.05). The piperacillin 4.0 g-tazobactam 0.5 g regimen provided 40-50% T>MIC for MIC values 8-16 microg/ml; a similar value for the piperacillin 3.0 g-tazobactam 0.375 g regimen was 16-32 microg/ml. CONCLUSION: Although statistically significant differences in the pharmacodynamic profile were noted for the regimens, both provide adequate T>MIC against commonly encountered pathogens considered susceptible to piperacillin-tazobactam. However, for treatment of Pseudomonas aeruginosa infection, combination therapy or higher-dosage regimens (e.g., piperacillin 3.0 g-tazobactam 0.375 g every 4 hours, piperacillin 4.0 g-tazobactam 0.5 g every 6 hours, or continuous-infusion piperacillin 12 g-tazobactam 1.5 g/day) may be a prudent option when full MIC data are unavailable.

Clinical efficacy and pharmacoeconomics of a continuous-infusion piperacillin-tazobactam program in a large community teaching hospital.

STUDY OBJECTIVE: To compare continuous versus intermittent administration of piperacillin-tazobactam with regard to clinical, microbiologic, and economic outcomes. DESIGN: Prospective, open-label controlled study SETTING: Community teaching hospital. PATIENTS: Ninety-eight hospitalized patients prescribed piperacillin-tazobactam. INTERVENTION: Substitutions were implemented so that 47 patients initially prescribed intermittent infusion of piperacillin-tazobactam were switched to continuous infusion of this drug combination. Dosages varied in accordance with the type of infection and each patient's renal function. Fifty-one other patients with similar demographics and types of infection received intermittent infusion with piperacillin-tazobactam. MEASUREMENTS AND MAIN RESULTS: Clinical success rates were 94% for the continuous-infusion group and 82% for the intermittent-infusion group (p=0.081). Microbiologic success rates were 89% for the continuous-infusion group and 73% for the intermittent-infusion group (p=0.092). Days to normalization of fever were significantly lower (p=0.012) in the continuous-infusion group (1.2 +/- 0.8 days) than in the intermittent-infusion group (2.4 +/- 1.5 days). Level 1 and level 2 costs/patient were both reduced by continuous infusion, although the difference was statistically significant only for level 2 costs ($399.38 +/- 407.22 for continuous infusion vs $523.49 +/- 526.85 for intermittent infusion, p=0.028). CONCLUSION: Continuous infusion of piperacillin-tazobactam provided clinical and microbiologic outcomes equivalent to those for intermittent infusion. Compared with intermittent infusion, continuous infusion significantly shortened the time to temperature normalization, while also offering a significant reduction in level 2 expenditures.