Treatment Of Complicated Intra-abdominal Infections Research Articles

Current Rational to Prescribe Tigecycline: Critical Analysis of the Evidence and Usage Algorithms by an Argentinean Experts Panel

Tigecycline is the first of a new class of antibiotics named glycylcyclines and is active in vitro against a variety of gram-positive and gram-negative organisms, including nosocomial resistant pathogens such as vancomycin-resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus, extended-spectrum β-lactamase-producing Enterobacteriaceae, and multidrug-resistant- Acinetobacter spp. This medication has been approved by the US Food and Drug Administration (FDA) for the treatment of complicated intra-abdominal infections (cIAI), complicated skin and skin structure infections (cSSSI) and community-acquired bacterial pneumonia. Tigecycline's pharmacological and microbiological profile has also encouraged physicians’ to use the drug in other infections caused by resistant pathogens featuring limited therapeutics options (i.e. hospital-acquired pneumonia-HAP). In this study we publish the conclusions of an expert panel that identify and evaluate the evidence to support the use of Tigecycline in hospitalized patients with one of the following three infections: cSSSI, cIAI and HAP, including ventilator-associated pneumonia. Based on this data the panel developed an Algorithm Rational to Prescribe Tigecycline (ART) for each pathology.

Community-acquired complicated intra-abdominal infections in children hospitalized during 1995–2004 at a paediatric surgery department

Information on the epidemiologic, clinical, microbiologic and therapeutic aspects of community-acquired complicated intra-abdominal infections in paediatrics is limited. The objectives of this study were to investigate the epidemiologic, clinical, microbiologic and therapeutic characteristics of community-acquired complicated intra-abdominal infections occurring in children aged 1 month-15 y. Medical charts and microbiology data of all children hospitalized with complicated intra-abdominal infections were retrospectively examined. Complicated intra-abdominal infections were defined as infections extending beyond the viscus of origin into the peritoneal space, with subsequent development of abscess or peritonitis. One hundred and twenty-three patients with complicated intra-abdominal infections (99/123, 80% >5 y of age) were included; 113 (92%) had complicated acute appendicitis. Twelve (10%) patients underwent computerized tomography-guided percutaneous drainage of periappendicular abscesses. The mean rate of complicated intra-abdominal infections among patients with complicated acute appendicitis was 10% without significant changes during the study years. Positive intra-abdominal cultures were recorded in 97/108 (90%) evaluable patients; 65/97 (67%) cases were characterized by mixed bacterial flora growth. One hundred and ninety pathogens (aerobes n=164, 86%; anaerobes n=26, 14%) were isolated. Escherichia coli was the most common pathogen (94 isolates, 57%). In vitro amoxicillin/clavulanate coverage of E. coli and Klebsiella spp was modest (81% and 86%, respectively). The ampicillin/gentamicin/metronidazole regimen was more appropriate in vitro than the amoxicillin/clavulanate regimen (3/80, 4% resistant pathogens compared with 8/43, 19%; p=0.02). Post-operative complications were recorded in 33/123 (27%) patients. Time until defervescence to < 37.5 degrees C was shorter in children with periappendicular abscess than in children with generalized peritonitis (6+/-4 vs 4+/-3 days; p=0.009). (1) most community-acquired complicated intra-abdominal infections occurred as a result of acute appendicitis; (2) the rate of complicated intra-abdominal infections among patients with acute appendicitis was low and without significant changes during the study period; (3) E. coli was the most frequently isolated pathogen; (4) amoxicillin/clavulanate provided only partial coverage for complicated intra-abdominal infection pathogens and should be used with caution in the empiric treatment of complicated intra-abdominal infections.

Doripenem monohydrate, a broad-spectrum carbapenem antibiotic

Background: Doripenem monohydrate, a broad-spectrum carbapenem antibiotic, has been approved by the US Food and Drug Administration for the treatment of complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs). Objective: This article reviews available information on doripenem in the management of patients with complicated bacterial infections, including its chemistry, spectrum of activity, resistance mechanisms, pharmacokinetics, pharmacodynamics, drug interactions, therapeutic efficacy, tolerability, and dosing and administration. Also discussed are pharmacoeconomic considerations associated with doripenem. Methods: Pertinent English-language literature was identified from searches of MEDLINE (1996–October 2008) and BIOSIS (1993–October 2008). Search terms included, but were not limited to, doripenem, S-4661, spectrum of activity, resistance, pharmacology, pharmacokinetics, pharmacodynamics, adverse events, and therapeutic use. Additional publications were found by searching the reference lists of identified articles and reviewing abstracts from meetings of the Interscience Conference on Antimicrobial Agents and Chemotherapy (2003–2007). Results: Doripenem is a parenteral carbapenem antibiotic with in vitro activity against gram-positive, gram-negative, and anaerobic organisms. It is stable against a wide variety of β-lactamases, including extended-spectrum and AmpC β-lactamases; it is, however, inactivated by organisms that produce class A enzymes, KPC enzymes, class B metallo-β-lactamases, and class D enzymes. Doripenem is eliminated primarily in the urine (68%–80% unchanged). It should be used cautiously in patients receiving valproic acid, as combined use may lead to a precipitous decline in serum concentrations of valproic acid. A large Phase III study in the treatment of cIAIs found doripenem noninferior to meropenem (clinical cure rates, 83.9% and 85.9%, respectively; difference, −2.1; 95% CI, −9.8 to 5.6). A Phase III study in the treatment of cIAIs, including pyelonephritis, found doripenem non-inferior to levofloxacin (clinical cure rates, 95.1% and 90.2%, respectively; 95% CI, 0.2 to 9.6). With respect to the treatment of nosocomial pneumonia, one Phase III study found doripenem noninferior to imipenem (clinical cure rates, 68.3% and 64.8%, respectively; difference, 3.5%; 95% CI, −9.1 to 16.1), and another found it noninferior to piperacillin/tazobactam (clinical cure rates, 81.3% and 79.8%, respectively; difference, 1.5%; 95% CI, −9.1 to 12.1). Adverse events with doripenem were similar to those of other antibiotics with which it has been compared. Adverse events in clinical trials of doripenem have included anaphylaxis and rash (l%-5%), gastrointestinal effects (25%–32%, including nausea [1.1%–12.0%], diarrhea [1.9%–11.0%], and vomiting [1.5%-6.6%]), and central nervous system effects (headache [2.1%–16.0%], insomnia [3.7%], anxiety [2.9%], and, rarely, seizures). Conclusions: In Phase III studies, doripenem was noninferior to meropenem in the treatment of cIAIs; noninferior to levofloxacin in the treatment of cUTIs; and noninferior to imipenem and piperacillin/tazobactam in the treatment of nosocomial pneumonia. As with all new antibiotics, because of the risk of selecting for resistant organisms, use of doripenem should be reserved for infections in which a multidrug-resistant gram-negative organism, polymicrobial infection, or Pseudomonas aeruginosa is suspected.

Stability of doripenem in vitro in representative infusion solutions and infusion bags

Background: Doripenem, a new parenteral carbapenem with broad-spectrum antibacterial activity, is indicated for the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis. According to the US prescribing information, the carbapenems imipenem and meropenem are stable in sodium chloride for 4 hours.Objective: The aim of this study was to assess the stability of doripenem following constitution (50 mg/mL) and in injection solutions in vitro (0.9% sodium chloride and 5% dextrose) at a concentration of 5 mg/mL in room and refrigerated conditions.Methods: The stability of doripenem was assessed (1) under room-temperature conditions (25°C ± 2°C, 60% ± 5% relative humidity, under fluorescent light) immediately after constitution in vials with sterile water; (2) under room conditions and refrigerated conditions (5°C ± 3°C, 60% relative humidity, protected from light) immediately after constitution with sodium chloride or dextrose in 3 different infusion bags (polyvinyl chloride [PVC], PVC with vial adapter, and polyethylene); and (3) under room and refrigerated conditions using 500-mg doripenem vials that had been stored for 12 months in room temperature and protected from light before constitution with water and dilution in sodium chloride or dextrose injection. Doripenem 5 mg/mL and related substances (degradation products and impurities related to doripenem) were measured using a validated high-performance liquid chromatography method. Doripenem was considered stable if its concentration remained within 90% to 110% of the initial concentration and the total concentration of degradation products and impurities related to doripenem was ≤5%. Appearance of the solutions was assessed using clarity and comparison to color standards; pH, using standard methodologies; and particulate matter, using light-obscuration and microscopy.Results: Three lots of doripenem were assessed. Doripenem potency in constituted suspension (50 mg/mL) remained unchanged (means, 99.2% and 99.3%, respectively, of initial doripenem amount) for up to 60 minutes in room or refrigerated conditions prior to transfer to infusion bags. The doripenem 5-mg/mL infusion solution retained its potency for 12 and 72 hours under room and refrigerated conditions, respectively, in 0.9% sodium chloride injection, and for 4 and 48 hours under room and refrigerated conditions, respectively, in 5% dextrose injection (mean percentages of initial doripenem concentration, 95.5% and 96.6% under room and refrigerated conditions, respectively). Comparable results were obtained with vials of doripenem that had been stored for 12 months at room temperature and protected from light and then constituted (50 mg/mL). Doripenem 5 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection retained its potency in room conditions at the end of a 4-hour drip period when used with conventional infusion sets (mean, 96.6%) or Di(2-ethylhexyl)phthalate-free infusion sets (mean, 99.3%).Conclusions: Doripenem 5 mg/mL was stable for up to 12 hours in vitro in 0.9% sodium chloride at room temperature. Therefore, doripenem can be constituted, mixed with infusion fluids in the pharmacy, stored, delivered, and infused into a patient within a time frame suitable for 4-hour extended infusions.

The Efficacy and Safety of Tigecycline for the Treatment of Complicated Intra-Adominal Infections - The European Experience

The polymicrobial nature of complicated intra-abdominal infections makes these infections particularly challenging to treat. The initial selection of antimicrobial therapy is therefore extremely important. Inappropriate empiric antimicrobial therapy has been shown to delay clinical resolution, increase length of hospital stay, and increase the risk of mortality. In addition, the increasing frequency with which resistant isolates (e.g., extended spectrum beta-lactamases [ESBLs]) are recovered from patients mandates that empiric antimicrobial therapy covers these difficult-to-treat organisms.Here, we assessed the efficacy of a new antimicrobial agent, tigecycline. This is a combined analysis of data from the European sites that participated in two Phase III, double-blind trials to evaluate the efficacy and safety of tigecycline, versus that of imipenem/cilastatin, in adults with complicated intra-abdominal infections. Patients received either tigecycline (initial dose of 100 mg, followed by 50 mg intravenously every 12 hours) or imipenem/cilastatin (500/500 mg intravenously every 6 hours) for 5-14 days. The primary end point was the clinical response at the test-of-cure visit (12-44 days after therapy) in the co-primary microbiologically evaluable (ME) and microbiological modified intent-to-treat (m-mITT) populations. For the ME group, clinical cure rates at the test-of-cure visit were 92.4% (219/237) for tigecycline versus 88.8% (198/223) for imipenem/cilastatin (95% CI = −2.2, 9.4). Clinical cure rates for the m-mITT populations were 87.3% (247/283) for tigecycline versus 83.5% (228/273) for imipenem/cilastatin (95% CI = −2.5, 10.0) at the test-of-cure visit. Pretherapy in vitro activity against baseline isolates for tigecycline and imipenem/cilastatin were also determined. The mean MIC90 for tigecycline against the most commonly isolated aerobes and anaerobes was >2.0 μg/mL. No pretherapy isolates displayed resistance to tigecycline based on the breakpoints used. Bacterial susceptibilities to tigecycline appeared to be consistent with clinical responses. Most commonly reported treatment emergent adverse events for tigecycline and imipenem/cilastatin were nausea (14.7% and 11.8%, respectively, p = 0.267) and vomiting (10.7% and 7.3%, respectively p = 0.146). This combined analysis demonstrates that tigecycline is safe and effective for the treatment of complicated intra-abdominal infections, and reflects the findings of the global population.

Doripenem (Doribax): The Newest Addition to the Carbapenems

Carbapenems are a class of antimicrobials structurally related to penicillin. Doripenem, the newest agent in this class, was recently approved by the Food and Drug Administration for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. Its spectrum of activity is similar to that of meropenem and imipenem/cilastatin. Some studies indicate that approximately 29% of carbapenem-resistant Pseudomonas aeruginosa isolates may remain sensitive to doripenem, although the clinical relevance of that finding has not been determined. Clinical studies, which have been published only in abstract form to date, have found doripenem to be similar to comparator agents. The most common adverse effects related to doripenem therapy were headache, nausea, diarrhea, rash, and phlebitis. Doripenem, like the other carbapenems, may also cause seizures. Because of the lack of published data, the lack of clear advantages over meropenem, and the increased cost compared with meropenem, doripenem will not be available for use at Baylor University Medical Center except by infectious diseases specialists.

Indications of a new antibiotic in clinical practice: results of the tigecycline initial use registry

Tigecycline is the first of a new class of antibiotics named glycylcyclines and it was approved for the treatment of complicated intra-abdominal infections and complicated skin and skin structure infections. Notwithstanding this, tigecycline's pharmacological and microbiological profile which includes multidrug-resistant pathogens encourages physicians' use of the drug in other infections. We analyzed, during the first months after its launch, the tigecycline prescriptions for 113 patients in 12 institutions. Twenty-five patients (22%) received tigecycline for approved indications, and 88 (78%) for "off label" indications (56% with scientific support and 22% with limited or without any scientific support). The most frequent "off label" use was ventilator associated pneumonia (VAP) (63 patients). The etiology of infections was established in 105 patients (93%). MDR-Acinetobacter spp. was the microorganism most frequently isolated (50% of the cases). Overall, attending physicians reported clinical success in 86 of the 113 patients (76%). Our study shows that the "off label" use of tigecycline is frequent, especially in VAP. due to MDR-Acinetobacter spp., where the therapeutic options are limited (eg: colistin). Physicians must evaluate the benefits/risks of using this antibiotic for indications that lack rigorous scientific support.

Rx Report

Rx Report

Meta‐analysis: ertapenem for complicated intra‐abdominal infections

Ertapenem is a new member of the carbapenem class of antibiotics, with a favourable pharmacokinetic profile, but a narrower spectrum of antimicrobial activity, compared with older representatives of this class. To evaluate the effectiveness and safety of ertapenem for treatment of complicated intra-abdominal infections. We performed a meta-analysis of randomized-controlled trials identified in PubMed, Cochrane and Scopus that compared ertapenem with other antimicrobial regimens, in patients of all ages, with complicated intra-abdominal infections. The primary outcomes evaluated were clinical success (cure or improvement) in the modified intention-to-treat population and clinical adverse events. Six randomized-controlled trials involving patients with complicated intra-abdominal infections, mainly of mild-to-moderate severity (three with a double-blind design; one performed in children) that compared ertapenem treatment (once daily) against piperacillin/tazobactam, ceftriaxone plus metronidazole and ticarcillin/clavulanic acid (in three, two and one randomized-controlled trials respectively) were included. No difference was found between adult patients with complicated intra-abdominal infections treated with ertapenem vs. comparators, regarding clinical success (five randomized-controlled trials, 2002 patients, fixed-effect model, odds ratio: 1.11, 95% confidence interval (CI): 0.89-1.39); clinical adverse events (four randomized-controlled trials, 1530 patients, fixed-effect model, OR: 0.86, 95% CI: 0.61-1.20); microbiological success; mortality and withdrawals because of adverse events. Ertapenem was associated with more laboratory adverse events (four randomized-controlled trials, 1530 patients, fixed-effect model, OR: 1.73, 95% CI: 1.14-2.61), but none was reported as serious. This meta-analysis provides additional evidence that ertapenem can be used as effectively and safely, as other recommended antimicrobial regimens, for the treatment of complicated intra-abdominal infections, particularly of mild-to-moderate severity.

Initial use of tigecycline in Argentina

Tigecycline is a new class of antibiotics active against emerging nosocomial pathogens as methicillin-resistant Staphylococcus aureus, extended spectrum (3-lactamases-producing enterobacteria and multidrug-resistant Acinetobacter sp. It was approved for the treatment of complicated intra-abdominal infections and complicated skin and skin structure infections, but its pharmacological and microbiological profile is attractive to physicians for using it in other pathologies caused by resistant pathogens. The aim of this study was to evaluate in which indications tigecycline was used in Argentinian usual clinical settings during the first months after its launch. We analyzed tigecycline prescriptions in 69 patients with severe infections in 15 institutions. Fifteen patients (21%) received tigecycline for approved indications, and 54 (79%) for off label indications (56%) with scientific support and 23%> with limited or without any scientific support). The most frequent off label use was ventilator associated pneumonia (VAP) (36 patients). The etiology of the infections was established in 61%> of the patients. In all cases the isolated bacteria were multi-drug resistant (MDR) Acinetobacter s/?.-carbapenems included. Our study shows that the off label use of tigecycline is frequent, specially in VAP. One of the reasons could be that for MDR-Acinetobacter sp. -VAP, there are few therapeutic options (for instance: colistin). Physicians must evaluate the benefits/risks to use this antibiotic for indications that lack rigorous scientific support.

Uso inicial de tigeciclina en Argentina

Tigecycline is a new class of antibiotics active against emerging nosocomial pathogens as methicillin-resistant Staphylococcus aureus, extended spectrum (3-lactamases-producing enterobacteria and multidrug-resistant Acinetobacter sp. It was approved for the treatment of complicated intra-abdominal infections and complicated skin and skin structure infections, but its pharmacological and microbiological profile is attractive to physicians for using it in other pathologies caused by resistant pathogens. The aim of this study was to evaluate in which indications tigecycline was used in Argentinian usual clinical settings during the first months after its launch. We analyzed tigecycline prescriptions in 69 patients with severe infections in 15 institutions. Fifteen patients (21%) received tigecycline for approved indications, and 54 (79%) for off label indications (56%) with scientific support and 23%> with limited or without any scientific support). The most frequent off label use was ventilator associated pneumonia (VAP) (36 patients). The etiology of the infections was established in 61%> of the patients. In all cases the isolated bacteria were multi-drug resistant (MDR) Acinetobacter s/?.-carbapenems included. Our study shows that the off label use of tigecycline is frequent, specially in VAP. One of the reasons could be that for MDR-Acinetobacter sp. -VAP, there are few therapeutic options (for instance: colistin). Physicians must evaluate the benefits/risks to use this antibiotic for indications that lack rigorous scientific support.

Acinetobacter spp. susceptibility to tigecycline: a worldwide perspective

Sir, In the April 2007 issue of the Journal of Antimicrobial Chemotherapy, Navon-Venezia et al. reported high resistance rates to tigecycline in multiple clones of multidrug-resistant (MDR) Acinetobacter baumannii (n 1⁄4 82). The authors found that 66% (54/82) were resistant to tigecycline (MIC 8 mg/L), 12% (10/82) were intermediate (MIC 4–6 mg/L) and 22% (18/ 82) were susceptible (MIC 2 mg/L). They used Etest to determine MICs and all the values correlated 100% with inhibition zone diameters using the disc diffusion method with tigecycline discs. We agree with the authors that MDR in Acinetobacter spp. represents a global challenge to physicians; for this reason we will try to offer a wider point of view. The Tigecycline Evaluation and Surveillance Trial (TEST) is a worldwide programme that includes, at the moment, 4247 isolates of Acinetobacter spp. of which only 2% have a tigecycline MIC 2 mg/L. Based on this data, we compare the results of Navon-Venezia et al. with those of TEST, using the global data and the Argentinean sub-set data. We selected from the TEST database the isolates of MDR A. baumannii with the same resistance profile as those analysed by Navon-Venezia et al. (i.e. A. baumannii resistant to aminoglycosides, cephalosporins and fluoroquinolones) (Table 1). In contrast with the 78% published by Navon-Venezia et al., only 5.3% of the global isolates and 2% of the Argentinean sub-set isolates of MDR A. baumannii in TEST had tigecycline MICs 2 mg/L. We asked ourselves what would be the probability of encountering such a difference if all the isolates belong to the same population. We performed a proportion test to do so. The probability was very low (P ,, 0.0001). Regarding the MDR A. baumannii isolates as previously defined, and additionally resistant or intermediate to imipenem, the resistance ratio to tigecycline showed important differences (95%, 5.6% and 0% for Navon-Venezia et al., TEST global and Argentinean sub-set, respectively). Tigecycline has been approved for the treatment of complicated intra-abdominal infections and complicated skin and skin

Metabolism, Excretion, and Pharmacokinetics of [14C]Tigecycline, a First-In-Class Glycylcycline Antibiotic, after Intravenous Infusion to Healthy Male Subjects

Tigecycline, a novel, first-in-class glycylcycline antibiotic, has been approved for the treatment of complicated intra-abdominal infections and complicated skin and skin structure infections. The pharmacokinetics, metabolism, and excretion of [(14)C]tigecycline were examined in healthy male volunteers. Tigecycline has been shown to bind to bone; thus, to minimize the amount of radioactivity binding to bone and to maximize the recovery of radioactivity, tigecycline was administered intravenously (30-min infusion) as a single 100-mg dose, followed by six 50-mg doses, every 12 h, with the last dose being [(14)C]tigecycline (50 microCi). After the final dose, the pharmacokinetics of tigecycline in serum showed a long half-life (55.8 h) and a large volume of distribution (21.0 l/kg), whereas radioactivity in serum had a shorter half-life (6.9 h) and a smaller volume of distribution (3.3 l/kg). The major route of elimination was feces, containing 59% of the radioactive dose, whereas urine contained 32%. Unchanged tigecycline was the predominant drug-related compound in serum, urine, and feces. The major metabolic pathways identified were glucuronidation of tigecycline and amide hydrolysis followed by N-acetylation to form N-acetyl-9-aminominocycline. The glucuronide metabolites accounted for 5 to 20% of serum radioactivity, and approximately 9% of the dose was excreted as glucuronide conjugates within 48 h. Concentrations of N-acetyl-9-aminominocycline were approximately 6.5% and 11% of the tigecycline concentrations in serum and urine, respectively. Excretion of unchanged tigecycline into feces was the primary route of elimination, and the secondary elimination pathways were renal excretion of unchanged drug and metabolism to glucuronide conjugates and N-acetyl-9-aminominocycline.

The empiric treatment of nosocomial intra-abdominal infections

The treatment of complicated intra-abdominal infections continues to challenge physicians, primarily because of the polymicrobial nature of these infections coupled with the high risk of complications and even death among the more severe patients. The initial selection of antimicrobial therapy for treatment of nosocomial intraabdominal infections is extremely important because an association has been shown between inappropriate empiric antimicrobial therapy and delayed clinical resolution, increased length of hospital stay, and an increased risk of mortality. Moreover, it is becoming more frequent for isolates recovered from patients to possess multiple resistance factors (e.g., extended-spectrum beta-lactamases [ESBLs], vancomycin-resistant enterococci [VRE]). Therefore, when selecting empiric antimicrobial therapy, the physician must consider the likelihood of encountering one of these difficult-to-treat isolates and select an agent or agents with anticipated activity against such organisms. Here, we discuss the merits and limitations of empiric therapy for nosocomial intra-abdominal infections, review the current guidelines for treatment, and discuss the therapeutic options currently available.

Empiric therapy for secondary peritonitis: A pharmacodynamic analysis of cefepime, ceftazidime, ceftriaxone, imipenem, levofloxacin, piperacillin/tazobactam, and tigecycline using Monte Carlo simulation

Background:Inappropriate antibiotic therapy (ie, the selection of an empiric agent without activity against the responsible pathogen) of secondary peritonitis may result in poor patient outcomes. The selection of an appropriate agent can be challenging because of the emerging resistance of target organisms to commonly prescribed antibiotics. Objective:The aim of this study was to perform a pharmacodynamic analysis, using recent global surveillance data, of commonly prescribed antibiotic agents and a newer agent, tigecycline, indicated in 2005 for the treatment of complicated intra-abdominal infections, to determine their probability for achieving microbiologic success against aerobic bacteria associated with secondary peritonitis. Methods:A 2-compartment model was constructed using pharmacokinetic data from critically ill patients and global surveillance data on MIC distributions for microorganisms encountered in secondary peritonitis. A Monte Carlo simulation of the modeled data was performed to determine drug-appropriate pharmacodynamic end points, including free-drug time above the MIC, steady-state concentration above the MIC, and AUC/MIC ratios. A cumulative fraction of response (CFR) against aerobic bacteria involved in secondary peritonitis was calculated for cefepime, ceftazidime, ceftriaxone, imipenem, levofloxacin, pip eracillin/tazobactam, and tigecycline. A CFR ≥90% was considered microbiologic success. The following treatment regimens, administered as 30-minute N infusions, were examined: cefepime 1 and 2 g q12h, ceftazidime 1 and 2 g q8h, ceftriaxone 1 and 2 g q24h, imipenem 500 mg q6h, levofloxacin 750 mg q24h, pip eracillin/tazobactam 3.375 g q6h, and tigecycline 50 mg q12h, after a loading dose of 100 mg. Results:A CFR ≥90% against nonenterococcal bacteria was predicted for imipenem 500 mg q6h (96.8%), cefepime 2 and 1 g q12h (95.3% and 92.4%, respectively), ceftazidime 2 g q8h (94.2%), and piperacillin/tazobactam 3.375 g q6h (91.2%). A CFR of 84.5% was predicted for tigecycline 50 mg q12h. Ceftriaxone and levofloxacin were predicted to have a CFR <80%. When enterococci were included in the model, the predicted CFRs for imipenem, piperacillin/tazobactam, and tigecycline were 93.4%, 88.4%, and 86.7%, respectively. Conclusions:MIC distribution and pathogen prevalence strongly influence the likelihood of microbiological success in secondary peritonitis; therefore, decisions regarding empiric therapy should consider local epidemiology. Using current global data, the following regimens are adequate choices if Enterococcus is not targeted: Combination therapy (with metronidazole) using cefepime 1 g or 2 g q12h, or ceftazidime 2 g q8h; or monotherapy with imipenem 500 mg q6h or piperacillin-tazobactam 3.375 g q6h. When Enterococcus is included in the epidemiologic mix, imipenem, piperacillin/tazobactam, and tigecycline all appear to be viable monotherapeutic choices.

Predictors of Efficacy and Health Resource Utilization in Treatment of Complicated Intra-abdominal Infections: Evidence for Pooled Clinical Studies Comparing Tigecycline with Imipenem–Cilastatin

Duration of intravenous (IV) treatment, surgical/radiologic interventions for infection control, and hospital length of stay (LOS) are important cost considerations in complicated intra-abdominal infections (cIAIs). Data were pooled from two multinational, double-blind studies conducted in hospitalized adults with cIAIs who were randomized (1:1) to receive tigecycline (100 mg IV initial dose then 50 mg IV every 12 h) or imipenem-cilastatin (500 mg IV every 6 h) for 5 to 14 days in order to assess tigecycline safety and efficacy. This report focuses on developing predictors of cure and health care resource utilization, including the need for repeat surgical/radiologic interventions, duration of IV antibiotic therapy, and hospital LOS. Multiple regression models were applied for each of the above outcomes, incorporating both baseline and on-treatment potential covariates. Logistic modeling was used for categorical outcomes (cure; repeat surgical/radiologic interventions) and least squares modeling for continuous outcomes (duration of IV antibiotic therapy; LOS). Stepwise selection was used to retain only those predictors found to be significant (p < 0.05) independent risk factors. The most common causative pathogen was Escherichia coli (63.0%), with 63.3% of the patients exhibiting polymicrobial infections. The most common cIAI diagnosis was complicated appendicitis (51.9%). Lack of clinical cure (+ 6.1 days; p < 0.0001), perforation of the intestine (+3.7 days; p < 0.0001), an Acute Physiology and Chronic Health Evaluation (APACHE) score >15 (+3.1 days; p=0.039), abnormal plasma sodium concentration (+3.7 days; p=0.026), and repeat surgical/radiologic intervention (+2.2 days; p=0.0097) were identified as key risk factors for longer LOS. Inadequate source control was associated with reduced odds of cure, longer IV treatment duration (+1.5 days; p=0.007), and longer LOS. The treatment groups did not differ in terms of LOS, IV treatment duration, or clinical cure. Tigecycline was similar to imipenem-cilastatin in terms of both efficacy and health resource utilization. Risk factors identified in this study for both outcome measures are offered as support for guiding clinical practice.

Randomized, Multicenter, Double-Blind Study of Efficacy, Safety, And Tolerability of Intravenous Ertapenem Versus Piperacillin/Tazobactam in Treatment of Complicated Intra-Abdominal Infections in Hospitalized Adults

Complicated intra-abdominal infections are a common problem in surgical practice. This study compared the effectiveness of ertapenem (1 g qd) and piperacillin/tazobactam (3.375 g q6h) in the treatment of these infections. This was a multicenter, double-blinded, randomized study conducted in patients with complicated intra-abdominal infections. Of the 535 patients screened, 500 were stratified on the basis of disease severity (Acute Physiology and Chronic Health Evaluation [APACHE] II score < or =10 or >10), then randomized (1:1) to 4-14 days of treatment with one of the regimens and six weeks of followup. Nearly all patients (N = 494) were treated. The primary endpoint was the proportion of microbiologically evaluable patients with a favorable clinical response (cure) at two weeks. Non-inferiority of ertapenem was based on a difference in response rate of <15 percentage points compared with piperacillin/tazobactam (lower bound of the 95% CI > -15). Of the 494 treated patients, 231 were microbiologically evaluable, with 123 and 108 patients in the ertapenem and piperacillin/tazobactam groups, respectively. Statistically similar cure rates were observed in the ertapenem (82.1%) and piperacillin/tazobactam (81.7%) groups (difference 0.3 [95% CI: -9.6, 10.5]). The pathogens isolated most frequently were Escherichia coli, Bacteroides fragilis, and Bacteroides thetaiotamicron, typical isolates associated with intra-abdominal infections. There were no statistical differences between the groups in serious drug-related clinical adverse events, drug-related clinical adverse experiences leading to study discontinuation, or mortality. Ertapenem was non-inferior to piperacillin/tazobactam in the cure of intra-abdominal infections caused by susceptible pathogens. Both study drugs generally were well tolerated.

TIGECYCLINE USE IN CRITICALLY ILL OLDER PATIENTS: CASE REPORTS AND CRITICAL ANALYSIS

TIGECYCLINE USE IN CRITICALLY ILL OLDER PATIENTS: CASE REPORTS AND CRITICAL ANALYSIS

Randomized Controlled Trial of Moxifioxacin Compared With Piperacillin–Tazobactam and Amoxicillin–Clavulanate for the Treatment of Complicated Intra-abdominal Infections

Randomized Controlled Trial of Moxifioxacin Compared With Piperacillin–Tazobactam and Amoxicillin–Clavulanate for the Treatment of Complicated Intra-abdominal Infections

Randomized, Open-Label, Comparative Study of Piperacillin-Tazobactam Administered by Continuous Infusion versus Intermittent Infusion for Treatment of Hospitalized Patients with Complicated Intra-Abdominal Infection

The purpose of this randomized, multicenter, open-label study was to compare the continuous infusion of piperacillin-tazobactam with the standard intermittent infusion in 262 hospitalized patients with complicated intra-abdominal infections. Within 1 day of surgical intervention, eligible patients were randomized (1:1) to piperacillin-tazobactam 12 g/1.5 g administered continuously over 24 h or 3 g/0.375 g administered over 30 min intermittently every 6 h for 4 to 14 days. The demographics of the patients in the groups were similar, with a median APACHE II score of 7 and a median length of hospitalization of 7 days. Among 167 clinically evaluable patients, 86.4% and 88.4% of the patients treated with the continuous infusion and the intermittent infusion, respectively, were clinically cured or improved at the test-of-cure visit (P = 0.817). Bacteriological success was observed in 83.9% and 87.9% of patients (P = 0.597) in the two groups, respectively, and no differences in bacteriological response by pathogen were noted. Defervesence and white blood cell count normalization occurred in the majority of patients within 3 days and were similar between patients receiving the continuous infusion and those receiving the intermittent infusion. Drug-related adverse events were generally mild and were reported in similar numbers of patients in each arm of the trial. The results of this study support continuous infusion as a safe and reasonable alternate mode of administration of piperacillin-tazobactam for the treatment of complicated intra-abdominal infection.