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Background: Imipenem combined with the β-lactamase inhibitor relebactam has broad antibacterial activity, including against carbapenem-resistant gram-negative pathogens. We evaluated efficacy and safety of imipenem/cilastatin/relebactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP)., Methods: This was a randomized, controlled, double-blind phase 3 trial. Adults with HABP/VABP were randomized 1:1 to imipenem/cilastatin/relebactam 500 mg/500 mg/250 mg or piperacillin/tazobactam 4 g/500 mg, intravenously every 6 hours for 7-14 days. The primary endpoint was day 28 all-cause mortality in the modified intent-to-treat (MITT) population (patients who received study therapy, excluding those with only gram-positive cocci at baseline). The key secondary endpoint was clinical response 7-14 days after completing therapy in the MITT population., Results: Of 537 randomized patients (from 113 hospitals in 27 countries), the MITT population comprised 264 imipenem/cilastatin/relebactam and 267 piperacillin/tazobactam patients; 48.6% had ventilated HABP/VABP, 47.5% APACHE II score ≥15, 24.7% moderate/severe renal impairment, 42.9% were ≥65 years old, and 66.1% were in the intensive care unit. The most common baseline pathogens were Klebsiella pneumoniae (25.6%) and Pseudomonas aeruginosa (18.9%). Imipenem/cilastatin/relebactam was noninferior (P < .001) to piperacillin/tazobactam for both endpoints: day 28 all-cause mortality was 15.9% with imipenem/cilastatin/relebactam and 21.3% with piperacillin/tazobactam (difference, -5.3% [95% confidence interval {CI}, -11.9% to 1.2%]), and favorable clinical response at early follow-up was 61.0% and 55.8%, respectively (difference, 5.0% [95% CI, -3.2% to 13.2%]). Serious adverse events (AEs) occurred in 26.7% of imipenem/cilastatin/relebactam and 32.0% of piperacillin/tazobactam patients; AEs leading to treatment discontinuation in 5.6% and 8.2%, respectively; and drug-related AEs (none fatal) in 11.7% and 9.7%, respectively., Conclusions: Imipenem/cilastatin/relebactam is an appropriate treatment option for gram-negative HABP/VABP, including in critically ill, high-risk patients., Clinical Trials Registration: NCT02493764., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Objectives: The primary objective of this study was to establish a novel method to assess the effect of imipenem/cilastatin (IMP) on liver function laboratory indexes in Chinese underage inpatients (inpatients aged <18 year-old)., Methods: A retrospective study was conducted in 188 underage inpatients who received IMP in Xiangya Hospital from January 2016 to April 2018. Demographic data and clinical information of these inpatients were collected. As there was no reference interval of minors, the occurrence of abnormal liver function was estimated by that of adults, temporarily. A new concept (mean-variance induced by drug, MVID) was introduced to analyze the characteristics of total bilirubin (TBil), direct bilirubin (DBil), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Effect of MVID of TBil, DBil, ALT and AST in different patients (aged<1 year old and aged ≥ 1 year old) were compared by Mann-Whitney U test., Results: Estimating by reference intervals of adults, 57.4% underage inpatients (108/188) had abnormal liver function. According to the probability distribution curve of MVID, IMP can cause the increase of AST in 24% (0.62-0.38) Chinese underage inpatients, and the increase of ALT in 20% (0.60-0.40) Chinese underage inpatients. And liver protecting drugs can decrease MVID of ALT and AST. There were not statistically significant differences in MVID of TBil, DBil, ALT and AST in different patients (aged<1 year old and aged ≥ 1 year old); P value was 0.711, 0.734, 0.067 and 0.086, respectively., Conclusion: IMP can affect the liver function of 20-24% Chinese underage inpatients mainly by increasing the AST and ALT. IMP may induce hepatocellular injury, but not cholestasis. And liver protecting drugs can reverse the side effects caused by IMP. Age may not affect the effect of IMP on liver function., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The β-lactamase inhibitor relebactam can restore imipenem activity against imipenem non-susceptible pathogens., Methods: To explore relebactam's safety, tolerability and efficacy, we conducted a randomized (1:1:1), controlled, Phase 2 trial comparing imipenem/cilastatin+relebactam 250 mg, imipenem/cilastatin+relebactam 125 mg and imipenem/cilastatin alone in adults with complicated urinary tract infections (cUTI) or acute pyelonephritis, regardless of baseline pathogen susceptibility. Treatment was administered intravenously every 6 h for 4-14 days, with optional step-down to oral ciprofloxacin. The primary endpoint was favourable microbiological response rate (pathogen eradication) at discontinuation of intravenous therapy (DCIV) in the microbiologically evaluable (ME) population. Non-inferiority of imipenem/cilastatin+relebactam over imipenem/cilastatin alone was defined as lower bounds of the 95% CI for treatment differences being above -15%., Results: At DCIV, 71 patients in the imipenem/cilastatin + 250 mg relebactam, 79 in the imipenem/cilastatin + 125 mg relebactam and 80 in the imipenem/cilastatin-only group were ME; 51.7% had cUTI and 48.3% acute pyelonephritis. Microbiological response rates were 95.5%, 98.6% and 98.7%, respectively, confirming non-inferiority of both imipenem/cilastatin + relebactam doses to imipenem/cilastatin alone. Clinical response rates were 97.1%, 98.7% and 98.8%, respectively. All 23 ME patients with imipenem non-susceptible pathogens had favourable DCIV microbiological responses (100% in each group). Among all 298 patients treated, 28.3%, 29.3% and 30.0% of patients, respectively, had treatment-emergent adverse events. The most common treatment-related adverse events across groups (1.0%-4.0%) were diarrhoea, nausea and headache., Conclusions: Imipenem/cilastatin + relebactam (250 or 125 mg) was as effective as imipenem/cilastatin alone for treatment of cUTI. Both relebactam-containing regimens were well tolerated. (NCT01505634)., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Elderly patients, in particular, have been reported to develop psychiatric side effects from antibiotics. Clarithromycin, quinolones, sulfamethoxazole-trimethoprim, isoniazid, penicillin, and cephalosporins have been reported to cause psychosis. This case report bridges a void in the medical literature with regards to the psychiatric adverse effects of imipenem-cilastatin., Case Presentation: A 64-year-old Hispanic man in septic shock due to urinary tract infection was initiated on imipenem-cilastatin and mechanically ventilated, following admission to hospital. His mentation was normal for 72 hours after extubation and discontinuation of sedatives and opioids, following which he was noted to be in acute psychosis. Our patient's imipenem-cilastatin dose had been increased 24 hours prior to his violent visual and auditory hallucinations because his renal function had improved. The physical examination and laboratory tests did not reveal evidence of a new central nervous infection or endocrinopathy. His mentation improved after his antibiotic was switched to ceftriaxone, based on culture and sensitivity testing. Similar psychiatric symptoms developed 2 months later when he was treated with imipenem for a recurrent urinary tract infection. His symptoms again resolved with modification of his antibiotic regimen., Conclusions: Endocrine dysfunctions (thyroid, adrenal, and pituitary disorders) and toxic ingestions are medical disorders known to cause brief psychotic episodes. Fluoroquinolones, penicillins, and trimethoprim-sulfamethoxazole are common antibiotics associated with this rare adverse effect. Several pharmacokinetic hypotheses have been proposed for this adverse effect: (1) N-methyl-D-aspartate receptor hypofunctioning, (2) sequential blockade of folic acid production, (3) inhibition of prostaglandin E2 and proinflammatory cytokine production, (4) increased central dopamine turnover, and (5) accumulation of toxic levels of the drug. Pre-existing psychopathology, relevant comorbidities, slow acetylation status, and increased permeability of the blood-brain barrier have been suggested to make patients more prone to developing psychosis. According to the literature, this psychiatric manifestation resolves within 2 weeks of discontinuing the offending agent. There appears to be underreporting of the psychiatric manifestations of imipenem-cilastatin, contrary to post-marketing surveillance data. It is imperative that physicians recognize these psychiatric side effects of antibiotics, because they are a fundamental treatment option.

Drugs, toxins, and infections are known to cause acute eosinophilic pneumonia. Daptomycin and minocycline are the commonly reported antibiotics associated with acute eosinophilic pneumonia. In this study, we present a case of imipenem/cilastatin-induced acute eosinophilic pneumonia. The patient presented with fever, acute hypoxic respiratory distress, and diffuse ground-glass opacities on the chest CT a day after the initiation of imipenem/cilastatin. Patient also developed peripheral eosinophilia. A reinstitution of imipenem/cilastatin resulted in recurrence of the signs and symptoms. A bronchoscopy with bronchoalveolar lavage showed 780 nucleated cells/mm(3) with 15% eosinophil. The patient's clinical condition improved significantly after the discontinuation of imipenem/cilastatin therapy and the treatment with corticosteroid., (2016 BMJ Publishing Group Ltd.)

The present study is a non-inferiority study based on a descriptive and comparative case series for comparison of generic vs. original intravenous antimicrobials in septic oncology patients at an oncology private ICU. 1906 cancer patients admitted to Arturo Lopez Perez Foundation, Chile, were included in this study. After recruitment, a first retrospective group of 206 septic cancer patients recorded from 1st January, 2008 until July 14th, 2010, treated with original antibiotics (cefoperazone-sulbactam, imipenem-cilastatin, piperacillin-tazobactam) were included for analyses and a second prospective group of 143 septic cancer patients recorded from July 15th, 2010 until January 02, 2013, treated with the same but generic antibiotics were also included for comparisons. The trial protocol was developed in accordance with Helsinki and Good Clinical Practices recommendations. The results of this study showed no significant differences between the 2 groups in days of treatment, rate of success and lab test determinations (white cell count, PCR and procalcitonin), with lower, but not significant, total bed days and CPU bed days for generic antibiotics. Therefore, we conclude that the safety and efficacy of the generic antibiotics cefactam®, imipen® and Piperazam® are not inferior to original antibiotics for the treatment of severe sepsis in hospitalised patients at the Arturo Lopez Perez Foundation., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: We conducted a randomized controlled trial to evaluate the clinical efficacy and safety of intravenous doripenem (DRPM) in patients with biliary tract infection requiring biliary drainage in comparison with imipenem/cilastatin (IPM/CS)., Methods: After the initial collection of bile, patients were randomly assigned by the registration system of the Clinical Research Organization to receive intravenous drip infusion of DRPM 0.5 g or IPM/CS 0.5 g three times daily in a randomized, open-label manner., Results: A total of 127 patients were enrolled in the trial (DRPM 62, IPM/CS 65). The characteristics of the 122 patients evaluated for efficacy were well balanced, except for the percentage of patients previously receiving antimicrobials, which was higher in the DRPM group than in the IPM/CS group. The clinical response rate was not significantly different between the DRPM group (93.1 %, 54/58 patients) and the IPM/CS group (93.8 %, 60/64). Non-inferiority assessment using confidence intervals demonstrated the non-inferiority of DRPM-IPM/CS. The incidence of adverse events, for which a causal relationship with either treatment was not ruled out, was 3.3 % (2/60) in the DRPM group and 3.1 % (2/65) in the IPM/CS group, and none was serious., Conclusions: The clinical efficacy of DRPM in treating moderate or severe biliary tract infection requiring drainage was comparable to that of IPM/CS. DRPM was associated with no serious adverse events and a low incidence of adverse events. The results of this trial demonstrate that DRPM is a useful therapeutic option for moderate or severe biliary tract infection.

We conducted an open-label, randomized study to evaluate the clinical efficacy of cefozopran, meropenem or imipenem-cilastatin using cefepime as a control in febrile neutropenia (FN) patients. Three hundred and seventy-six patients received cefepime, cefozopran, meropenem or imipenem-cilastatinas initial therapy for FN. The primary endpoint was the non-inferiority of response rates including modification at day 7 in cefozopran, meropenem or imipenem-cilastatin patients compared with cefepime in the per-protocol population (delta = 10%). The response rates for cefozopran, meropenem and imipenem-cilastatin were not significantly different compared with cefepime (cefozopran: 54/90 (60%), meropenem: 60/92 (65%), and IPM/CS: 63/88 (72%) versus cefepime: 56/85 (66%) (p = 0.44, 1.0 and 0.51, respectively)), and the differences in treatment success for cefozopran, meropenem and imipenem-cilastatin compared with cefepime were -5.9% (95% confidence interval (CI): -20.1-8.4), -0.7% (95% CI: -14.6-13.3), and 5.7% (95% CI: -8.1-19.4), respectively. The same tendency was seen in the modified intention-to-treat population. Based on the evaluation of initial drug efficacy performed on days 3-5, there was no significant difference between the four drugs. In the subgroup with an absolute neutrophil count ≤ 100 × 10(6)/L for longer than seven days, there was significantly better efficacy in the carbapenem arm compared to 4th generation beta-lactams (52% versus 27% at days 3-5, p = 0.006, and 76% versus 48% at day 7, p = 0.002). Our results suggest that the effects of these four drugs as empiric therapy were virtually the same for adult FN patients, although non-inferiority was shown only in imipenem-cilastatin compared with cefepime (clinical trial number: UMIN000000462)., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: We sought to evaluate the safety of imipenem and meropenem in the treatment of infections in neurosurgical patients., Methods: An observational retrospective study was conducted of consecutive cases treated with imipenem from Sept. 2007 to Sept. 2009 and meropenem within 1 year from Sept. 2008 in Beijing Tiantan Hospital, China. Data including the dosage and duration of the drug use, occurrence of seizures and mortality outcome was collected from the electronic pharmacy records. The incidence of epilepsy, epileptic standardized morbidity rate (SMR) were reported. Attention was paid to the relationship between the use of imipenem/meropenem and the incidence of epilepsy., Results: The imipenem patients within two years amounted to 71, with mean age 45.9±20.2 years, male to female ratio 46/25. The incidence of epilepsy was 11.3% (8 cases). Among them, 1 case occurred during treatment (1/633, 1.6/1000 patient-days), and the remaining 7 cases occurred before treatment (7/2819, 2.5/1000 patient-days), with the standardized incidence rate 0.64, 95% CI (0.08-5.18).The meropenem patients within one year amounted to 92, mean age 45.1±19.4 years, male to female ratio 51/41. The incidence of epilepsy was 6.5% (6 cases). 2 occurred during treatment (2/582, 2.0/1000 patients-hospital days) and 4 before treatment (4/2047, 3.4/1000 patients-inpatient days), standardized incidence rate 1.76, 95% CI (0.32-9.63)., Conclusion: Despite many other epileptogenic factors, imipenem or meropenem did not increase the risk of seizures in neurosurgical patients. There was not further risk for patients with pre-existing seizures or creatinine clearance abnormalities when dosed appropriate.

Background: Carbapenems are commonly used in hospitalized infants despite a lack of complete safety data and associations with seizures in older children. We compared the incidence of adverse events in hospitalized infants receiving meropenem versus imipenem/cilastatin., Methods: We conducted a retrospective cohort study of 5566 infants treated with meropenem or imipenem/cilastatin in neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2010. Multivariable conditional logistic regression was performed to evaluate the association between carbapenem therapy and adverse events, controlling for infant factors and severity of illness., Results: Adverse events were more common with use of meropenem compared with imipenem/cilastatin (62.8/1000 infant days versus 40.7/1000 infant days, P < 0.001). There was no difference in seizures with meropenem versus imipenem/cilastatin (adjusted odds ratio 0.96; 95% confidence interval: 0.68, 1.32). The incidence of death, as well as the combined outcome of death or seizure, was lower with meropenem use-odds ratio 0.68 (0.50, 0.88) and odds ratio 0.77 (0.62, 0.95), respectively., Conclusion: In this cohort of infants, meropenem was associated with more frequent but less severe adverse events when compared with imipenem/cilastatin.

In a previous phase 3 study, the cure rates that occurred in patients with hospital-acquired pneumonia treated with tigecycline at the approved dose were lower than those seen with patients treated with imipenem and cilastatin (imipenem/cilastatin). We hypothesized that a higher dose of tigecycline is necessary in patients with hospital-acquired pneumonia. This phase 2 study compared the safety and efficacy of two higher doses of tigecycline with imipenem/cilastatin in subjects with hospital-acquired pneumonia. Subjects with hospital-acquired pneumonia were randomized to receive one of two doses of tigecycline (150 mg followed by 75 mg every 12 h or 200 mg followed by 100 mg every 12 h) or 1 g of imipenem/cilastatin every 8 h. Empirical adjunctive therapy was administered for initial coverage of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa infection, depending on the randomization regimen. Clinical response, defined as cure, failure of treatment, or indeterminate outcome, was assessed 10 to 21 days after the last day of therapy. In the clinically evaluable population, clinical cure with tigecycline 100 mg (17/20, 85.0%) was numerically higher than with tigecycline 75 mg (16/23, 69.6%) and imipenem/cilastatin (18/24, 75.0%). No new safety signals with the high-dose tigecycline were identified. A numerically higher clinical response was observed with the 100-mg dose of tigecycline. This supports our hypothesis that a higher area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) may be necessary to achieve clinical cure in patients with hospital-acquired pneumonia. Further studies are necessary. (The ClinicalTrials.gov identifier for this clinical trial is NCT00707239.).

Objectives: The aim of this prospective phase II, randomized, investigator-blinded study (NCT00690378) was to compare the efficacy and safety of ceftazidime-avibactam and imipenem-cilastatin in hospitalized adults with serious complicated urinary tract infection (cUTI) due to Gram-negative pathogens., Patients and Methods: Patients aged between 18 and 90 years with cUTI were enrolled and stratified by infection type (acute pyelonephritis or other cUTI) and randomized 1:1 to receive intravenous ceftazidime 500 mg plus avibactam 125 mg every 8 hours or imipenem-cilastatin 500 mg every 6 hours. Patients meeting pre-specified improvement criteria after 4 days could be switched to oral ciprofloxacin. Patients were treated for a total of 7-14 days. The primary efficacy objective was a favorable microbiological response at the test-of-cure (TOC) visit 5-9 days post-therapy in microbiologically evaluable (ME) patients., Results: Overall, 135 patients received study therapy (safety population); 62 were included in the ME population (ceftazidime-avibactam, n = 27; imipenem-cilastatin, n = 35). The predominant uropathogen was Escherichia coli. Favorable microbiological response was achieved in 70.4% of ME patients receiving ceftazidime-avibactam and 71.4% receiving imipenem-cilastatin at the TOC visit (observed difference -1.1% [95% CI: -27.2%, 25.0%]). Among ME patients with ceftazidime-resistant uropathogens, response was observed in 6/7 (85.7%) receiving ceftazidime-avibactam. Adverse events were observed in 67.6% and 76.1% of patients receiving ceftazidime-avibactam and imipenem-cilastatin, respectively. Limitations of the study include the small number of patients in the ME population., Conclusion: The results suggest that the efficacy and safety of ceftazidime-avibactam may be similar to that of imipenem-cilastatin.

Objective: To evaluate the efficacy and safety of domestic imipenem cilastatin sodium for the treatments of severe aspiration pneumonia., Methods: A randomize, open, parallel-controlled trial was conducted. Sixty-eight patients with severe aspiration pneumonia were divided into trial group (n=36) and control group (n=32) by random distribution method. The application of trial group domestic imipenem cilastatin sodium was 1.0 g intravenous drip, every 6-8 hours for 7-14 days. The control group application with imported injection imipenem cilastatin sodium was 1.0 g intravenous drip, every 6-8 hours for 7-14 days. The highest daily temperature (T), heart rate (HR), breathing rate (RR), pulse blood oxygen saturation (SpO(2)), blood oxygen partial pressure (PaO(2)), inhaled oxygen concentration (FiO(2)), oxygenation index (PaO(2)/FiO(2)), airway peak pressure (Paw), minute ventilation (MV) and white blood count (WBC), pro calcitonin (PCT), high-sensitivity C-reactive protein (hs-CRP) index before and 1, 3, 7 days after treatment, and liver and kidney function, chest X-rays, and sputum cultures of drug sensitive test were conducted. And the effectiveness and safety were determined according to the standards., Results: After treatment indexes of the two groups were obviously improved, i. e. T, HR, RR, Paw, MV, the WBC, PCT, CRP were gradually declined, PaO(2)/FiO(2) was gradually raised. There were statistical significance before and 3 days after treatment in the trial and the control group [T: 37.35±0.91 centigrade vs. 38.43±1.06 centigrade, 37.28±0.88 centigrade vs. 38.35±1.11 centigrade; HR: 90.25±10.60 bpm vs. 118.94±15.46 bpm, 89.31±11.17 bpm vs. 124.34±17.87 bpm; RR: 25.14±3.17 bpm vs. 32.28±4.49 bpm, 24.81±2.43 bpm vs. 33.13±4.17 bpm; Paw: 23.03±3.04 cm H(2)O vs. 33.22±4.59 cm H(2)O, 22.75±3.22 cm H(2)O vs. 33.63±4.79 cm H(2)O; MV: 8.67±1.26 L/min vs. 11.80±2.01 L/min, 8.88±1.45 L/min vs. 13.21±2.90 L/min; WBC: 11.26±1.96 ×10(9)/L vs. 14.57±3.10 ×10(9)/L, 12.28±3.38 ×10(9)/L vs. 15.25±4.93 ×10(9)/L; PCT: 6.90±5.46 μg/L vs. 16.97±7.93 μg/L, 6.17±6.13 μg/L vs. 21.26±11.54 μg/L; CRP: 85.50±37.91 mg/L vs. 120.17±45.47 mg/L, 94.31±38.51 mg/L vs. 142.34±53.57 mg/L; PaO(2)/ FiO(2): 182.06±40.88 mm Hg vs. 98.67±20.62 mm Hg, 184.09±43.78 mm Hg vs. 96.22±22.59 mm Hg, all P<0.05]. There was no significant change in SpO(2) before and after treatment in two groups. And the total clinical effective rate in trial and control group were 83.4% and 81.2%, adverse reaction rate were 13.9% and 9.4%, bacterial removal rate were 90.3% and 87.0% respectively, and there was no significant difference between the two groups (all P>0.05)., Conclusion: Domestic imipenem cilastatin sodium can effectively control severe aspiration pneumonia, and it is safe and effective antibiotics.

To compare efficacy and safety of a tigecycline regimen with an imipenem/cilastatin regimen in hospital-acquired pneumonia patients, a phase 3, multicenter, randomized, double-blind, study evaluated 945 patients. Coprimary end points were clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure. Cure rates were 67.9% for tigecycline and 78.2% for imipenem (CE patients) and 62.7% and 67.6% (c-mITT patients), respectively. A statistical interaction occurred between ventilator-associated pneumonia (VAP) and non-VAP subgroups, with significantly lower cure rates in tigecycline VAP patients compared to imipenem; in non-VAP patients, tigecycline was noninferior to imipenem. Overall mortality did not differ between the tigecycline (14.1%) and imipenem regimens (12.2%), although more deaths occurred in VAP patients treated with tigecycline than imipenem. Overall, the tigecycline regimen was noninferior to the imipenem/cilastatin regimen for the c-mITT but not the CE population; this difference appears to have been driven by results in VAP patients., (Copyright © 2010. Published by Elsevier Inc.)

In this prospective, randomized, open-label clinical trial, we compared the efficacy and safety of two antibiotic regimens for severe diabetic foot infections (DFI). Sixty-two in-patients with DFI received either piperacillin/tazobactam (Pip-Tazo, n = 30) (4.5 g intravenously every 8h) or imipenem/cilastatin (IMP, n = 32) (0.5 g intravenously every 6h). The mean duration of treatment was 21 days for Pip-Tazo and 24 days for IMP. Twenty-two (73.3%) patients in the Pip-Tazo group and 26 (81.2%) patients in the IMP group had DFI associated with osteomyelitis. Successful clinical response was seen in 14 (46.7%) patients in the Pip-Tazo group and in nine (28.1%) patients in the IMP group [relative risk (RR) 1.6 (95% CI 0.84-3.25), p 0.130]. Two patients in the IMP group and none in the PIP-Tazo group relapsed [RR 2 (0.94-4.24), p 0.058]. Eighty-nine microorganisms were isolated: 38 (43%) Gram-positive and 51(57%) Gram-negative. Among patients with positive culture, 47 (96%) had complete and two (4%) had partial microbiological response. Microbiological response rates were similar in both groups (p 1.000). Amputation was performed in 18 (60%) and 22 (69%) patients in the Pip-Tazo and IMP groups (p 0.739) respectively. Side effects were more common in the Pip-Tazo group (30% vs. 9.4%), but they were generally mild and reversible. In conclusion, although the sample size was small and the results did not reach statistical significance, Pip-Tazo produced a better clinical response rate than IMP in the treatment of severe DFI. There was no significant difference between the treatment groups with respect to microbiological response, relapse and amputation rates.

Background: Tigecycline, a first-in-class broad-spectrum glycylcycline antibiotic, has broad-spectrum in vitro activity against bacteria commonly encountered in complicated intra-abdominal infections (cIAIs), including aerobic and facultative Gram-positive and Gram-negative bacteria and anaerobic bacteria. In the current trial, tigecycline was evaluated for safety and efficacy vs. imipenem/cilastatin in hospitalized Chinese patients with cIAIs., Methods: In this phase 3, multicenter, open-label study, patients were randomly assigned to receive IV tigecycline or imipenem/cilastatin for /=1 dose of study drug and comprised the modified intent-to-treat population. In the microbiologically evaluable population, 86.5% (45 of 52) of tigecycline- and 97.9% (47 of 48) of imipenem/cilastatin-treated patients were cured at the test-of-cure assessment (12-37 days after therapy); in the microbiologic modified intent-to-treat population, cure rates were 81.7% (49 of 60) and 90.9% (50 of 55), respectively. The overall incidence of treatment-emergent adverse events was 80.4% for tigecycline vs. 53.9% after imipenem/cilastatin therapy (P < 0.001), primarily due to gastrointestinal-related events, especially nausea (21.6% vs. 3.9%; P < 0.001) and vomiting (12.4% vs. 2.0%; P = 0.005)., Conclusions: Clinical cure rates for tigecycline were consistent with those found in global cIAI studies. The overall safety profile was also consistent with that observed in global studies of tigecycline for treatment of cIAI, as well as that observed in analyses of Chinese patients in those studies; no novel trends were observed., Trial Registration: ClinicalTrials.gov NCT00136201.

Background: Biapenem is an injectable carbapenem antibiotic. A clinical study was designed to evaluate its efficacy and safety in the treatment of respiratory and urinary infections compared to imipenem/cilastatin., Methods: A total of 216 patients with respiratory or urinary tract infections were enrolled into this multicenter, open-label, randomized controlled clinical study. Each patient was randomly assigned to either the treatment or control group; 106 patients in each group were included in the ITT analyses. The patients were given biapenem 300 mg or imipenem/cilastatin 500 mg/500 mg two or three times daily, i.v. g.t.t. for 7-14 days according to their conditions., Results: The cure and effective rates were 67.92 and 88.68% in the biapenem group and 76.02 and 93.40% in the imipenem/cilastatin group, the bacterial eradication rates were 93.83 and 98.82%, and the adverse-event rates were 6.54 and 7.41%, respectively. There were no significant differences between the two groups (p > 0.05)., Conclusion: Biapenem is as effective and well-tolerated as imipenem/cilastatin for the treatment of intermediate and severe bacterial infections., (Copyright © 2010 S. Karger AG, Basel.)

Background: Several generic imipenem/cilastatin formulations have been approved by Thai FDA and a generic imipenem/cilastatin (Yungjin) has been available in SirirajHospital since 2007. Since imipenem/cilastatin is usually given to the patients with serious hospital-acquired infections, the generic imipenem/cilastatin must be therapeutically equivalent to the original imipenem/cilastatin. The objective of the study was to compare effectiveness and safety of generic imipenem/cilastatin with original imipenem/cilastatin for therapy of infections in hospitalized patients at Siriraj Hospital., Material and Method: Medical records of adult hospitalized patients at Siriraj Hospital who received imipenem/cilastatin at least 48 hours during June 2007 to September 2008 were reviewed. The effectiveness data of 300 patients who received original imipenem/cilastatin were compared with those of 300 patients who received generic imipenem/cilastatin in order to determine if a difference in composite favorable outcome of both formulations was within 10%., Results: The demographics, clinical features of infections, site of infections, type of causative organisms and concomitant antibiotics of the patients in both groups were not significantly different. The overall favorable outcomes in the original imipenem/cilastatin and the generic imipenem/cilastatin groups were 65% and 58.7% respectively (absolute difference 6.3%, 95% CI -1.4% to 14%). Cure rates of infections in the original imipenem/cilastatin and the generic imipenem/cilastatin groups were 35% and 28.7% respectively (absolute difference 6.3%, 95% CI -1.1% to 13.7%). Super-infection rates in the original imipenem/cilastatin and the generic imipenem/cilastatin groups were 4.7% and 9% respectively (absolute difference -4.3%, 95% CI -8.5% to 0.3%). Mortality due to infections in the original imipenem/cilastatin and the generic imipenem/cilastatin groups were 18.3% and 21.3% respectively (absolute difference -3%, 95% CI -9.4% to 3.4%). Overall mortality in the original imipenem/cilastatin and the generic imipenem/cilastatin groups were 35.3% and 43% respectively (absolute difference -7.7%, 95% CI -15.3% to 0.1%). The occurrence of adverse events in the patients in both groups was not significantly different., Conclusion: Although the point estimate of composite favorable outcome of the patients who received generic imipenem/cilastatin (Yungjin) was < 10% of those who received original imipenem/cilastatin (Tienam), generic imipenem/cilastatin showed a trend for therapeutic non-equivalence to original imipenem/cilastatin because the upper limits of 95% confidence interval of differences of several important clinical outcomes were more than 10%.

Background: Administration of imipenem-cilastatin to patients with IgE-mediated hypersensitivity to beta-lactams has always been considered potentially harmful. Recent studies have demonstrated the tolerability of carbapenems (imipenem-cilastatin and meropenem) in patients with IgE-mediated hypersensitivity to beta-lactams; there are no studies on this topic regarding patients with cell-mediated allergy to beta-lactams. The aim of this study is to assess cross-reactivity and tolerability of imipenem in patients with cell-mediated allergy to beta-lactams., Methods: From our database we selected 73 patients with cell-mediated allergy to beta-lactams, diagnosed by means of immediate-type skin tests, delayed reading intradermal tests, patch tests and detection of specific IgE. Patients with negative patch tests with imipenem-cilastatin underwent an intramuscular test dosing., Results: Our patients had a total of 94 nonimmediate reactions to penicillins. All patients had positive patch tests and/or delayed reading intradermal tests for at least one of the penicillin reagent tested and negative immediate-type skin tests and specific IgE. Four patients out of 73 had a positive patch tests to at least one penicillin reagent and imipenem-cilastatin showing cross-reactivity. Sixty-four patients underwent the imipenem-cilastatin intramuscular test dosing and none of them had a clinical reaction., Conclusions: Our rate of cross-reactivity between imipenem-cilastatin and other beta-lactams was 5.5%. This result is different from previous findings and this may be explained by the fact that we investigated patients with cell-mediated allergy to beta-lactams. Patients with cell-mediated allergy to beta-lactams should undergo patch tests and a tolerance challenge test before treatment with imipenem-cilastatin.

A 73-year-old, ASA I patient scheduled for transurethral resection of the prostate under subarachnoid anesthesia received, prior to the beginning of the surgery, intravenous imipenem/cilastatin 1 g for a urinary infection with multiresistant Escherichia coli. The patient developed seizures during the surgical procedure. Central nervous toxicity of imipenem/cilastatin might have been the cause of the seizures. After appropriate management, the patient recovered well and was discharged without complications. The differential diagnosis between systemic toxicity of local anesthetics and imipenem-related seizures is discussed.

Imipenem is often used in treatment of acute exacerbations of severe chronic obstructive pulmonary disease (COPD). Superinfection following imipenem therapy is a common cause of treatment failure and high economic burden. This study is aimed to explore any clinical factors which determine the risk of superinfection after imipenem treatment in acute exacerbations of severe COPD. A prospective observational study was conducted in a 5-bed respiratory intensive care unit of a Chinese University hospital. Fifty-one patients with acute exacerbations of severe COPD who were hospitalised and treated with imipenem for more than 3 days were enrolled during 1.5 year. The associations between the risk of superinfection and potential factors were analysed by logistic regression. Forty-seven out of 51 patients (92.2%) had their symptoms and signs improved at the end of imipenem treatment. Superinfections were developed in 12 patients, and the superinfection rate was as high as 30.8% (12 out of 39 patients with definite bacteriologic responses). The frequent superinfecting organisms were Stenotrophomonas maltophilia and Pseudomonas aeruginosa. Among a wide range of potential risk factors, we found that lower blood pH, previous cephalosporines treatment and longer period of imipenem treatment are independently associated with a higher risk of superinfection. The risk of superinfection following imipenem treatment in hospitalised patients with acute exacerbations of COPD was high. Lower blood pH, previous cephalosporines treatment and longer period of imipenem treatment all increased the risk of superinfection.

Objective: To evaluate the clinical usefulness of sulbactam/ampicillin therapy for community-acquired pneumonia in the elderly., Methodology: A randomized prospective clinical study was conducted in the elderly patients with moderate-to-severe community-acquired bacterial pneumonia., Results: Overall clinical efficacy of sulbactam/ampicillin therapy (6 g/day) in these patients (efficacy rate: 91.4%) was comparable to that of imipenem/cilastatin therapy (1 g/day; efficacy rate: 87.5%), when each therapy was administered intravenously twice daily for 7-14 days. With regard to clinical efficacy based on disease severity, bacteriological efficacy, improvement of chest X-ray findings and adverse reactions, the two therapies were comparable., Conclusion: These results suggest that sulbactam/ampicillin therapy has excellent efficacy and tolerability and that it may be highly effective, even in severe cases of pneumonia. This regimen may thus serve as first-line treatment for the treatment of community-acquired pneumonia in elderly patients.

Imipenem (thienamycin formamidine), a broad-spectrum beta-lactam antibiotic, is always used in combination with cilastatin in order to avoid the premature breakdown of imipenem by renal tubular dipeptidase. As this dipeptidase also hydrolyzes the glutathione metabolite cysteinylglycine, the therapeutic association of imipenem and cilastatin might cause an accumulation of the aminothiol cysteinylglycine. We demonstrate here that when patients are treated with imipenem-cilastatin, their plasma levels of cysteinylglycine are significantly and specifically increased, while cysteine levels are decreased and homocysteine levels are unaffected. We conclude that antibiotic treatment using imipenem-cilastatin induces important metabolic changes that should not remain unrecognized.

The effects of phenytoin (PHT) and phenobarbital (PHB) on EEG activity and behavior was studied in the model of epilepsy induced by intracerebroventricular (i.c.v.) administration of imipenem/cilastatin (Imi/Cil). Under intraperitoneal (i.p.) sodium pentobarbital anesthesia adult male Wistar albino rats were implanted with electrodes and cannulas were placed into the right lateral ventricle. Animals were divided into groups: 1) Imi/Cil (100/100 microg, i.c.v.), 2) PHT (40 mg/kg) + Imi/Cil (100/100 microg, i.c.v), 3) PHT (80 mg/kg) + Imi/Cil (100/100 microg, i.c.v.), 4) PHT (160 mg/kg) + Imi/Cil (100/100 microg, i.c.v.), 5) PHB (50 mg/kg) + Imi/Cil (100/100 microg, i.c.v.), and 6) PHB (80 mg/kg) + Imi/Cil (100/100 microg, i.c.v.). PHT and PHB were injected intraperitoneally (i.p.) 1 h before Imi/Cil. Seizures were scored according to the scale: 0--normal behavior; 1--twitching, 2--head nodding, forelimb clonus, 3--rearing, and 4--clonic-tonic convulsions. Imi/Cil provoked maximal seizures in all animals, and all rats died 10 - 18 min after the injection. Epileptiform activity preceded behavioral seizures. Clonic-tonic seizures were associated with continuous bursts of high-frequency high-amplitude spikes in the EEG. PHT and PHB suppressed Imi/Cil-induced seizures dose-dependently. PHB reduced epileptiform discharges during behavioral seizures elicited by Imi/Cil, while PHT had no effect on EEG epileptic phenomena. These results suggest that PHT acts as anticonvulsant, and PHB as anticonvulsant and antiepileptic agent in the model of epilepsy induced by Imi/Cil.

In a randomized, evaluator-blind, multicenter trial, we compared cefepime (2 g three times a day) with imipenem-cilastatin (500 mg four times a day) for the treatment of nosocomial pneumonia in 281 intensive care unit patients from 13 centers in six European countries. Of 209 patients eligible for per-protocol analysis of efficacy, favorable clinical responses were achieved in 76 of 108 (70%) patients treated with cefepime and 75 of 101 (74%) patients treated with imipenem-cilastatin. The 95% confidence interval (CI) for the difference between these response rates (-16 to 8%) failed to exclude the predefined lower limit for noninferiority of -15%. In addition, therapy of pneumonia caused by an organism producing an extended-spectrum beta-lactamase (ESBL) failed in 4 of 13 patients in the cefepime group but in none of 10 patients in the imipenem group. However, the clinical efficacies of both treatments appeared to be similar in a secondary intent-to-treat analysis (95% CI for difference, -9 to 14%) and a multivariate analysis (95% CI for odds ratio, 0.47 to 1.75). Furthermore, the all-cause 30-day mortality rates were 28 of 108 (26%) patients in the cefepime group and 19 of 101 (19%) patients in the imipenem group (P = 0.25). Rates of documented or presumed microbiological eradication of the causative organism were similar with cefepime (61%) and imipenem-cilastatin (54%) (95% CI, -23 to 8%). Primary or secondary resistance of Pseudomonas aeruginosa was detected in 19% of the patients treated with cefepime and 44% of the patients treated with imipenem-cilastatin (P = 0.05). Adverse events were reported in 71 of 138 (51%) and 62 of 141 (44%) patients eligible for safety analysis in the cefepime and imipenem groups, respectively (P = 0.23). Although the primary end point for this study does not exclude the possibility that cefepime was inferior to imipenem, some secondary analyses showed that the two regimens had comparable clinical and microbiological efficacies. Cefepime appeared to be less active against organisms producing an ESBL, but primary and secondary resistance to imipenem was more common for P. aeruginosa. Selection of a single agent for therapy of nosocomial pneumonia should be guided by local resistance patterns.

Objective: To report a successful case of rapid imipenem desensitization in a critically ill patient with multidrug-resistant Acinetobacter baumannii ventilator-associated pnemonia (VAP)., Case Summary: A 40-year-old white man who had a lengthy stay in the intensive care unit (ICU) following a motorcycle accident developed VAP caused by A. baumannii. treatment with imipenem was necessary due to the bacteria's resistance to all other antibiotics. However, this patient was diagnosed with an allergy to imipenem following exposure earlier in his hospitalization in addition to a positive penicillin skin test. Thus, we attempted rapid desensitization to imipenem using a continuous infusion protocol. The patient was desensitized within 4 hours and was successfully treated for 21 days with a continuous infusion of imipenem combined with daily amikacin. He experienced no adverse reaction during the desensitization process or the remainder of his treatment course., Discussion: The protocol used in this case was modified from a previously reported case, and differed in the speed of desensitization and total daily dose. We assumed that a more gradual escalation of the dose in our modified protocol would prevent the occurrence of adverse events, thereby resulting in more rapid desensitization. Rapid desensitization was necessary in this patient due to the presence of a life-threatening infection. The lower total daily dose of imipenem was in response to impaired renal function., Conclusions: Therapeutic options for multidrug-resistant pneumonia in the ICU are significantly limited in the presence of imipenem allergy. An option of last resort is to desensitize the patient using a rapid administration protocol. Our modified rapid imipenem desensitization protocol was successful and allowed for effective treatment of life-threatening pneumonia.

Objective: To evaluate the efficacy and safety of meropenem in Chinese patients, we conducted a study for the treatment of patients with lower respiratory tract infections, urinary tract infections and other infections., Methods: A total of 182 hospitalized patients were enrolled in the study. 90 patients received 500 mg meropenem every 12 hours (or 1 g every 12 hours if necessary) and 92 patients received imipenem/cilastatin 500 mg/500 mg every 12 hours (or 1 g every 12 hours if necessary) by intravenous infusion. The duration of treatment was 7 - 14 days for both groups., Results: Seventy of 90 cases receiving meropenem and 70 of 92 cases receiving imipenem/cilastatin were assessable for clinical efficacy. The overall efficacy rates were 90% for the meropenem group and 87% for the imipenem/cilastatin group, and the bacterial eradication rates were 86% in both groups. 93 (76%) of 123 strains isolated from patients produced beta-lactamases. Adverse drug reactions were evaluated in 72 cases in the meropenem group and 70 cases in the imipenem/cilastatin group. The adverse drug reaction rates were 9.7% and 8.6%, respectively. The results showed that there were no statistical differences between these two groups (P > 0.05)., Conclusion: Meropenem is effective and safe for the treatment of bacterial infections caused mainly by beta-lactamase-producing strains.

This randomised, double-blind, multicentre trial compared piperacillin/tazobactam (2 g/0.5 g/q8h) and imipenem/cilastatin (0.5 g/0.5 g/q8h) as monotherapy in patients with acute pyelonephritis or complicated urinary tract infections. In total, 237 patients were randomised to receive either piperacillin/tazobactam (n=161) or imipenem/cilastatin (n=166). At the early follow-up (=test-of-cure-visit) 5-9 days after antibiotic therapy, clinical success was noted in 122/147 (83.0%) piperacillin/tazobactam recipients compared with 123/154 (79.9%) imipenem/cilastatin recipients, thus proving that both treatments were equally effective. On a descriptive level, an advantage of piperacillin/tazobactam was demonstrated. Microbiological success at the early follow-up was 78/135 (57.8%) for piperacillin/tazobactam and 70/144 (48.6%) for imipenem/cilastatin. These results were confirmed by equivalent success rates on the last therapy day. Both drugs were generally well tolerated.

We describe a patient who suffered from intestinal perforation after abdominal trauma. Perioperatively, he was treated with a single dose of piperacillin and 9 doses of imipenem/cilastatin over 3 days. The patient was discharged 5 days after surgery in good clinical condition and with normal liver values except for a marginal elevation of alanine aminotransferase. Two weeks after discharge, he developed fatigue, fever and pruritus, necessitating rehospitalization. He was jaundiced and had elevated alkaline phosphatase and transaminases. After exclusion of an intra-abdominal fluid collection, a vascular problem, and infectious or autoimmune liver disease, a liver biopsy was performed. The biopsy revealed centrizonal bilirubinostasis, a portal infiltrate rich in eosinophils and cholangitis. Lymphocyte transformation tests for piperacillin and imipenem/cilastatin were positive, suggesting an immunological mechanism for the observed hepatopathy. Cholestasis gradually decreased but was detectable for several weeks. The patient had a full clinical and biochemical recovery after 3 months. We conclude that short-term therapy with piperacillin, imipenem/cilastatin or the combination of these drugs can lead to the same type of hepatopathy as described for amoxycillin/clavulanic acid or antistaphylococcal penicillins. Liver biopsy and positive lymphocyte transformation are compatible with an immunological mechanism.

The purpose of this retrospective study was to assess cross-hypersensitivity between imipenem/cilastatin and penicillin in patients with reported penicillin allergies. Medical records of febrile neutropenic, penicillin-allergic bone marrow transplant recipients who received imipenem/cilastatin treatment were retrospectively reviewed. The findings of this study indicate the incidence of cross-reactivity between imipenem/cilastatin and penicillin among patients with a history of penicillin allergy may be lower than previously reported.

Proconvulsive tendency of imipenem/cilastatin is one of its well-known side effects. Most studies report incidence rates ranging from 1.5 to 3%. There is no study on the incidence rate among children with systemic malignancies. Eighty-two patients with various malignancies who received imipenem/cilastatin 143 times for neutropenic fever between March 1994 and October 1999 in Department of Pediatric Oncology, Gazi University, were identified. Three of these patients had convulsions attributed to imipenem/cilastatin; 3.6% of the patients had seizure, or 2% of imipenem/cilastatin administrations was followed by a seizure attack.

An open, multicenter study with 144 patients, aged between 18 and 94 years, was performed to compare the efficacy and safety of meropenem with imipenem/cilastatin in the hospital treatment of community-acquired pneumonia. Patients were randomized to receive either intravenous meropenem (500 mg every 8 h) or intravenous imipenem/cilastatin (1,000 mg every 12 h). The primary end point was considered to be clinical efficacy and the secondary end points were bacteriological response and safety assessment. At the end of therapy, cure or improvement in signs and symptoms as a satisfactory clinical response was observed in 57 of 64 (89.1%) meropenem-treated patients and in 60 of 66 (90.9%) imipenem/cilastatin patients. The mean duration of treatment was 10 days for meropenem and 9.7 days for imipenem/cilastatin. In patients who were followed up for weeks 2-4, the response was satisfactory (100%) for both treatments. A satisfactory bacteriological response, defined as either presumed or confirmed eradication of all pathogens, was found in eight patients who had received meropenem and in 14 patients who had received imipenem/cilastatin. Response was considered satisfactory in 100% of the meropenem group and in 92.9% of the imipenem/cilastatin group and at follow-up, it was 100% for both treatments. Drug-related adverse events were reported in three (4.2%) meropenem-treated patients and in eight (11.0%) imipenem/cilastatin-treated patients. None of these events was classified as serious. The results of this study show that the clinical and bacteriological efficacy and tolerability of meropenem (500 mg every 8 h) are similar to that of imipenem/cilastatin (1,000 mg every 12 h) in the hospital treatment of community-acquired pneumonia.

The total costs of the hospital treatment of patients with secondary peritonitis were investigated with a prospective, randomized, multicenter study. Moreover, the cost-effectiveness of an initial therapy with Imipenem/Cilastatin was compared to selected alternative antibiotic regimens. Altogether 154 patients (77 Imipenem/Cilastatin group, 77 alternative group) that displayed Mannheim Peritonitis Scores between 16 and 26 (average 20.8) were analyzed. The average total cost of treatment was DM 11,140 per patient (range DM 2794-45,526). Patients receiving an initial therapy with Imipenem/Cilastatin incurred average costs of DM 10,455, while patients with alternative regimens caused average costs of DM 11,826. The difference between the two treatment groups was statistically significant (P = 0.037).

This open, comparative, randomized, multicentre equivalence study compared cefepime 2 g bd and imipenem-cilastatin 1 g tds (50 mg/kg/day) as empirical monotherapy for febrile episodes in a homogeneous cohort of cancer patients with short duration neutropenia following chemotherapy for solid tumour, lymphoma or myeloma. The study was conducted in 17 French anti-cancer centres in 1995 and 1996. Response to monotherapy was assessed 7 days after treatment and was based on resolution of fever and signs and symptoms, eradication of pathogens, absence of new infection, relapse, and death of infectious origin, without addition of other antibiotics. Patients were treated for a minimum of 4 days. Of the 400 episodes randomized, 344 (86%) were evaluable for efficacy. Patient characteristics were comparable between treatment groups. Success of monotherapy was observed in 79% of episodes with cefepime and 72% with imipenem-cilastatin (equivalence, P <0.0001). The response rate for microbiologically documented infections was 66% with cefepime and 61% with imipenem-cilastatin (bacteraemic episodes: 63% for cefepime; 44% for imipenem-cilastatin). A second antibiotic (usually a glycopeptide) was added in 20% and 21% of the cases, respectively. Overall, the response to therapy, with or without an additional antibiotic, was 95% (cefepime) and 90% (imipenem-cilastatin). Survival was similar in both groups (95% and 98%, respectively). Cefepime treatment was better tolerated, with 9% of the patients experiencing related intercurrent events compared with 19% in the imipenem-cilastatin group (P = 0.003). Nausea/vomiting was significantly more frequent in the imipenem-cilastatin group (15%) than in the cefepime group (5%; P = 0.001). Cefepime monotherapy was as effective as, and better tolerated than, imipenem-cilastatin in the empirical treatment of fever during short duration neutropenia.

Efficacy and safety of imipenem/cilastatin in neonatal Klebsiella pneumonia sepsis was investigated in 45 infants compared to 39 control infants on conventional antibiotic regimen. Sensitivity to imipenem was 94% followed by cephoxitin (88%), quinolons (80%), and amikacin (52%) according to susceptibility results in the study group. Treatment duration of surviving infants was 16.5 +/- 4.6 and 20.3 +/- 6.4 days in the study and control groups respectively (p < 0.05). Five infants (11%) vs 27 (69%) were unresponsive (septic deaths) to treatment in the study and control groups respectively (p < 0.001). The cure rates were 73% and 28% respectively (p < 0.001). Sequelae free discharge rates were 67% and 23% respectively (p < 0.001). The most frequent adverse effects of imipenem/cilastatin were Candida albicans superinfection (20%); Candida albicans colonisation (10%); impairment of liver and renal functions (19% and 10% respectively); seizures (5%); thrombocytosis (3%); thrombophlebitis (3%); urine discoloration (3%); and Staphylococcus epidermidis colonisation (2%). Imipenem is considered a good alternative for neonatal Klebsiella pneumonia sepsis with these results, however, one must be aware of the increased risk of Candida albicans superinfection.

A cost-effectiveness analysis was performed following a double-blind, randomized study of ampicillin/sulbactam (A/S) versus imipenem/cilastatin (I/C) for the treatment of limb-threatening foot infections in 90 diabetic patients. There were no significant differences between the treatments in terms of clinical success rate, adverse-event frequency, duration of study antibiotic treatment, or length of hospitalization. Costs of the study antibiotics, treatment of failures and adverse events, and hospitalization were calculated. Mean per-patient treatment cost in the A/S group was $14,084, compared with $17,008 in the I/C group (P = .05), primarily because of lower drug and hospitalization costs and less-severe adverse events in the A/S group. Sensitivity analyses varying drug prices or hospital costs demonstrated that A/S was consistently more cost-effective than I/C. Varying the clinical success rate for each drug revealed that I/C would have to be 30% more effective than A/S to change the economic decisions.

Imipenem/cilastatin (I/C) monotherapy was used as salvage treatment in 55 neutropenic patients (58 fever episodes) after treatment failure on first-line antibiotic therapy. Successful antibiotic treatment was defined as eradication of all signs, symptoms and microbiologic evidence of infection on I/C monotherapy alone. Twenty-five out of the 58 episodes (43%) were classified as success, 6 episodes (10%) as initial response but the regimen had to be modified (amphotericin B was added) and 27 episodes (47%) as failures. In episodes with documented infections 9 out of 23 (39%) were classified as success. All patients survived during the first 72 hours after change to I/C therapy. One patient had to discontinue I/C due to a skin rash. In conclusion, the use of a treatment algorithm with I/C monotherapy as second-line treatment was safe and effective. Other antimicrobial agents, most often vancomycin and/or amphotericin B, had to be added in half of the patients.

Meropenem was compared with imipenem/cilastatin for the treatment of serious bacterial infections in a randomized, prospective multicentre study. Both study drugs were given intravenously 1 g every 8 h and no other antimicrobial agents were permitted concomitantly. Of the 204 patients enrolled, the treatment of 177 was evaluable for clinical efficacy and 115 for bacteriological efficacy. In the clinically evaluable treatment population, 75 (83%) of the 90 patients in the meropenem group and 78 (90%) of the 87 in the imipenem/cilastatin group had a single site of infection whereas the remainder had two or more sites of infection. Infections of the lower respiratory tract and peritoneal cavity predominated accounting for 95 and 75 cases respectively. Other infections included skin and soft tissue infections, complicated urinary tract infections, bacteraemia and a case of meningitis treated with meropenem and one of mediastinitis treated with imipenem/cilastatin. One hundred and nineteen (67%) patients were in an intensive care unit, 105 (59%) were receiving assisted ventilation and 93 (53%) of the patients had failed previous antibiotic therapy. One hundred and ten organisms were identified as pathogens in the meropenem group and 109 in the imipenem/cilastatin group. Overall, treatment with meropenem was clinically successful in 68 (76%) of 90 cases and imipenem/cilastatin in 67 (77%) of 87 cases and the corresponding eradication rates of bacteria were 85 of 110 (77%) and 90 of 109 (83%) respectively. Superinfections due to resistant bacteria occurred in two patients treated with meropenem and three cases given imipenem/cilastatin. No statistically significant differences in the clinical or bacteriological outcome were observed between the treatment groups for any of the infection sites analysed. Both drugs were well tolerated with adverse events considered to be related to therapy being recorded for 10 (9%) of 106 patients treated with meropenem and 12 (12%) of 98 of those who had been given imipenem/cilastatin. Empirical monotherapy with meropenem was therefore as effective and as well tolerated as that with imipenem/cilastatin for the treatment of serious bacterial infections.

118 patients with complicated intra-abdominal infections participated in an open randomized comparative multicenter trial in order to compare the clinical and microbiological efficacy and safety of biapenem with imipenem/cilastatin (Tienam). 31 men and 27 women (mean age 52.3 years) were enrolled in the biapenem group, and 43 men and 17 women (mean age 52.3 years) in the imipenem/cilastatin group. The patients received either biapenem 500 mg every 8 h or imipenem/cilastatin 500 mg/500 mg every 6 h by intravenous infusion for up to 13 days (mean 6.5 days). 28/43 evaluable patients (65.1%) receiving biapenem and 27/40 evaluable patients (67.5%) in the imipenem/cilastatin group were clinically cured. The microbiological response was satisfactory in 28/43 evaluable patients (65.1%) receiving biapenem and in 27/40 evaluable patients (67.5%) receiving imipenem/cilastatin. No significant differences in clinical or microbiological efficacy between the two treatment groups were found. The present study shows that biapenem may be useful in the treatment of intra-abdominal infections.

515 patients with intra-abdominal infection participated in an open randomized comparative multicenter trial in order to compare the efficacy, safety, and tolerance of imipenem/cilastatin with cefuroxime/metronidazole. 258 patients (mean age 56 years) received imipenem/cilastatin 1.5-2.0 g/day, and 257 patients (mean age 54 years) received cefuroxime 3.0-4.5 g/day plus metronidazole 1.0-1.5 g/day for at least 3 days. 130/161 evaluable patients (80.8%) receiving imipenem/cilastatin and 124/145 evaluable patients (85.5%) receiving cefuroxime/metronidazole were clinically cured. The microbiological response was favorable in 86.9% in the imipenem/cilastatin group and in 90.8% in the cefuroxime/metronidazole group. The two treatment groups were similar with respect to median time to defervescence which was 4 days. The median duration of treatment was 6 days and the median time to discharge from hospital was 9 days in both groups. Drug-related adverse reactions were observed in 14 patients receiving iminpenem/cilastatin and in 8 patients receiving cefuroxime/metronidazole. 19 patients in the imipenen/cilastatin group and 12 patients in the cefuroxime/metronidazole group died. No correlation was found between the deaths and the study drugs. The present study shows that intra-abdominal infections can be treated successfully with imipenem/cilastatin as well as with cefuroxime/metronidazole.

The safety and efficacy of meropenem and imipenem/cilastatin were compared in the treatment of hospitalized patients with complicated urinary tract infections (UTIs) in a prospective, multicenter, open, parallel-group trial. Patients were randomized to receive 500-mg intravenous doses of either meropenem every 8 hours (n = 116) or imipenem/cilastatin every 6 hours (n = 119). Data from 95 patients given meropenem and 82 patients given imipenem/cilastatin were included in the evaluation of efficacy. Meropenem produced satisfactory clinical and bacteriologic responses in 99% and 90% of cases, respectively. These results were similar to those obtained with imipenem/cilastatin, which produced clinical improvement in 99% of cases and bacteriologic improvement in 81%. Two patients given meropenem and five patients given imipenem/cilastatin developed superinfections. The rate of relapse was similar in the two groups. Patients who received meropenem had fewer drug-related adverse reactions than did recipients of imipenem/cilastatin (8% vs. 19%). The results of this study demonstrate that meropenem is a safe and effective alternative to imipenem/cilastatin in the treatment of hospitalized patients with complicated UTIs.

The efficacy of thienam, a product of Merck, Sharp and Dohme (USA) composed of imipenem and cylastatin was studied in the treatment of 52 patients with surgical infection. In 48 and 4 patients the drug was used therapeutically and prophylactically respectively. When the drug was used therapeutically the recovery and improvement were observed in 41 out of 44 patients (93.2 per cent), 4 patients being excluded from the treatment group because of adverse reactions such as hyperthermia and skin eruption. When the drug was used prophylactically the recovery and improvement were stated in all the 4 patients. The pathogens were eradicated in the wound in 40 patients (91 per cent). 114 clinical isolates were tested and the imipenem resistance was detected only in 6.5 per cent of the Staphylococcus aureus strains, in 20 per cent of the Pseudomonas aeruginosa strains and in 50 per cent of the P. mirabilis and P. vulgaris strains. All the isolates of Escherichia coli, Enterobacter, Acinetobacter and Citrobacter were susceptible or moderately susceptible to imipenem.

Intravenously administered ciprofloxacin was compared with imipenem for the treatment of severe pneumonia. In this prospective, randomized, double-blind, multicenter trial, which included an intent-to-treat analysis, a total of 405 patients with severe pneumonia were enrolled. The mean APACHE II score was 17.6, 79% of the patients required mechanical ventilation, and 78% had nosocomial pneumonia. A subgroup of 205 patients (98 ciprofloxacin-treated patients and 107 imipenem-treated patients) were evaluable for the major efficacy endpoints. Patients were randomized to receive intravenous treatment with either ciprofloxacin (400 mg every 8 h) or imipenem (1,000 mg every 8 h), and doses were adjusted for renal function. The primary and secondary efficacy endpoints were bacteriological and clinical responses at 3 to 7 days after completion of therapy. Ciprofloxacin-treated patients had a higher bacteriological eradication rate than did imipenem-treated patients (69 versus 59%; 95% confidence interval of -0.6%, 26.2%; P = 0.069) and also a significantly higher clinical response rate (69 versus 56%; 95% confidence interval of 3.5%, 28.5%; P = 0.021). The greatest difference between ciprofloxacin and imipenem was in eradication of members of the family Enterobacteriaceae (93 versus 65%; P = 0.009). Stepwise logistic regression analysis demonstrated the following factors to be associated with bacteriological eradication: absence of Pseudomonas aeruginosa (P < 0.01), higher weight (P < 0.01), a low APACHE II score (P = 0.03), and treatment with ciprofloxacin (P = 0.04). When P. aeruginosa was recovered from initial respiratory tract cultures, failure to achieve bacteriological eradication and development of resistance during therapy were common in both treatment groups (67 and 33% for ciprofloxacin and 59 and 53% for imipenem, respectively). Seizures were observed more frequently with imipenem than with ciprofloxacin (6 versus 1%; P = 0.028). These results demonstrate that in patients with severe pneumonia, monotherapy with ciprofloxacin is at least equivalent to monotherapy with imipenem in terms of bacteriological eradication and clinical response. For both treatment groups, the presence of P. aeruginosa had a negative impact on treatment success. Seizures were more common with imipenem than with ciprofloxacin. Monotherapy for severe pneumonia is a safe and effective initial strategy but may need to be modified if P. aeruginosa is suspected or recovered from patients.

The antimicrobial activity of imipenem/cilastatin (IPM/CS) was determined for a broad spectrum of 7,157 organisms isolated from the Clinical Microbiology Laboratory of Chang Gung Memorial Hospital, Linkou Medical Center, between April 1 and June 30, 1988. Ninety eight point one percent of 4,389 gram negative aerobes, 95.8% of 2391 gram positive rods, and 95.9% of 507 anaerobes, were shown to be sensitive to IPM/CS. Ninety nine point two percent of 837 Pseudomonas aeruginosa isolates were sensitive to this antibiotic. This study also disclosed that this agent was much more active against Pseudomonas aeruginosa than any other tested aminoglycosides (gentamicin, amikacin, netilmicin) or third generation cephalosporins (cefotaxime, latamoxef, ceftazidime). Twelve critically ill patients with polymicrobial and mixed infection were recruited into this trial. All patients received IPM/CS 500 mg intravenously every six hours except one patient with poor renal function had 250 mg every six hours. The average duration of therapy was 12.5 days. All patients were evaluated according to the selection criteria. IPM/CS achieved favorable clinical response in 83.7 percent. The antibiotic was well tolerated. One patient discontinued treatment because of jaundice. One patient had superinfection of fungemia. The results suggested that IPM/CS is very useful in the treatment of patients with mixed infections due to gram positive, gram negative, and anaerobic bacteriae, even when empirical therapy with other antibiotics fails.