cilastatin--imipenem-drug-combination and Sepsis

An urgent need exists for antibiotics to treat infections caused by carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (ABC). Sulbactam-durlobactam is a β-lactam-β-lactamase inhibitor combination with activity against Acinetobacter, including multidrug-resistant strains. In a phase 3, pathogen-specific, randomised controlled trial, we compared the efficacy and safety of sulbactam-durlobactam versus colistin, both in combination with imipenem-cilastatin as background therapy, in patients with serious infections caused by carbapenem-resistant ABC.. The ATTACK trial was done at 59 clinical sites in 16 countries. Adults aged 18 years or older with ABC-confirmed hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, ventilated pneumonia, or bloodstream infections were randomised 1:1 using a block size of four to sulbactam-durlobactam (1·0 g of each drug in combination over 3 h every 6 h) or colistin (2·5 mg/kg over 30 min every 12 h) for 7-14 days. All patients received imipenem-cilastatin (1·0 g of each drug in combination over 1 h every 6 h) as background therapy. The primary efficacy endpoint was 28-day all-cause mortality in patients with laboratory-confirmed carbapenem-resistant ABC (the carbapenem-resistant ABC microbiologically modified intention-to-treat population). Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference was less than +20%. The primary safety endpoint was incidence of nephrotoxicity assessed using modified Risk, Injury, Failure, Loss, End-stage renal disease criteria measured by creatinine level or glomerular filtration rate through day 42. This trial is registered at ClinicalTrials.gov, NCT03894046.. Between Sep 5, 2019, and July 26, 2021, 181 patients were randomly assigned to sulbactam-durlobactam or colistin (176 hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, or ventilated pneumonia; and five bloodstream infections); 125 patients with laboratory-confirmed carbapenem-resistant ABC isolates were included in the primary efficacy analysis. 28-day all-cause mortality was 12 (19%) of 63 in the sulbactam-durlobactam group and 20 (32%) of 62 in the colistin group, a difference of -13·2% (95% CI -30·0 to 3·5), which met criteria for non-inferiority. Incidence of nephrotoxicity was significantly (p<0·001) lower with sulbactam-durlobactam than colistin (12 [13%] of 91 vs 32 [38%] of 85). Serious adverse events were reported in 36 (40%) of 91 patients in the sulbactam-durlobactam group and 42 (49%) of 86 patients in the colistin group. Treatment-related adverse events leading to study drug discontinuation were reported in ten (11%) of 91 patients in the sulbactam-durlobactam group and 14 (16%) of 86 patients in the colistin group.. Our data show that sulbactam-durlobactam was non-inferior to colistin, both agents given in combination with imipenem-cilastatin, for the primary endpoint of 28-day all-cause mortality. Sulbactam-durlobactam was well tolerated and could be an effective intervention to reduce mortality from serious infections caused by carbapenem-resistant ABC, including multidrug-resistant strains.. Entasis Therapeutics and Zai Lab.

Topics: Acinetobacter baumannii; Adult; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Cilastatin, Imipenem Drug Combination; Colistin; Humans; Microbial Sensitivity Tests; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Sepsis

This study aimed to investigate the efficiency of imipenem to prevent infectious complications in predicted severe acute pancreatitis (AP).. Consecutive AP patients were randomized to imipenem 3 × 500 mg intravenously daily or an identical placebo. Exclusion criteria were prior AP, chronic pancreatitis, active malignancy, immune deficiency, active infection, concomitant antibiotic treatment, pregnancy, and patients younger than 18 years. Infectious complications including infected pancreatic necrosis, pneumonia, urinary tract infection, positive blood cultures, sepsis, and other infections were assessed as the primary outcome. Secondary outcomes included mortality, persistent organ failure, systemic inflammatory response syndrome, local complications, serious adverse events, and need for surgical intervention.. Forty-nine patients were randomized to each group. Infectious complications were present in 10 versus 12 of 49 patients (relative risk [RR], 0.833; 95% confidence interval [CI], 0.398-1.747). There were no significant differences in infected pancreatic necrosis (RR, 1.5; 95% CI, 0.262-8.588), pneumonia (RR, 1.5; 95% CI, 0.262-8.588), urinary tract infection (RR, 0.6; 95% CI, 0.152-2.374), positive blood cultures (RR, 0.5; 95% CI, 0.047-5.336), sepsis (RR, 0.333; 95% CI, 0.036-3.095), and other (RR, 1.333; 95% CI, 0.315-5.648). We found no significant differences in secondary outcomes.. Concordantly to available evidence, there is currently no ground to support prophylactic use of antibiotics in predicted severe AP.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Antibiotic Prophylaxis; Bacterial Infections; Cilastatin, Imipenem Drug Combination; Double-Blind Method; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Pancreatitis; Pneumonia; Prospective Studies; Sepsis; Urinary Tract Infections

In order to investigate the effect of carbapenems on systemic endotoxemia, 20 patients with severe sepsis due to ventilator-associated pneumonia and Gram-negative bacteremia were enrolled; 10 (group A) were administered 1 g t.i.d. of imipenem/cilastatin and 10 (group B) 2 g t.i.d. of meropenem. Blood was sampled at 0 time and after 1, 2, 4, 6, 12, 24, 36, 48, 60, 72, 84 and 96 hours for detection of endotoxins (LPS), interleukin-6 (IL-6), C-reactive protein (CRP) and drug levels. LPS were determined by the QCL-1000 LAL assay, IL-6 by an enzymeimmunoassay, CRP by nephelometry and carbapenem levels by a microbiological assay. We did not find that carbapenems had any effect on the kinetics of LPS and CRP; IL-6 of group A was lower than group B at 72 and 84 hours. No correlation was observed between drug levels of any carbapenem and LPS, IL-6 or CRP. It is concluded that in septic patients with Gram-negative bacteremia administration of either imipenem or meropenem did not affect systemic endotoxemia. The above data support the safe administration of both carbapenems in patients with severe sepsis.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; C-Reactive Protein; Carbapenems; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Endotoxemia; Female; Gram-Negative Bacterial Infections; Humans; Imipenem; Interleukin-6; Lipopolysaccharides; Male; Middle Aged; Pneumonia, Ventilator-Associated; Sepsis

We compared two imipenem regimens for prevention of septic complications in patients with severe acute necrotizing pancreatitis (ANP).. Prospective, randomized open clinical trial involving intensive care units of 14 Spanish Hospitals.. 92 patients with ANP.. Imipenem/cilastatin was administered at 500 mg four times daily starting at the time of diagnosis of ANP, within the first 96 h from the onset of symptoms. Patients were randomized to receive antibiotic prophylaxis either for 14 days (group 1) or at least for 14 days and as long as major systemic complications of the disease persisted (group 2).. Antibiotic was maintained in group 2 for 19.7+/-10.9 days. The incidence of infected pancreatic necrosis, pancreatic abscess, and extrapancreatic infections was 11%, 17%, and 28% in group 1 and 17.4%, 13%, and 35% in group 2 (n.s.). Pancreatic or extrapancreatic infection by Candida albicans occurred in 7% and 22% of patients. Global mortality was 18.5% (10.9% secondary to septic complications), without differences between groups. In patients with persisting systemic complications at day 14 mortality was almost always secondary to septic complications and decreased from 25% (group 1) to 8.8% (group 2) by maintaining antibiotic prophylaxis.. Compared to a 14-day imipenem prophylaxis, a longer antibiotic administration in patients with ANP is not associated with a reduction in the incidence of septic complications of the disease. However, prolonged imipenem administration in patients with persisting systemic complications tends to reduce mortality in ANP compared to a 14-days regimen.

Topics: Aged; Antibiotic Prophylaxis; APACHE; Cause of Death; Cilastatin; Cilastatin, Imipenem Drug Combination; Cross Infection; Drug Administration Schedule; Drug Combinations; Female; Hospital Mortality; Humans; Imipenem; Incidence; Infection Control; Male; Middle Aged; Pancreatitis, Acute Necrotizing; Prospective Studies; Sepsis; Severity of Illness Index; Spain; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

Meropenem and imipenem are beta-lactam antibiotics of the carbapenem group. Carbapenems have bactericidal activity against a broad spectrum of bacteria, including most gram-positive cocci, gram-negative bacilli and anaerobes. Experience in using meropenem in Chinese patients has not been previously reported.. Meropenem (2 g daily) and imipenem/cilastatin (2 g daily) were compared in an open, randomized, prospective study on the treatment of hospitalized Chinese septic patients. All participants (male or female) were hospitalized with a diagnosis of sepsis. All patients were randomly allocated to one of the two treatment groups: the meropenem group or the imipenem/cilastatin group. Clinical status was evaluated daily during treatment and at the end of therapy or when treatment was withdrawn. Patients were checked every day for potential side-effects, according to subjective and objective symptoms.. Fifty-three patients were enrolled in the study; 50 were evaluated for clinical efficacy and 27 patients were evaluated for bacteriologic efficacy. The most frequent clinical diagnoses were pneumonia and urinary tract infection. The predominant pathogens were Pseudomonas aeruginosa, Escherichia coli and Enterobacter cloacae. There were 31 pathogens isolated from 27 patients. A single pathogen was identified in 23 patients, and two pathogens were isolated from four patients. Satisfactory clinical outcome (excellent and good) was 84% in the meropenem group and 76% in the imipenem/cilastatin group. Satisfactory bacteriologic response was 80% in the meropenem group and 75% in the imipenem/cilastatin group. Transiently elevated liver enzymes were the most common side-effect. One patient treated with imipenem/cilastatin experienced a seizure during the study, while another patient treated with meropenem withdrew due to urticaria.. The efficacy and safety data presented in this report indicate that meropenem was well tolerated and appeared to be as effective as standard monotherapy with imipenem in bacteremic patients. Meropenem and imipenem/cilastatin were highly effective for the treatment of bacteremia in Chinese patients and only mild or negligible side-effects were noted.

Topics: Adult; Aged; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Therapy, Combination; Female; Humans; Imipenem; Male; Meropenem; Middle Aged; Prospective Studies; Sepsis; Thienamycins

An open, randomized, multinational, multicentre study was conducted to compare the efficacy, safety and tolerability of levofloxacin 500 mg twice daily with imipenem/cilastatin 1 g iv three-times daily in the treatment of hospitalized adult patients with clinically suspected bacteraemia/ sepsis. Levofloxacin patients could change from iv to oral administration after a minimum of 48 h iv treatment if clinical signs and symptoms of sepsis had improved. The primary efficacy analysis was based on the clinical and bacteriological response at clinical endpoint. A total of 503 patients were randomized and 499 included in the intent-to-treat population. The per-protocol population comprised 287 patients with bacteriologically proven infection. Clinical cure rates at clinical endpoint in the intent-to-treat population and per-protocol population were 77% (184/239) and 89% (125/140), respectively, for levofloxacin and 68% (178/260) and 85% (125/147), respectively, for imipenem/cilastatin. At follow-up, the cure rates in the per-protocol population were 84% for levofloxacin and 69% for imipenem/cilastatin. The 95% confidence interval for both populations showed that levofloxacin was as effective as imipenem/cilastatin. A satisfactory bacteriological response was obtained in 87% (96/110) of levofloxacin patients and 84% (97/116) of imipenem/cilastatin patients at clinical endpoint. Adverse events possibly related to the study drug were reported in 74 (31%) levofloxacin patients and 79 (30%) imipenem/cilastatin patients. There were no clinically appreciable differences between the treatment groups. Levofloxacin 500 mg twice daily, either iv or as sequential iv/oral therapy, was as effective and well tolerated as imipenem/cilastatin 1 g iv three-times daily in the treatment of hospitalized patients with suspected bacteraemia/sepsis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Infective Agents; Bacteremia; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Therapy, Combination; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Imipenem; Levofloxacin; Middle Aged; Ofloxacin; Protease Inhibitors; Sepsis; Thienamycins

The authors share their experiences with treatment of 12 patients using the antibiotic Tienam. No complications resulting from the administration of this medicine were noted. High therapeutic efficiency of Tienam has been shown. Recovery was noted in 11 out of 12 patients.

Topics: Acute Disease; Adult; Aged; Bacteria; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Therapy, Combination; Humans; Imipenem; Microbial Sensitivity Tests; Middle Aged; Sepsis

Prompt initiation of empiric antibiotic therapy is the cornerstone in the therapy of chemotherapy-induced neutropenic sepsis in cancer patients. Ceftriaxone plus gentamicin (ceftriaxone/gentamicin) is the most widely used combination of empiric antibiotics in the Department of Medical Oncology, Singapore General Hospital. However, imipenem/cilastatin has been shown to be a practical alternative. To compare the efficacy and cost effectiveness of monotherapy with our usual combination antibiotic therapy, 50 evaluable neutropenic cancer patients admitted for fever were randomised to empiric imipenem/cilastatin or ceftriaxone/gentamicin. Ceftriaxone/gentamicin was started in 24 patients. The initial clinical response rate to ceftriaxone/gentamicin was 62.5% and 84.6% to imipenem/cilastatin (P = 0.075). The average cost of antibiotics per patient started on ceftriaxone/gentamicin including cost of change of antibiotics was S$63 per day of antibiotic use and for imipenem/cilastatin it was S$252 (P < 0.02). In conclusion, although more patients receiving imipenem/cilastatin had an initial clinical response than those receiving ceftriaxone/gentamicin, this difference was not statistically significant. It would appear that imipenem/cilastatin is equivalent to ceftriaxone/gentamicin for the treatment of neutropenic sepsis. However, ceftriaxone/gentamicin was more cost effective.

Topics: Antineoplastic Agents; Ceftriaxone; Cilastatin; Cilastatin, Imipenem Drug Combination; Costs and Cost Analysis; Drug Combinations; Drug Therapy, Combination; Female; Fever; Gentamicins; Humans; Imipenem; Male; Middle Aged; Neutropenia; Sepsis

One hundred and thirty-nine consecutive episodes of fever were evaluated in 55 patients with hematological disorders during persistent neutropenia. In 121 instances, patients were given trimethoprim-sulfamethoxazole + amikacin (TMP/SMZ + AMI) as an initial antibiotic regimen with clinical success in 51% (i.e. antibiotic treatment was not changed within the first 7 days). Imipenem/cilastatin (I/C) therapy was instituted in: (a) 22 episodes with clinical failure and fever of unknown origin during TMP/SMZ + AMI therapy and (b) 18 episodes with a second fever episode during initially successful TMP/SMZ + AMI therapy. The response rate for all 40 I/C treated episodes was 80%. One neutropenic patient in the whole series died from infectious complications within four weeks from institution of therapy. TMP/SMZ+AMI seems to be a safe and inexpensive "standard" antibiotic regimen in neutropenic patients. I/C appears to have good efficacy when used as secondary therapy after failure with TMP/SMZ+AMI.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amikacin; Bacterial Infections; Bone Marrow Transplantation; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Therapy, Combination; Female; Fever; Hematologic Diseases; Humans; Imipenem; Leukemia; Lymphoma; Male; Middle Aged; Neutropenia; Pneumocystis Infections; Sepsis; Trimethoprim, Sulfamethoxazole Drug Combination

In four prospective randomized clinical trials between November 1983 and March 1988, we studied 270 patients with severe bacterial infections, mainly lower respiratory tract ones. We compared ciprofloxacin and imipenem/cilastatin in the first study, ciprofloxacin and ofloxacin in the second study, ciprofloxacin and ticarcillin/clavulanic acid in the third study, and ofloxacin and cefpirome in the fourth study. A total of 90 pneumonias, 139 LRTIs, 22 septicaemias and 19 other bacterial infections were treated; the dominant pathogens were Pseudomonas aeruginosa and enterobacteria. Clinical success rates were high; cure or improvement was registered in 89% of the patients on ciprofloxacin, 89% on ofloxacin and 85% on beta-lactams. Treatment failures occurred mainly in ICU patients with terminal underlying diseases. Bacteriologically, eradication rates were high for enterobacteria and Staphylococcus aureus, but a relatively high persistence rate was seen for P. aeruginosa due to increased resistance and/or specific type and location of the infections. The incidence of side-effects was relatively high (23%-29%) which was related to careful monitoring. Adverse effects were group-specific (CNS reactions with quinolones, diarrhoea with beta-lactam antibiotics).

Topics: Cilastatin; Cilastatin, Imipenem Drug Combination; Ciprofloxacin; Clavulanic Acids; Drug Combinations; Drug Therapy, Combination; Humans; Imipenem; Ofloxacin; Pneumonia; Prospective Studies; Remission Induction; Respiratory Tract Infections; Sepsis; Ticarcillin

We studied the clinical efficacy and safety of imipenem, a broad spectrum beta-lactam antibiotic, in acute bacterial infections in 21 patients with AIDS or AIDS-related complex (ARC). Imipenem/cilastatin was administered as a 30-min intravenous infusion using a dose of 500 mg/8 h. Bacterial pathogens were isolated before treatment in 80% of cases; 87.5% of all strains were susceptible to imipenem in vitro. Treatment resulted in rapid control of the infections in 80% of patients. Clinical and laboratory adverse reactions probably related to imipenem treatment were noted in 8 patients.

Topics: Acquired Immunodeficiency Syndrome; Acute Disease; Adult; AIDS-Related Complex; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Female; Humans; Imipenem; Infusions, Intravenous; Male; Middle Aged; Respiratory Tract Infections; Risk Factors; Sepsis

In an open study to determine the efficacy, safety and tolerance of intravenously administered imipenem/cilastatin (Tienam 500; Logos) in the treatment of septicaemia, 34 patients were given this thienamycin antibiotic in doses ranging from 1.5 g to 2 g daily for an average of 8.6 days (range 3-44 days). Based on clinical assessment, the study drug appeared to be effective in treating the septicaemia in 28 out of 34 patients and bacteriologically assessed eradication of the isolated pathogen was proven in 24 out of 34 patients. The drug appeared to be well tolerated in all but 4 patients, 3 of whom developed mild phlebitis and 1 a skin rash.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Evaluation; Female; Humans; Imipenem; Infusions, Intravenous; Male; Middle Aged; Multicenter Studies as Topic; Sepsis

The clinical efficacy and safety of imipenem/cilastatin in the empirical treatment of adult non-immunocompromised patients with severe bacterial septicemia was studied in a prospective and open trial. The dosage of imipenem/cilastatin was 500 mg q 6 h. Of 58 patients included, 41 were evaluable for efficacy. In those patients, 35 had chronic underlying diseases and the foci of bacteremia were identified in 37; the most common ones being cardiovascular, urologic or intraabdominal infections. All isolated organisms were sensitive to imipenem with an MIC for 90% of the strains of 1 mg/l. Imipenem/cilastatin treatment resulted in rapid control of the infections in 39 of the 41 evaluable patients (95.5%). In the remaining two patients treatment had to be prematurely discontinued due to adverse effects. The causative bacterial strains were eradicated from blood in all patients who received more than one day of imipenem/cilastatin treatment but persisted sensitive to imipenem in peripheral foci in five patients (17%). Clinical and laboratory adverse reactions were noted in seven patients. In conclusion, imipenem/cilastatin was a well tolerated and effective empirical drug for treatment of septicemia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Infections; Cilastatin; Cilastatin, Imipenem Drug Combination; Clinical Trials as Topic; Cyclopropanes; Drug Combinations; Female; Humans; Imipenem; Male; Microbial Sensitivity Tests; Middle Aged; Prospective Studies; Sepsis; Thienamycins

Antibiotic dosing in critically ill patients is complicated by variations in the pharmacokinetics of antibiotics in this group. The dosing of imipenem/cilastatin is usually determined by severity of illness and renal function.. To determine the correlation between estimated glomerular filtration rates (eGFRs) calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and imipenem trough levels in critically ill patients.. This prospective observational study was done in the surgical intensive care unit (ICU) at Steve Biko Academic Hospital, Pretoria, South Africa. Imipenem trough levels were measured by high-performance liquid chromatography and compared with eGFRs calculated with the CKD-EPI equation. Correlation was evaluated by the Pearson product-moment correlation coefficient.. The study population consisted of 68 critically ill patients aged between 18 and 81 years; 43 (63%) were male, and the mean weight was 78 kg (range 40 - 140). On admission, 30 patients (44%) had sepsis, 16 (24%) were admitted for trauma, and 22 (32%) were admitted for miscellaneous surgical conditions. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores ranged from 4 to 39 (mean 18). The 28-day mortality rate was 29%. The mean albumin level was 16 g/L (range 7 - 25), the mean creatinine level 142 μmol/L (range 33 - 840), and the mean eGFR 91 mL/min/1.73 m2 (range 6 - 180). Imipenem trough levels ranged between 3.6 and 92.2 mg/L (mean 11.5). The unadjusted Pearson product-moment correlation coefficient between eGFR and imipenem trough level was -0.04 (p=0.761).. Considering the high mortality rate of sepsis in ICUs and the rapid global increase in antimicrobial resistance, it is crucial to dose antibiotics appropriately. Owing to the variability of antibiotic pharmacokinetics in critically ill patients, this task becomes almost impossible when relying on conventional dosing guidelines. This study found that eGFRs do not correlate with imipenem blood levels in critically ill patients and should not be used to determine the dose of imipenem/cilastatin. Instead, the dose should be individualised for patients through routine therapeutic drug monitoring.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Albumins; Anti-Bacterial Agents; Cilastatin, Imipenem Drug Combination; Creatinine; Critical Illness; Female; Glomerular Filtration Rate; Humans; Imipenem; Male; Middle Aged; Renal Insufficiency, Chronic; Sepsis; South Africa; Young Adult

In February 2018, one 54-year-old male patient with severe scald complicated with pneumonia and sepsis was transferred to Qingdao Municipal Hospital from other hospital. Drugs including cephalosporin, vancomycin, and imipenem/cilastatin combined with ciprofloxacin were used successively for anti-infective treatment, with no obvious effect. Multiple bacterial culture results of sputum, blood, and wound exudate showed infection of extensively drug resistant. 2018年2月，青岛市市立医院收治1例经外院转入的严重烫伤合并肺炎和脓毒症的54岁男性患者。先后使用头孢菌素、万古霉素、亚胺培南/西司他丁＋环丙沙星等抗感染治疗，但无明显效果。痰液、血液及创面分泌物多次细菌培养结果提示泛耐药铜绿假单胞菌感染。入院第4天调整抗感染治疗方案，补充血浆、红细胞及白蛋白，行营养支持及对症处理，同时进行用药监护，关注药物相关不良反应。经过10余天的治疗，患者感染得到有效控制，病情逐渐好转。本病例提示，严重烧伤患者易发生严重且致命的全身性感染，抗菌药物的不规范使用增加了泛耐药菌的感染风险，清晰的抗感染思路和抗菌药物的有效应用有助于提高感染治疗的成功率，对改善严重烧伤患者的预后具有重要价值。.

Topics: Anti-Bacterial Agents; Burns; Cilastatin, Imipenem Drug Combination; Humans; Male; Middle Aged; Pneumonia; Pseudomonas aeruginosa; Sepsis

Optimisation of antibiotic therapy for extracorporeal membrane oxygenation (ECMO) patients remains a pharmacological challenge. The objective of this study was to observe the plasma concentrations of commonly used antibiotics in intensive care for patients treated with extracorporeal membrane oxygenation.. The PHARMECMO study was a pilot, prospective study, conducted in a cardiac surgery intensive care unit. Every adult patient under ECMO support, with known or suspected sepsis and receiving antibiotic therapy, was eligible for inclusion. Plasma concentrations of antibiotics were determined by a combination of liquid chromatography and mass spectrometry.. Forty-four eligible patients were enrolled for 68 inclusions on a twelve-month period. For the association piperacillin-tazobactam (n=19), 68.7% of CT50 and 93.7% of Cmin reached the pharmacokinetic goals defined (64 mg.L-1 for CT50 and 16 mg.L-1 for Cmin). For cefotaxime (n=12), the pharmacokinetic goals (4 mg.L-1 for CT50 and 1 mg.L-1 for Cmin) were achieved in 100% of the cases for CT50 and in 81.8% of the cases for Cmin. Regarding imipenem (n=10), the pharmacokinetic goals were 16 mg.L-1 for CT50 and 4 mg.L-1 for Cmin. Only one CT50 was above 16 mg.L-1. For Cmin, 60% of the doses did not reach the target concentration. In our 10 patients, only one patient was considered as reaching the pharmacokinetic goals. Finally, for amikacin (n=6), four Cmax (66.7%) were infra-therapeutics for a target between 60 and 80 mg.L-1.. These preliminary results suggest that therapeutic drug monitoring could optimise the achievement of pharmacokinetic objectives associated with an effective antibiotic therapy. For most patients, the recommended doses of imipenem and amikacin did not achieve the pK targets.

Topics: Aged; Amikacin; Anti-Bacterial Agents; Cefotaxime; Cilastatin, Imipenem Drug Combination; Coronary Care Units; Drug Monitoring; Extracorporeal Membrane Oxygenation; Female; Gentamicins; Humans; Male; Middle Aged; Pilot Projects; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Sepsis; Tobramycin

Sepsis still constitutes an unmet clinical need, which could benefit from novel adjunctive strategies to conventional antibiotic therapy. The soluble form of the scavenger-like human CD6 lymphocyte receptor (shCD6) binds to key pathogenic components from Gram-positive and -negative bacteria and shows time- and dose-dependent efficacy in mouse models of monobacterial sepsis. The objective of the present work was to demonstrate the effectiveness of infusing mouse and human sCD6 by different systemic routes, either alone or as adjunctive therapy to gold standard antibiotics, in a lethal model of polymicrobial sepsis. To this end, C57BL/6 mice undergoing high-grade septic shock induced by cecal ligation and puncture (CLP; ≥90% lethality) were infused via the intraperitoneal (i.p.) or intravenous (i.v.) route with shCD6 at different doses and time points, either alone or in combination with imipenem/cilastatin (I/C) at a dose of 33 mg/kg of body weight every 8 h. Significantly reduced mortality and proinflammatory cytokine levels were observed by i.p. infusion of a single shCD6 dose (1.25 mg/kg) 1 h pre- or post-CLP. When using the i.v. route, mice survival was significantly extended by starting shCD6 infusion at later time points post-CLP (up to 6 h after CLP). Significant adjunctive effects on mouse survival were observed by i.p. or i.v. infusion of shCD6 in combination with i.p. I/C post-CLP. Similar results were obtained in mice expressing high sustained levels (5 to 10 μg/ml) of mouse sCD6 in serum by means of transduction with hepatotropic adeno-associated virus (AAV). Taken together, the data support the conserved antibacterial effects of human and mouse sCD6 and their use as adjunctive therapy in experimental models of complex and severe polymicrobial sepsis.

Topics: Animals; Anti-Bacterial Agents; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Cecum; Cilastatin; Cilastatin, Imipenem Drug Combination; Cytokines; Dependovirus; Disease Models, Animal; Drug Combinations; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Imipenem; Ligation; Male; Mice; Mice, Inbred C57BL; Receptors, Scavenger; Sepsis

To study the therapeutic effect of phages on extensively drug-resistant Acinetobacter baumannii-induced sepsis in mice.. (1) Sixty BALB/c mice were divided into blank control group, sepsis control group, antibiotics treatment group, phage treatment group, and phage control group according to the random number table, with 12 mice in each group. Mice in blank control group were intraperitoneally (the same injection position below) injected with 1 mL normal saline. Mice in sepsis control group, antibiotics treatment group, and phage treatment group were injected with 1 mL extensively drug-resistant Acinetobacter baumannii (the strain was isolated from the blood of a severely burned patient hospitalized in our unit) in the concentration of 5×10(7) colony-forming unit/mL to reproduce sepsis model. Two hours later, mice in sepsis control group, antibiotics treatment group, and phage treatment group were injected with 1 mL saline, 1 mg/mL imipenem/cilastatin, and 1×10(8) plaque-forming unit (PFU)/mL phages screened based on above-mentioned Acinetobacter baumannii (the same phages below) respectively. Mice in phage control group were injected with 1 mL phages in the titer of 1×10(8) PFU/mL. The injection was performed continuously for 7 days in each living mouse, and the survival situation of mice was observed each day to calculate the survival ratio in one week. (2) Another 60 BALB/c mice were grouped and treated as in experiment (1), and the injection was performed continuously for 5 days in each living mouse. On experiment day 2, 4, and 6, 3 mice from each group were selected (if the number of survived mouse in any group was less than 3 at sample collecting, all the survived mice were selected), and blood was drawn to determine white blood cell count (WBC, with 3 samples at each time point in each group). On experiment day 2, blood was drawn from the mice that had their blood taken earlier for bacterial culture, and lung, liver, kidney, and spleen tissue was collected from the same mice. The tissue samples were added to the LB solid medium after being homogenized and diluted for bacterial culture. The content of bacteria was calculated after the bacterial colony number was counted. Data were processed Wilcoxon rank sum test, one-way analysis of variance, LSD test and Kruskal-Wallis rank sum test.. (1) On experiment day 7, there were 12, 8, 10, and 12 mice survived in blank control group, antibiotics treatment group, phage treatment group, and phage control group respectively, while no mouse survived in sepsis control group. Compared with that in sepsis control group, the survival ratio of mice was significantly higher in the other four groups (with Z values from 55.635 to 106.593, P values below 0.05). The survival ratio of mice in phage treatment group was slightly higher than that in antibiotics treatment group, without statistically significant difference (Z=2.797, P>0.05). (2) On experiment day 2, WBC data of mice in blank control group, phage treatment group, and phage control group were close[respectively (5.60±0.94)×10(9)/L, (5.16±0.36)×10(9)/L, and (5.26±1.89)×10(9)/L], all significantly lower than the datum in sepsis control group[(8.64±0.64)×10(9)/L, P<0.05 or P<0.01], and the WBC data in the latter two groups were significantly lower than the datum in antibiotics treatment group[(7.80±1.76)×10(9)/L, with P values below 0.05]. On experiment day 4, WBC data of mice in antibiotics treatment group, phage treatment group, and phage control group were close, all significantly lower than the datum in blank control group (P<0.05 or P<0.01), and WBC data in the above-mentioned four groups were all lower than the datum in sepsis control group (with P values below 0.01). On experiment day 6, there was no statistically significant difference in WBC among blank control group, antibiotics treatment group, phage treatment group, and phage control group (χ(2)=4.128, P>0.05). On experiment day 2, respectively 12, 7, and 2 mice were detected as blood bacterial culture-positive in sepsis control group, antibiotics treatment group, and phage treatment group, while no positive result was detected in the other two groups. Positive ratios of blood bacterial culture of mice in blank control group, phage treatment group, phage control group were significantly lower than the ratio in sepsis control group (with χ(2) values from -30.000 to 30.000, P values below 0.01). Positive ratio of blood bacterial culture of mice in antibiotics treatment group was significantly higher than that in blank control group or phage control group (with χ(2) values respectively 17.500 and -17.500, P values below 0.05). On experiment day 2, except for the kidney tissue of mice in phage treatment group, the bacteria load in each viscus of mice in blank control group, phage treatment gro. Phages can significantly improve survival ratio, control inflammation response, and effectively clean bacteria in lung, liver, spleen, and kidney in treating extensively drug-resistant Acinetobacter baumannii-induced sepsis in mice.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacteriophages; Burns; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Resistance, Multiple, Bacterial; Humans; Imipenem; Liver; Mice; Mice, Inbred BALB C; Random Allocation; Sepsis; Soft Tissue Infections; Stem Cells

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.

Topics: Administration, Intravenous; Anti-Bacterial Agents; Cefoperazone; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drugs, Generic; Female; Humans; Imipenem; Male; Middle Aged; Oncology Service, Hospital; Penicillanic Acid; Pilot Projects; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Retrospective Studies; Sepsis; Sulbactam; Treatment Outcome

Infection with methicillin-resistant Staphylococcus aureus (MRSA) has become a worldwide problem and is no longer acquired only in a hospital setting. Community-associated MRSA is an emerging pathogen of increasing interest to both obstetricians and neonatologists, reported in all three trimesters of pregnancy and postpartum, and in neonatal intensive care units, leading to severe outcomes, including neonatal death. This case report describes a serious and potentially life-threatening infection (including wound abscess, septicemia, septic thrombophlebitis, and septic pulmonary emboli) that developed in an otherwise healthy postpartum woman who had screened positive for MRSA in nares, vagina, and rectum at the time of her prior admission in labor as part of a research study. We conclude that asymptomatic nasal, vaginal, and rectal colonization with MRSA occurs in pregnancy and may be a risk factor for serious systemic infection after delivery.

Topics: Abscess; Anti-Bacterial Agents; Anticoagulants; Carrier State; Cesarean Section; Cilastatin; Cilastatin, Imipenem Drug Combination; Drainage; Drug Combinations; Female; Heparin; Humans; Imipenem; Methicillin-Resistant Staphylococcus aureus; Pregnancy; Puerperal Infection; Pulmonary Embolism; Radiography; Sepsis; Staphylococcal Infections; Surgical Wound Infection; Thrombophlebitis; Vancomycin; Young Adult

A 78-year-old man underwent a left lower sleeve lobectomy and lymph node dissection for lung cancer. His postoperative course had been uneventful until postoperative day (POD) 3, but severe dyspnea occurred suddenly and the chest X-p showed infiltration shadow on POD 3. Streptococcus pneumonia antigen in the urine was elevated, suggesting pneumonia caused by Streptococcus pneumonia. The patient was treated with double dose of imipenem/cilastatin sodium and supported with a mechanical ventilator in an intensive care unit. Although the patient recovered from penicillin resistant Streptococcus pneumonia, he was suffered from Klebsiella sepsis and expired on the POD 26.

Topics: Aged; Carcinoma, Squamous Cell; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Fatal Outcome; Humans; Imipenem; Klebsiella Infections; Lung Neoplasms; Male; Penicillin Resistance; Pneumonia, Pneumococcal; Postoperative Complications; Sepsis; Streptococcus pneumoniae; Ventilators, Mechanical

We present a case of sepsis caused by isolated sphenoiditis.. The case being described concerns 61-year-old woman treated at the Department of Occupational Diseases of Wroclaw Medical University due to body temperature maintaining for 2 months at above 38 degrees C, leucocytosis reaching 14-16 thousand and weight loss of about 4 kg. Detailed diagnostics did not confirm the preliminary diagnosis of system or neoplastic disease. Bacteriological blood examination revealed the presence of staphylococcus aureus susceptible to Vancomycin and Tienam. The attempt of pharmacological treatment did not produced the expected effect. NMR examination of the facial skeleton proved partial shadowing of the Sphenoidal sinus. The patient was admitted for surgical treatment. After the sphenoidal sinus was cut open, mucopurulent contents was found inside. During microbiological examination, staphylococcus aureus with identical susceptibility was cultured from the mucopurulent contents. After 3-week guided antibiotic therapy, permanent temperature regression and permanent improvement of the patient's condition were achieved.. Surgical treatment combined with intensive antibiotic therapy caused the complete regression of symptoms.. Isolated sphenoiditis occurs rarely but it still is a serious diagnostic and therapeutic problem. Diagnosis delay and disease progress may lead to life-threatening complications.

Topics: Abscess; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Female; Humans; Imipenem; Middle Aged; Radiography; Sepsis; Sphenoid Sinus; Sphenoid Sinusitis; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Vancomycin

Topics: Bacteria; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Imipenem; Sepsis; Suppuration

Topics: Adult; Anti-Bacterial Agents; Cilastatin; Cilastatin, Imipenem Drug Combination; Dose-Response Relationship, Drug; Drug Combinations; Drug Monitoring; Hemofiltration; Humans; Imipenem; Kidney Transplantation; Male; Multiple Organ Failure; Sepsis; Serum Albumin; Teicoplanin

The present study addressed the role of IL-12 in a murine model of septic peritonitis, induced by cecal ligation and puncture (CLP). Although CLP surgery induced IL-12 production at 6 and 24 h after surgery, IL-12 immunoneutralization was clearly deleterious in this model: 54% of CLP mice receiving preimmune serum survived, whereas mice administered IL-12 antisera prior to CLP experienced a 25% survival rate. IL-12 immunoneutralization not only led to increased mortality, but also appeared to promote a shift away from IL-12 and IFN-gamma, in favor of IL-10. This cytokine shift corresponded to changes in bacterial load, as CLP mice receiving IL-12 antiserum yielded more CFUs from the peritoneal cavity at 24 h after CLP. To address the role of bacterial infection in IL-12 antiserum-induced mortality following CLP, antibiotics were administered for 4 days after surgery. Despite regular antibiotic administration, IL-12 immunoneutralization still reduced survival in CLP mice. Furthermore, histology of the ceca revealed that mice administered IL-12 antisera failed to show typical organization of the damaged cecum wall. Accordingly, Gram staining revealed bacteria within peritoneal fluids from these mice, while peritoneal fluids from CLP mice that received preimmune serum and antibiotics were free of bacteria. Altogether, these data suggested multiple important roles for IL-12 in the evolution of murine septic peritonitis.

Topics: Acute Disease; Animals; Cecal Diseases; Cilastatin; Cilastatin, Imipenem Drug Combination; Disease Models, Animal; Drug Combinations; Drug Therapy, Combination; Female; Fibrosis; Imipenem; Immune Sera; Immunization, Passive; Interferon-gamma; Interleukin-10; Interleukin-12; Intestinal Perforation; Ligation; Mice; Peritoneum; Peritonitis; Sepsis; Wound Healing

To study the therapeutic effects of volume support, antibiotics, and a monoclonal antiendotoxin antibody on the mortality rate and blood concentrations of endothelin and other mediators in fulminant intra-abdominal sepsis in rats.. Prospective, randomized, controlled trial.. Research laboratory in a university hospital.. Adult male Wistar rats.. Fulminant polymicrobial intra-abdominal sepsis was induced by a 4-mm cecal perforation. Treatment was performed with saline volume support, the antibiotic imipenem/cilastatin, and the monoclonal antiendotoxin antibody E5, both as monotherapy and as a combined regimen. Mortality rates were recorded and concentrations of bacteria, endotoxin, tumor necrosis factor (TNF), big endothelin, and endothelin-1 (21 amino acids) in blood were determined.. Substantial increases in circulating big endothelin and endothelin-1 concentrations were observed during sepsis. The combination of volume support with antibiotics reduced the mortality rate, but neither as monotherapy nor as a combined regimen did this intervention modify plasma endothelin-1 concentrations. This finding suggests that hypovolemia and bacteria per se are not important stimuli for endothelin synthesis and a high plasma level of endothelin-1 does not necessarily predict poor outcome in sepsis. The inactive big endothelin is enzymatically cleaved, leaving the biologically active 21-residue endothelin-1. Intervention with E5 substantially reduced the mortality rate and concentrations of endotoxin, TNF, and plasma endothelin-1, while big endothelin and total endothelin immunoreactivity did not decrease. This finding indicates a suppressed conversion of big endothelin to endothelin-1 after E5 treatment. Because E5 has no direct effect on endothelin metabolism, E5 probably reduces the synthesis of endothelin-1 by suppressing the endothelin-activators endotoxin and TNF. A triple combination of volume support, imipenem/cilastatin, and E5 was the only regimen that reduced all of the end points: mortality rate, hemoconcentration, bacteria, endotoxin, TNF, and endothelin-1.. The concentration of plasma endothelin was increased during fulminant intra-abdominal sepsis in rats. Combining volume support with antibiotic therapy reduced the mortality rate, but did not modify concentrations of plasma endothelin-1. The monoclonal antiendotoxin antibody E5 reduced the mortality rate and concentrations of endotoxin, TNF, and endothelin-1, but not big endothelin. This finding indicates that E5 therapy inhibits the conversion of big endothelin to 21-residue endothelin-1.

Topics: Animals; Antibodies, Monoclonal; Blood Volume; Cilastatin; Cilastatin, Imipenem Drug Combination; Combined Modality Therapy; Drug Combinations; Drug Evaluation, Preclinical; Drug Therapy, Combination; Endothelins; Fluid Therapy; Imipenem; Immunoglobulins; Male; Peritonitis; Prospective Studies; Random Allocation; Rats; Rats, Wistar; Sepsis; Time Factors

Male Wistar albino rats were allocated to three groups-sham operated (n: 10), splenectomized (n: 20) and splenic autotransplanted (n: 10). Twelve weeks after operation, all were challenged with 1.8 x 10(8) cfu/ml Pseudomonas aeruginosa intranasally. Half of the splenectomized rats received imipenem-cilastatin after 2 h of bacterial challenge. Mortality was then observed for the next 12 days. All animals were autopsied and liver, kidney, spleen and lung specimens were processed for microbiological culture and histopathological examination. In 80% of autotransplanted rats, splenic tissue regeneration was histopathologically verified. Hemoglobin oxidation of erythrocytes increased in splenectomized rats and remained close to control levels in the autotransplanted group. No significant difference was detected between IgM levels of splenectomized and autotransplanted groups. Mortality rates were the same for all groups, except that splenectomized animals given antimicrobial therapy had increased survival rates. In conclusion, it is likely that the spleen has no role in protection against pulmonary sepsis and that only appropriate antimicrobial therapy can protect the splenectomized host from Pseudomonas sepsis.

Topics: Animals; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Therapy, Combination; Hemoglobins; Imipenem; Immunoglobulin M; Lung; Male; Oxygen; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Rats; Rats, Wistar; Sepsis; Spleen; Splenectomy; Transplantation, Autologous

Calculated chemotherapy is based on the knowledge of the typical bacterial agents of a particular infection. From January 1983 to August 1985 bacteriological findings from surgical patients with peritonitis, septicemia or pneumonia treated in an intensive care unit were analysed. The study concentrated on those findings only which differed from previous bacteriological investigations. During the first three days 53 patients on assisted ventilation suffering from peritonitis exhibited mainly enterobacteria in their peritoneal secretions. At day 10 or later we also found bacteria from the pseudomonas group. At that time the bacterial spectrum of bronchial secretions was comparable to that of the peritoneal secretions of the same patient. After day 10, the bacterial spectrum was similar in 36 ventilated patients without peritonitis, in 56 patients suffering from post-operative pneumonia and in peritonitis patients. According to our findings, calculated chemotherapy may be based on the fact that patients with peritonitis who cannot be cured within a few days have a bacterial flora comparable to that of patients with septicemia or pneumonia. Patients with severe infections following surgery, such as potentially fatal pneumonia, generalised peritonitis or septicemia were treated with imipenem/cilastatin, according to the above definitions of calculated chemotherapy. 37 of 46 patients treated between May and December 1985, were clinically cured. Microorganisms persisted in five clinically cured patients. Development of resistance to imipenem was observed in one case. In one case treatment had to be stopped because of an allergic skin reaction. Monotherapy of peritonitis by imipenem/cilastatin appeared more satisfactory than treatment with combinations of other antibiotics.

Topics: Adult; Bacterial Infections; Cilastatin; Cilastatin, Imipenem Drug Combination; Cyclopropanes; Drug Combinations; Female; Humans; Imipenem; Male; Middle Aged; Peritonitis; Pneumonia; Postoperative Complications; Respiration, Artificial; Retrospective Studies; Sepsis; Thienamycins