cilastatin--imipenem-drug-combination and Pneumonia--Bacterial

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

Although early use of broad-spectrum antimicrobials in critically ill patients may increase antimicrobial adequacy, uncontrolled use of these agents may select for more-resistant organisms. This study investigated the effects of early use of broad-spectrum antimicrobials in critically ill patients with hospital-acquired pneumonia.. We compared the early use of broad-spectrum antimicrobials plus subsequent de-escalation (DE) with conventional antimicrobial treatment (non-de-escalation, NDE) in critically ill patients with hospital-acquired pneumonia (HAP). This open-label, randomized clinical trial was performed in patients in a tertiary-care center medical intensive care unit (MICU) in Korea. Patients (n=54) randomized to the DE group received initial imipenem/cilastatin plus vancomycin with subsequent de-escalation according to culture results, whereas patients randomized to the NDE group (n=55) received noncarbapenem, nonvancomycin empiric antimicrobials.. Between November 2004 and October 2006, 109 MICU patients with HAP were enrolled. Initial antimicrobial adequacy was significantly higher in the DE than in the NDE group for Gram-positive organisms (100% versus 14.3%; P<0.001), but not for Gram-negative organisms (64.3% versus 85.7%; P=0.190). Mean intensive care unit (ICU) stay, and 14-day, 28-day, and overall mortality rates did not differ in the two groups. Among culture-positive patients, mortality from methicillin-resistant Staphylococcus aureus (MRSA) pneumonia was higher in the DE group, even after early administration of vancomycin. Multidrug-resistant organisms, especially MRSA, were more likely to emerge in the DE group (adjusted hazard ratio for emergence of MRSA, 3.84; 95% confidence interval, 1.06 to 13.91).. The therapeutic advantage of early administration of broad-spectrum antimicrobials, especially with vancomycin, was not evident in this study.

Topics: Aged; Anti-Infective Agents; Cilastatin; Cilastatin, Imipenem Drug Combination; Cross Infection; Drug Combinations; Female; Hospital Mortality; Humans; Imipenem; Intensive Care Units; Male; Middle Aged; Pneumonia, Bacterial; Time Factors; Treatment Outcome; Vancomycin

Ventilator-associated pneumonia (VAP) remains a significant challenge in critical care. We conducted a secondary analysis of a multicenter, prospective, randomized trial comparing levofloxacin (750 mg iv q24h) with imipenem-cilastatin (500-1000 mg iv q6-8h) for treatment of nosocomial pneumonia and focused on the subgroup of patients with VAP. The study cohort included 222 patients, with half (111) of the patients assigned to each treatment group. The patients in both groups were similar with respect to age, severity of illness, and duration of mechanical ventilation before the onset of VAP. Among the intention-to-treat population, clinical success was achieved in 58.6% of patients receiving levofloxacin, compared with 63.1% of patients receiving imipenem-cilastatin (P=.49; 95% confidence interval for the difference, -8.77% to 17.79%). Microbiological success and 28-day mortality rates were also comparable. Multivariate analysis demonstrated that assignment to antibiotic treatment (i.e., levofloxacin vs. imipenem-cilastatin) was not predictive of outcomes, thus suggesting that the treatment regimens were equivalent. Both levofloxacin and imipenem-cilastatin regimens were well tolerated and had similar adverse event profiles.

Topics: Anti-Bacterial Agents; Cilastatin; Cilastatin, Imipenem Drug Combination; Cohort Studies; Cross Infection; Double-Blind Method; Drug Combinations; Drug Resistance, Bacterial; Female; Humans; Imipenem; Levofloxacin; Male; Middle Aged; Multivariate Analysis; Ofloxacin; Pneumonia, Bacterial; Prospective Studies; Thienamycins; Treatment Outcome; Ventilators, Mechanical

In this open, prospective, study were enrolled 204 hospitalized elderly patients with severe (88 males, 116 females, age range 70-94). Patients were randomized to receive one of the following antibiotic treatment regimens: meropenem 500 mg i.v. t.i.d. (52); imipenem/cilastatin 500 mg i.v. t.i.d. (51), clarithromycin 500 mg + ceftriaxone 1 g i.v. b.i.d. (52), clarithromycin 500 mg + amikacin 250 mg i.v. b.i.d. (49). In 99 cases causative germs were isolated (24 meropenem, 26 imipenem, 23 clarithromycin + ceftriaxone, 26 ceftriaxone + amikacin). A satisfactory clinical, bacteriological response was achieved respectively in 86.5% 77% in meropenem; 86.3% 71% in imipenem/cilastatin; 69% 61% in ceftriaxone + clarithromycin and in 85.7% 77% in clarithromycin + amikacin. The mean total cost for each patient was $1,560; $1,620; $1,760 and $1,792 in meropenem, imipenem/cilastatin, clarithromycin + ceftriaxone and clarithromycin + amikacin respectively. This study shows that treatment with either meropenem or imipenem is as efficacious as conventional therapy in the treatment of community acquired pneumonia (CAP), and that meropenem is the most cost-effective.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Carbapenems; Ceftriaxone; Cilastatin; Cilastatin, Imipenem Drug Combination; Clarithromycin; Community-Acquired Infections; Costs and Cost Analysis; Drug Combinations; Drug Costs; Drug Therapy, Combination; Female; Hospitalization; Humans; Imipenem; Male; Meropenem; Pneumonia, Bacterial; Prospective Studies; Thienamycins; Treatment Outcome

The identification of the optimal agent for administration via the respiratory tract when treating pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB).. A murine model of acute CRAB pneumonia was established by intratracheal (i.t.) inoculation with 2.5 × 10⁷ colony-forming units (CFU) of A. baumannii strain Ab396 plus 10% porcine mucin. After 4h the infected BALB/c mice were treated intratracheally with 25μl of either 0.85% saline (control group), colistimethate sodium (CMS) (166 666 U/kg, CMS group), imipenem/cilastatin (30/30 mg/kg, imipenem group), or meropenem (20mg/kg, meropenem group), every 8h. The therapeutic efficacy of these agents was examined.. A. baumannii strain Ab396 was susceptible to CMS only. However, meropenem treatment did give a significantly superior survival rate (100%) compared to treatment with imipenem (50%), CMS (33%), or saline (0%) (p<0.001 vs. the control and CMS groups, p=0.006 vs. the imipenem group, by log-rank test). Furthermore, compared to the other groups, the meropenem group demonstrated significantly more favorable results in terms of tissue penetration of the antibiotic, bacterial clearance, normalization of the wet lung-to-body weight ratio, and down-regulation of pro-inflammatory cytokine levels in the lungs.. Administration of meropenem via the respiratory tract proved to have the best therapeutic efficacy among the antibiotics tested when treating advanced murine CRAB pneumonia.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Acute Disease; Animals; Anti-Bacterial Agents; Carbapenems; Cilastatin; Cilastatin, Imipenem Drug Combination; Colistin; Cytokines; Disease Models, Animal; Drug Combinations; Drug Resistance, Bacterial; Female; Imipenem; Meropenem; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Pneumonia, Bacterial; Stem Cells; Thienamycins

Ralstonia pickettii, formerly known as Burkholderia pickettii, is a non-fermentative gram-negative bacillus. It is emerging as an opportunistic pathogen both in the hospital setting and in the environment, leading to outbreaks especially in the intensive care units. The available literature revealed two case reports of pneumonia associated with R. pickettii in adults. In this report, a case of pneumoniae due to R. pickettii, in a patient with chronic obstructive pulmonary disease was presented. Fifty-six years old male patient was admitted to the hospital with complaints of shortness of breath, cough, purulent sputum, weakness, fatigue and green colorred diarrhea lacking blood. Lung auscultation revealed decreased respiratory sounds in the right lower lobe. Laboratory findings yielded decreased arterial pH and paO2 and increased pCO2 values, while hemoglobin, hematocrite, blood urea and creatinine levels were increased. Chest X-ray showed an infiltration on right lower zone. The patient was intubated and imipenem 1 x 500 mg/day and netilmicin 1 x 80 mg/day were initiated. Deep tracheal aspirate specimen revealed gram-negative rods and leukocytes, and cultures yielded growth of non-fermentative gram-negative bacilli on blood agar and EMB agar. These bacilli were identified as R. pickettii by using VITEK 2 system (bi-oMerieux Inc, Mercy L'etoil, France). Antibiotic sensitivity test performed by VITEK 2 GP system (bioMerieux Inc, Mercy L'etoil, France) revealed sensitivity to ceftriaxone, imipenem/cilastatin, piperacillin/tazobactam, amikacin, gentamicin, cefoperazone-sulbactam and ciprofloxacin. Treatment with imipenem/cilastatin was continued for 14 days and the patient was completely recovered. This case was presented in order to call attention to R. pickettii as a pathogen that may cause community-acquired lower respiratory tract infection.

Topics: Anti-Bacterial Agents; Cilastatin; Cilastatin, Imipenem Drug Combination; Community-Acquired Infections; Drug Combinations; Gram-Negative Bacterial Infections; Humans; Imipenem; Male; Middle Aged; Opportunistic Infections; Pneumonia, Bacterial; Protease Inhibitors; Pulmonary Disease, Chronic Obstructive; Ralstonia pickettii; Treatment Outcome

Strong data are lacking on the cross-reactivity between individual carbapenems. We describe a 48-year-old woman with ventilator-associated Pseudomonas aeruginosa pneumonia who received an 8-day course of imipenem-cilastatin and experienced a delayed (i.e., nonimmediate) hypersensitivity reaction, evidenced by an extensive erythematous macular morbilliform rash and an increased eosinophil count. Eight days after completion of therapy, the pneumonia returned, and it was decided to avoid using imipenem-cilastatin; she was administered a 14-day course of meropenem. To our knowledge, this is the first report of a nonimmediate hypersensitivity reaction to imipenem-cilastatin without cross-reactivity to meropenem. This suggests that if carbapenem therapy is unavoidable, meropenem may be cautiously administered in patients with a known allergy to imipenem-cilastatin.

Topics: Anti-Bacterial Agents; Cilastatin; Cilastatin, Imipenem Drug Combination; Cross Reactions; Drug Combinations; Drug Hypersensitivity; Female; Humans; Hypersensitivity, Delayed; Imipenem; Meropenem; Middle Aged; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

We evaluated the clinical features of multidrug-resistant Pseudomonas aeruginosa cases determined by sputum culture between April, 2005 and December, 2006. The clinical features of most cases were: (1) pneumonia in the elderly with cerebrovascular diseases, (2) previous administration of carbapenems and antipseudomonal cephems, (3) PIPC, CAZ and ISP sensitve MDRP, (4) MRSA was isolated concurrently, (5) not necessary of therapy against MDRP, (6) good outcome.

Topics: Adult; Aged; Amikacin; Cilastatin; Cilastatin, Imipenem Drug Combination; Ciprofloxacin; Drug Combinations; Drug Resistance, Multiple, Bacterial; Female; Hospitals, University; Humans; Imipenem; Japan; Klebsiella pneumoniae; Male; Methicillin Resistance; Middle Aged; Pneumonia, Bacterial; Prognosis; Pseudomonas aeruginosa; Retrospective Studies; Sputum; Staphylococcus aureus; Time Factors

We present a case of pulmonary nocardiosis in a patient suffering from idiopathic thrombocytopenic purpura (ITP), an autoimmune disorder in which platelets are immunologically destroyed. ITP corticosteroid therapy, as well as the patient's diabetes mellitus history caused immunosuppression, leading to an incidental lung infection by nocardia asteroides. The combination of pulmonary nocardiosis and ITP is, as far as we know, very rare.

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Cilastatin; Cilastatin, Imipenem Drug Combination; Diabetes Complications; Drug Combinations; Drug Therapy, Combination; Fatal Outcome; Humans; Imipenem; Immune Tolerance; Male; Middle Aged; Nocardia asteroides; Nocardia Infections; Pneumonia, Bacterial; Purpura, Thrombocytopenic; Tomography, X-Ray Computed; Trimethoprim, Sulfamethoxazole Drug Combination

To report a successful case of rapid imipenem desensitization in a critically ill patient with multidrug-resistant Acinetobacter baumannii ventilator-associated pnemonia (VAP).. 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.. 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.. 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.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Amikacin; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Hypersensitivity; Drug Resistance, Multiple, Bacterial; Humans; Imipenem; Male; Pneumonia, Bacterial; Protease Inhibitors

Acinetobacter organisms, which are a common cause of ventilator-associated pneumonia (VAP) in some health care centers, are becoming more resistant to such first-line agents as imipenem-cilastatin (Imi-Cil). Sulbactam has good in vitro activity against Acinetobacter organisms; thus, ampicillin-sulbactam (Amp-Sulb) may be a viable treatment alternative. The outcomes for critically ill trauma patients with Acinetobacter VAP treated with either Amp-Sulb or Imi-Cil were compared retrospectively. A total of 77 episodes in 75 patients were studied. Fourteen patients were treated with Amp-Sulb, and 63 patients were treated with Imi-Cil. Treatment efficacy was similar in the Amp-Sulb and Imi-Cil groups (93% vs. 83%, respectively; P>.05). No statistically significant differences between groups were noted with regard to associated mortality, duration of mechanical ventilation, or length of stay in the intensive care unit or hospital. However, adjunctive aminoglycoside therapy was used more often in the Amp-Sulb group. Patients generally received Amp-Sulb because of imipenem resistance. Amp-Sulb was effective in treating a small number of patients with Acinetobacter VAP; however, more data are needed.

Topics: Acinetobacter; Adult; Ampicillin; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Therapy, Combination; Female; Humans; Imipenem; Male; Pneumonia, Bacterial; Retrospective Studies; Sulbactam; Treatment Outcome; Ventilators, Mechanical

An 80-year-old blind man with lepromatous leprosy suffered from right femoral neck and humeral neck fractures on July 9, 1993. Because of fever (38.6 degrees C), difficult expectoration and diffuse bilateral perihilar infiltrates with consolidation in the left lower lung field on his chest radiograph, severe pneumonia was diagnosed. With intravenous hyperalimentation, imipenem/cilastatin (IPM/CS), ceftazidime, minocycline, gentamicin (GM), and human immunoglobulin were administrated. On July 29, hip screw-plate fixation was done. Citrobacter freundii was isolated from the sputum and its susceptibility was IPM/CS+, GM3+. Multi-drug therapy with GM and other antibiotics improved the patients' condition, but Citrobacter freundii were still detected and 43 days of medication were needed. According to a report by the Ministry of Health and Welfare in 1992, the resistance rate of IPM/CS against Citrobacter freundii is only 0.7%, and IPM/CS is more effective than beta-Lactams. This is a very rare case of severe pneumonia in an elderly patient caused by Citrobacter freundii that was suspected to have low susceptibility to IPM/CS.

Topics: Aged; Aged, 80 and over; Cilastatin; Cilastatin, Imipenem Drug Combination; Citrobacter freundii; Drug Combinations; Drug Resistance, Microbial; Drug Therapy, Combination; Enterobacteriaceae Infections; Gentamicins; Humans; Imipenem; Male; Pneumonia, Bacterial