Pharmacokinetic parameters of CAZ-AVI in the normal lung and in models of pneumonia: lessons for treatment optimization in critical care.

The spread of multidrug-resistant Gram-negative bacterial infections is a significant issue for worldwide public health. Gram-negative organisms regularly develop resistance to antibiotics, especially to ß-lactam antimicrobials, which can drastically restrict the number of therapies. A third-generation cephalosporin and the non-ß-lactam ß-lactamase inhibitor avibactam, which exhibits broad-spectrum ß-lactamase inhibition in vitro, are combined to form ceftazidime-avibactam (CAZ-AVI). In this narrative review, we summarize data on pharmacokinetic (PK) parameters for CAZ-AVI in both animal and human models of pneumonia, as well as in healthy individuals. We assessed current literature performing an extensive search of the literature, using as search words 'CAZ-AVI', 'pharmacokinetics', 'pneumonia', 'lung', and 'epithelial lining fluid'. Overall, lung exposure studies of CAZ-AVI revealed that the epithelial lining fluid penetration ranges between 30% and 35% of plasma concentration. Despite the fair lung penetration of CAZ-AVI, this antimicrobial agent has a pivotal role in managing patients with multi-drug resistant Gram-negative pneumonia, however further studies are needed to better assess its PK profile.

Clinical results with the use of ceftaroline and ceftobiprole: real-life experience in a tertiary care hospital.

INTRODUCTION: Ceftaroline and ceftobiprole show activity against resistant Gram-positive cocci as well as good tolerability and are increasingly used in diverse infections. No comparative data on the efficacy and safety of ceftaroline and ceftobiprole in real-life are available. METHODS: In this single-centre, observational, retrospective clinical study, the outcomes of patients treated with ceftaroline or ceftobiprole in our hospital were compared, assessing clinical data, use and drug exposure of study antibiotics, and outcomes. RESULTS: A total of 138 patients were included in this study, including 75 treated with ceftaroline and 63 treated with ceftobiprole. Patients treated with ceftobiprole had more comorbidities [median Charlson comorbidity index 5 (4-7) vs. 4 (2-6) for ceftaroline; P = 0.003], a higher prevalence of multiple site infections (P < 0.001) and were more often treated empirically (P = 0.004), whilst ceftaroline was more frequently used in patients with healthcare-related infections. No differences were observed in terms of hospital mortality, length of stay, and rates of clinical cure, improvement or failure. The only independent predictor of outcome was Staphylococcus aureus infection. Both treatments were generally well tolerated. CONCLUSION: In our real-life experience, ceftaroline and ceftobiprole, applied in different clinical scenarios, were comparable in terms of clinical efficacy and tolerability in a range of severe infections with variable aetiology and different levels of clinical severity. We believe our data may support the clinician in choosing the best option for each therapeutic setting.

Clinical efficacy and safety of cefiderocol for resistant Gram-negative infections: a real-life, single-centre experience.

OBJECTIVES: Cefiderocol is a 'siderophore' cephalosporin active against Gram-negative bacteria, including carbapenem-resistant strains. Data on the use of cefiderocol in real life are limited. We evaluated the efficacy and safety of cefiderocol in the context of our hospital clinical practice. METHODS: This was a single-centre, observational, retrospective clinical study. We collected data for all patients who received cefiderocol therapy in our hospital, with a focus on clinical outcomes and adverse events. RESULTS: The study cohort included 28 patients, with a median age of 73 years (25-83 years) and a high burden of co-morbidities. Up to 45 Gram-negative isolates were cultured from the study patients, the most common pathogen being Acinetobacter baumannii (31.1%). Cefiderocol was mostly prescribed for pneumonia (37.8% of cases), bloodstream infection (24.4%), urinary tract infection (22.2%) and intra-abdominal infection (20%), and largely as salvage therapy (92.8%). Of the 18 patients for whom follow-up cultures were available, 14 (77.8%) achieved eradication of the causative micro-organism. Therapeutic success (improvement/resolution of infection) occurred in 64.3% of cases at 7 days and 50% at 14 days from treatment start. Treatment failed in 9 cases (32.1%). No effects on kidney, liver or bone marrow function were observed. CONCLUSIONS: Cefiderocol showed fair efficacy and excellent tolerability in highly co-morbid patients with a range of multiresistant infections. It may be an option for infections due to colistin-resistant pathogens, when other regimens fail or in cases at risk of kidney dysfunction.

Long-Term Outcome of Infective Endocarditis Involving Cardiac Implantable Electronic Devices: Impact of Comorbidities and Lead Extraction.

(1) Background: Management of cardiac implantable electronic device-related infective endocarditis (CIED-IE) hinges on complete hardware removal. We assessed whether long-term prognosis is affected by device removal, considering baseline patient comorbid conditions; (2) Methods: A total of 125 consecutive patients hospitalized for CIED-IE were included in this retrospective analysis. Outcomes were in-hospital, one-year, and long-term mortality. There were 109 patients who underwent device removal, 91 by transvenous lead extraction (TLE) and 18 by open heart surgery (OHS); (3) Results: TLE translated into lower hospital mortality (4.4% vs. 22.5% with OHS; p = 0.03). Septic pulmonary embolism was the only independent predictor of in-hospital mortality (OR:7.38 [1.49-36.6], p = 0.013). One-year mortality was in contrast independently associated to tricuspid valve involvement (p = 0.01) and Charlson comorbidity index (CCI, p = 0.039), but not the hardware removal modality. After a median follow-up of 41 months, mortality rose to 24%, and was significantly influenced only by CCI. Specifically, patients with a higher CCI who were also treated with TLE showed a survival rate not significantly different from those managed with medical therapy only; (4) Conclusions: In CIED-IE, TLE is the strategy of choice for hardware removal, improving early outcomes. Long-term benefits of TLE are lessened by comorbidities. In cases of CIED-IE with high CCI, a more conservative approach might be an option.

Incidence, Risk Factors and Clinical Implications of Glucose Metabolic Changes after Heart Transplant.

Diabetes mellitus (DM) arising de novo after transplant is a common complication, sharing many features with type 2 DM but also specific causes, such as administration of steroids and immunosuppressive drugs. Although post-transplant DM (PTDM) is generally assumed to worsen recipients' outcomes, its impact on renal function, cardiac allograft vasculopathy and mortality remains understudied in heart transplant (HT). We evaluated incidence and risk factors of PTDM and studied glucose metabolic alterations in relation to major HT outcomes. 119 subjects were included in this retrospective, single centre, observational study. A comprehensive assessment of glucose metabolic state was done pre-transplant and a median of 60 months [IQR 30-72] after transplant. Most patients were males (75.6%), with prior non-ischemic cardiomyopathy (64.7%) and median age of 58 years [IQR 48-63]. 14 patients developed PTDM, an incidence of 3.2 cases/100 patient-years. Patients with worsening glucose metabolic pattern were the only who showed a significant increase of BMI and metabolic syndrome prevalence after transplant. 23 (19.3%) patients died during follow up. Early mortality was lower in those with stably normal glucose metabolism, whereas improvement of glucose metabolic state favorably affected mid-term mortality (log-rank p = 0.028). No differences were observed regarding risk of infections and cancer. PTDM is common, but glucose metabolism may also improve after HT. PTDM is strictly related with BMI increase and metabolic syndrome development and may impact recipient survival.

Clinical Characteristics and Outcome of MDR/XDR Bacterial Infections in a Neuromuscular Semi-Intensive/Sub-Intensive Care Unit.

(1) Background: The aim of this study was to assess the clinical and microbiological characteristics of multidrug-resistant infections in a neuromuscular semi-intensive/sub-intensive care unit; (2) Methods: Retrospective analysis on data from 18 patients with NMD with proven MDRO/XDRO colonisation/infection from August 2021 to March 2022 was carried out; (3) Results: Ten patients were males (55.6%), with a median age of 54 years, and there were fourteen patients (77.8%) with amyotrophic lateral sclerosis. All patients had at least one invasive device. Ten (55.6%) patients developed MDRO/XDRO infection (with a median time of 24 days) while six (33.3%) were colonised. The Charlson comorbidity index was >2 in both groups but higher in the infected compared with the colonised (4.5 vs. 3). Infected patients were mostly females (seven patients) with a median age of 62 years. The most common pathogens were Acinetobacter baumannii and Pseudomonas aeruginosa, infecting four (28.6%) patients each. Of eighteen infectious episodes, nine were pneumonia (hospital-acquired in seven cases). Colistin was the most commonly active antibiotic while carbapenems were largely inactive. Eradication of infection occurred in seven infectious episodes (38.9%). None of those with infection died; (4) Conclusions: MDRO/XDRO infections are common in patients with neuromuscular diseases, with carbapenem-resistant non-fermenting Gram-negative bacilli prevailing. These infections were numerically associated with the female sex, greater age, and comorbidities. Both eradication and infection-related mortality appeared low. We highlight the importance of infection prevention in this vulnerable population.

Oral Vancomycin Prophylaxis for Primary and Secondary Prevention of Clostridioides difficile Infection in Patients Treated with Systemic Antibiotic Therapy: A Systematic Review, Meta-Analysis and Trial Sequential Analysis.

BACKGROUND: Clostridioides difficile infection (CDI) is associated with substantial morbidity and mortality as well as high propensity of recurrence. Systemic antibiotic therapy (SAT) represents the top inciting factor of CDI, both primary and recurrent (rCDI). Among the many strategies aimed to prevent CDI in high-risk subjects undergoing SAT, oral vancomycin prophylaxis (OVP) appears promising under a cost-effectiveness perspective. METHODS: A systematic review with meta-analysis and trial sequential analysis (TSA) of studies assessing the efficacy and the safety of OVP to prevent primary CDI and rCDI in persons undergoing SAT was carried out. PubMed and EMBASE were searched until 30 September 2021. The protocol was pre-registered on PROSPERO (CRD42019145543). RESULTS: Eleven studies met the inclusion criteria, only one being a randomized controlled trial (RCT). Overall, 929 subjects received OVP and 2011 represented the comparator group (no active prophylaxis). OVP exerted a strong protective effect for CDI occurrence: odds ratio 0.14, 95% confidence interval 0.04-0.38. Moderate heterogeneity was observed: I2 54%. This effect was confirmed throughout several subgroup analyses, including prevention of primary CDI versus rCDI. TSA results pointed at the conclusive nature of the evidence. Results were robust to a variety of sensitivity and quantitative bias analyses, although the underlying evidence was deemed as low quality. No differences between the two groups were highlighted regarding the onset of vancomycin-resistant Enterococcus infections. CONCLUSIONS: OVP appears to be an efficacious option for prevention of CDI in high-risk subjects undergoing SAT. Nevertheless, additional data from RCTs are needed to establish OVP as good clinical practice and define optimal dosage and duration.

Dalbavancin treatment for spondylodiscitis: multi-center clinical experience and literature review.

Dalbavancin is a novel lipoglycopeptide antibiotic, characterized by a broad spectrum of activity against Gram-positive cocci. However, its efficacy in spondylodiscitis treatment is not fully established. All adult patients diagnosed with spondylodiscitis and treated with dalbavancin were included across four Italian medical centers from January 2018 to April 2021. We collected clinical and laboratory data, and presented follow-up findings along with a thorough literature review. 13 patients (mean age= 65 years) were included in this study. Dalbavancin was administered as first line treatment in six (46%) of the patients. Reasons for using Dalbavancin included treatment simplification (62%) and clinical failure of previous antibiotics (23%). In general, Dalbavancin was well tolerated with minimal adverse events, and clinical success was achieved in 11/13 (85%) of the patients during hospitalization with additional antibiotics required in the remaining two cases. Five months after discharge, no mortality was observed, however, 42% of patients required additional antibiotics for signs of infection on follow-up imaging. Our study suggests that Dalbavancin could be an effective and safe option in treating spondylodiscitis, however, the scarcity of studies on the topic is concerning. Thus, further studies with large samples and long-term follow-up are warranted to compare the efficacy of Dalbavancin with other available treatment options.

Emerging Treatment Options for Multi-Drug-Resistant Bacterial Infections.

Antimicrobial resistance (AMR) remains one of the top public health issues of global concern. Among the most important strategies for AMR control there is the correct and appropriate use of antibiotics, including those available for the treatment of AMR pathogens. In this article, after briefly reviewing the most important and clinically relevant multi-drug-resistant bacteria and their main resistance mechanisms, we describe the emerging antimicrobial options for both MDR Gram-positive cocci and Gram-negative bacilli, including recently marketed agents, molecules just approved or under evaluation and rediscovered older antibiotics that have regained importance due to their antimicrobial spectrum. Specifically, emerging options for Gram-positive cocci we reviewed include ceftaroline, ceftobiprole, tedizolid, dalbavancin, and fosfomycin. Emerging treatment options for Gram-negative bacilli we considered comprise ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, aztreonam-avibactam, minocycline, fosfomycin, eravacycline, plazomicin, and cefiderocol. An exciting scenario is opening today with the long awaited growing availability of novel molecules for the treatment of AMR bacteria. Knowledge of mechanisms of action and resistance patterns allows physicians to increasingly drive antimicrobial treatment towards a precision medicine approach. Strict adherence to antimicrobial stewardship practices will allow us to preserve the emerging antimicrobials for our future.

Risk Factors and Outcome of Multidrug-Resistant Infections after Heart Transplant: A Contemporary Single Center Experience.

(1) Background: The aim of this study was to assess risk factors for multidrug-resistant/extensively drug-resistant (MDR/XDR) bacterial infections in heart transplant (HT) patients within three months after surgery and its impact on patient outcome. (2) Methods: Retrospective analysis of clinical, hemato-chemical, imaging, treatment and outcome data from 47 heart transplant recipients from January 2016 to December 2018. MDR/XDR infections were compared to non-MDR/XDR and noninfected patients. (3) Results: Most participants were males, median age 51 years: 35 (74.5%) developed an infection after HT; 14 (29.8%) were MDR/XDR infections. Prolonged hospital stay before HT correlated to MDR/XDR infection (p < 0.001). Sequential organ failure assessment (SOFA) score at sampling day was higher in MDR/XDR (p = 0.027). MDR/XDR were mostly blood-stream (BSI) (p = 0.043) and skin-soft tissue (SSTI) (p = 0.047) infections. Gram-negative infections were the most frequent, specifically carbapenem-resistant Klebsiella pneumoniae. Antibiotic therapy duration for MDR/XDR infections was longer (p = 0.057), eradication rate lower (p = 0.083) and hospital stay longer (p = 0.005) but not associated with a worse outcome. (4) Conclusions: MDR/XDR infections affect compromised HT recipients with a history of prolonged hospitalization, causing a lower rate of eradication and increased hospital stay. These frequently present as BSI and SSTI. We emphasize the need to prevent contamination of central venous catheters and the surgical site.

Excluded versus included patients in a randomized controlled trial of infections caused by carbapenem-resistant Gram-negative bacteria: relevance to external validity.

BACKGROUND: Population external validity is the extent to which an experimental study results can be generalized from a specific sample to a defined population. In order to apply the results of a study, we should be able to assess its population external validity. We performed an investigator-initiated randomized controlled trial (RCT) (AIDA study), which compared colistin-meropenem combination therapy to colistin monotherapy in the treatment of patients infected with carbapenem-resistant Gram-negative bacteria. In order to examine the study's population external validity and to substantiate the use of AIDA study results in clinical practice, we performed a concomitant observational trial. METHODS: The study was conducted between October 1st, 2013 and January 31st, 2017 (during the RCTs recruitment period) in Greece, Israel and Italy. Patients included in the observational arm of the study have fulfilled clinical and microbiological inclusion criteria but were excluded from the RCT due to receipt of colistin for > 96 h, refusal to participate, or prior inclusion in the RCT. Non-randomized cases were compared to randomized patients. The primary outcome was clinical failure at 14 days of infection onset. RESULTS: Analysis included 701 patients. Patients were infected mainly with Acinetobacter baumannii [78.2% (548/701)]. The most common reason for exclusion was refusal to participate [62% (183/295)]. Non-randomized and randomized patients were similar in most of the demographic and background parameters, though randomized patients showed minor differences towards a more severe infection. Combination therapy was less common in non-randomized patients [31.9% (53/166) vs. 51.2% (208/406), p = 0.000]. Randomized patients received longer treatment of colistin [13 days (IQR 10-16) vs. 8.5 days (IQR 0-15), p = 0.000]. Univariate analysis showed that non-randomized patients were more inclined to clinical failure on day 14 from infection onset [82% (242/295) vs. 75.5% (307/406), p = 0.042]. After adjusting for other variables, non-inclusion was not an independent risk factor for clinical failure at day 14. CONCLUSION: The similarity between the observational arm and RCT patients has strengthened our confidence in the population external validity of the AIDA trial. Adding an observational arm to intervention studies can help increase the population external validity and improve implementation of study results in clinical practice. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov, number NCT01732250 on November 22, 2012.

Multidrug-Resistant Infections and Outcome of Critically Ill Patients with Coronavirus Disease 2019: A Single Center Experience.

Background: The aim of this study was to assess the drivers of multidrug-resistant (MDR) bacterial infection development in coronavirus disease 2019 (COVID-19) and its impact on patient outcome. Methods: Retrospective analysis on data from 32 consecutive patients with COVID-19, admitted to our intensive care unit (ICU) from March to May 2020. Outcomes considered were MDR infection and ICU mortality. Results: Fifty percent of patients developed an MDR infection during ICU stay after a median time of 8 [4-11] days. Most common MDR pathogens were carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumannii, causing bloodstream infections and pneumonia. MDR infections were linked to a higher length of ICU stay (p = 0.002), steroid therapy (p = 0.011), and associated with a lower ICU mortality (odds ratio: 0.439, 95% confidence interval: 0.251-0.763; p < 0.001). Low-dose aspirin intake was associated with both MDR infection (p = 0.043) and survival (p = 0.015). Among MDR patients, mortality was related with piperacillin-tazobactam use (p = 0.035) and an earlier onset of MDR infection (p = 0.042). Conclusions: MDR infections were a common complication in critically ill COVID-19 patients at our center. MDR risk was higher among those dwelling longer in the ICU and receiving steroids. However, MDR infections were not associated with a worse outcome.

Prognostic value of pro-adrenomedullin and copeptin in acute infective endocarditis.

BACKGROUND: Infective endocarditis (IE) is a life-threatening disease whose prognosis is often difficult to predict based on clinical data. Biomarkers have been shown to favorably affect disease management in a number of cardiac disorders. Aims of this retrospective study were to assess the prognostic role of procalcitonin (PCT), pro-adrenomedullin (pro-ADM) and copeptin in IE and their relation with disease characteristics and the traditional biomarker C-reactive protein (CRP). METHODS: We studied 196 patients with definite IE. Clinical, laboratory and echocardiography parameters were analyzed, with a focus on co-morbidities. PCT, pro-ADM and copeptin were measured on stored plasma samples obtained on admission during the acute phase of the disease. RESULTS: Pro-ADM and copeptin were significantly higher in older patients and associated with prior chronic kidney disease. Pro-ADM was an independent predictor of hospital mortality (OR 3.29 [95%C.I. 1.04-11.5]; p = 0.042) whilst copeptin independently predicted 1-year mortality (OR 2.55 [95%C.I. 1.18-5.54]; p = 0.017). A high PCT value was strictly tied with S. aureus etiology (p = 0.001). CRP was the only biomarker associated with embolic events (p = 0.003). CONCLUSIONS: Different biomarkers correlate with distinct IE outcomes. Pro-ADM and copeptin may signal a worse prognosis of IE on admission to the hospital and could be used to identify patients who need more aggressive treatment. CRP remains a low-cost marker of embolic risk. A high PCT value should suggest S. aureus etiology.

Dalbavancin for infective endocarditis: a single centre experience.

Infective endocarditis (IE) is a life-threatening disease, mostly caused by gram-positive cocci, needing a 4-6 weeks antibiotic course. Dalbavancin is a lipoglycopeptide active on gram-positive microorganisms, with a unique pharmacokinetic profile. We describe our experience with dalbavancin to complete the intravenous antibiotic regimen for difficult-to-treat IE cases due to gram-positive bacteria. We treated 10 severely ill patients, each presenting several comorbidities. Seven patients were microbiologically cured from IE, but two patients experienced IE relapse due to the same microrganism. Short-term mortality after dalbavancin was nil, but late mortality (within 1 year of hospital discharge) was 60%. No death was related to dalbavancin therapy. Treatment was generally well tolerated. Dalbavancin may be an option to complete IE treatment in selected cases, once blood culture clearance and improvement of clinical conditions under standard therapy is reached, allowing shortening of hospitalization.

Enterococcal infective endocarditis is a marker of current occult or future incident colorectal neoplasia.

BACKGROUND: Few studies suggest an association between Enterococcal infective endocarditis (EIE) and colorectal disease, including colorectal neoplasia (CRN) and colorectal cancer (CRC). In this study, we analyze differences in prevalence, risk factors and outcome of CRN and CRC between EIE and Streptococcus gallolyticus infective endocarditis (SGIE). METHODS: Single center, observational study of 166 patients with definite EIE or SGIE. Clinical data were collected prospectively in a standardized IE protocol. Colonoscopy data were collected retrospectively on 90 patients. RESULTS: 85 patients had EIE, 81 SGIE. EIE patients had a higher rate of prior cancer (20% vs 6%) and health-care associated infection (12% vs 1%), but similar mortality than SGIE. Colonoscopy performed in 90 patients showed intestinal diseases in 30 of 42 (71%) EIE patients vs. 40 of 48 (83%) SGIE patients (p = 0.174), with a predominance of CRN. Among 78 patients who underwent colonoscopy after IE diagnosis, no difference between EIE and SGIE was observed in the rate of non-neoplastic lesions (48% vs 47%), benign (32% vs 40%) or malignant (13% vs 15%) neoplastic lesions. Adverse events during colonoscopy were uncommon, although a careful handling of anticoagulation was required. CONCLUSIONS: EIE seems to be associated with colorectal disease, including colorectal neoplasia and colorectal cancer, to the same extent as SGIE. EIE should be considered a marker of colorectal neoplasia, even in patients with a clear health-care related acquisition. Colonoscopy is generally safe in EIE patients, and should be considered to early diagnose and treat colorectal disease.

Early experience with remdesivir in SARS-CoV-2 pneumonia.

At present, there is no definitive antiviral treatment for coronavirus disease 2019 (COVID-19). We describe our early experience with remdesivir in four critically ill COVID-19 patients. Patients received a 200 mg loading dose, followed by 100 mg daily intravenously for up to 10 days. All patients had been previously treated with other antivirals before remdesivir initiation. One patient experienced a torsade de pointes requiring cardiac resuscitation and one died due to multiple organ failure. Three patients showed biochemical signs of liver injury. Lymphocyte count increased in all patients soon after remdesivir initiation. Nasal swab SARS-CoV-2 RNA became negative in three of four patients after 3 days of therapy. We observed an in vivo virological effect of remdesivir in four critically ill, COVID-19 patients, coupled with a significant burden of adverse events. Although limited by the low number of subjects studied, our preliminary experience may be relevant for clinicians treating COVID-19.

Real-life experience with ceftobiprole in a tertiary-care hospital.

OBJECTIVES: Ceftobiprole is a new therapeutic option for bacterial pneumonia, with activity against most antimicrobial-resistant Gram-positive cocci, including methicillin-resistant Staphylococcus aureus. Data on the use of ceftobiprole in real life are limited. We evaluated the efficacy and safety of ceftobiprole in a context of a hospital practice. METHODS: In a single-centre, observational, retrospective clinical study, we collected data of 29 patients undergoing ceftobiprole therapy, with a focus on clinical outcomes and adverse events. RESULTS: There was a high burden of comorbidities in the study cohort, including kidney dysfunction (38%) and cancer (24%), and a high proportion of patients with sepsis/septic shock (72%), a central line (41%) or on mechanical ventilation (21%). Most infections were nosocomial (24, 82.8%). Ceftobiprole was mostly prescribed for pneumonia (17 patients, 58.6%), and bloodstream infections (10 patients, 34.5%), both empirically (9 cases, 31%) and as targeted therapy (20, 69%, with staphylococci as the dominant pathogens). It was the first-line drug in 15 cases (51.7%). Overall, a favourable clinical outcome was observed in the majority of cases (68.9%), with clinical cure in 3 (10.3%) and clinical improvement in 17 (58.6%). Failure of treatment occurred in seven cases (24.1%). Three patients experienced a definite ceftobiprole-related adverse event, with two cases of myoclonus. No major adverse effect on bone marrow, kidney or liver function was observed. CONCLUSIONS: Ceftobiprole, even outside current indications, may be a safe and effective treatment for resistant Gram-positive cocci infections where other drugs are inactive or poorly tolerated, and for salvage therapy.

Treatment Outcomes of Colistin- and Carbapenem-resistant Acinetobacter baumannii Infections: An Exploratory Subgroup Analysis of a Randomized Clinical Trial.

BACKGROUND: We evaluated the association between mortality and colistin resistance in Acinetobacter baumannii infections and the interaction with antibiotic therapy. METHODS: This is a secondary analysis of a randomized controlled trial of patients with carbapenem-resistant gram-negative bacterial infections treated with colistin or colistin-meropenem combination. We evaluated patients with infection caused by carbapenem-resistant A. baumannii (CRAB) identified as colistin susceptible (CoS) at the time of treatment and compared patients in which the isolate was confirmed as CoS with those whose isolates were retrospectively identified as colistin resistant (CoR) when tested by broth microdilution (BMD). The primary outcome was 28-day mortality. RESULTS: Data were available for 266 patients (214 CoS and 52 CoR isolates). Patients with CoR isolates had higher baseline functional capacity and lower rates of mechanical ventilation than patients with CoS isolates. All-cause 28-day mortality was 42.3% (22/52) among patients with CoR strains and 52.8% (113/214) among patients with CoS isolates (P = .174). After adjusting for variables associated with mortality, the mortality rate was lower among patients with CoR isolates (odds ratio [OR], 0.285 [95% confidence interval {CI}, .118-.686]). This difference was associated with treatment arm: Mortality rates among patients with CoR isolates were higher in those randomized to colistin-meropenem combination therapy compared to colistin monotherapy (OR, 3.065 [95% CI, 1.021-9.202]). CONCLUSIONS: Colistin resistance determined by BMD was associated with lower mortality among patients with severe CRAB infections. Among patients with CoR isolates, colistin monotherapy was associated with a better outcome compared to colistin-meropenem combination therapy. CLINICAL TRIALS REGISTRATION: NCT01732250.