Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii-calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK).

BACKGROUND: An urgent need exists for antibiotics to treat infections caused by carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (ABC). Sulbactam-durlobactam is a ß-lactam-ß-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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Entasis Therapeutics and Zai Lab.

Should Therapeutic Drug Monitoring Based on the Vancomycin Area Under the Concentration-Time Curve Be Standard for Serious Methicillin-Resistant Staphylococcus aureus Infections?-No.

In this counterpoint we critically appraise the evidence supporting therapeutic drug monitoring based on the vancomycin 24-hour area under the concentration-time curve (AUC24) for serious methicillin-resistant Staphylococcus aureus infections. We reveal methodologically weaknesses and inconsistencies in the data and suggest that, in the absence of clear and convincing evidence of benefit compared with modestly reducing trough targets, alternative strategies are more likely to result in superior safety and efficacy. These include focusing on fundamental antibiotic stewardship to limit vancomycin exposure overall, achieving earlier and more complete source control, and establishing alternative therapeutic options to vancomycin. Implementation of AUC24-based therapeutic drug monitoring will take resources away from these more promising, alternative solutions.

Secular trends in Acinetobacter baumannii resistance in respiratory and blood stream specimens in the United States, 2003 to 2012: A survey study.

BACKGROUND: Acinetobacter baumannii (AB) has evolved a variety of resistance mechanisms and exhibits unpredictable susceptibility patterns, making it difficult to select empiric therapy. OBJECTIVE: To examine US secular trends in the resistance of AB in respiratory infections and blood stream infections (BSI) to antimicrobial agents whose effectiveness is supported in the literature DESIGN: Survey. METHODS: We analyzed 3 time periods (2003-2005, 2006-2008, 2009-2012) in Eurofins' The Surveillance Network for resistance of AB to the following antimicrobials: carbapenems (imipenem, meropenem, doripenem), aminoglycosides (tobramycin, amikacin), tetracyclines (minocycline, doxycycline), polymyxins (colistin, polymyxin B), ampicillin-sulbactam, and trimethoprim-sulfamethoxazole. Resistance to ≥3 drug classes defined multidrug resistance (MDR). RESULTS: We identified 39,320 AB specimens (81.1% respiratory, 18.9% BSI). The highest prevalence of resistance was to doripenem (90.3%) followed by trimethoprim-sulfamethoxazole (55.3%), and the lowest to colistin (5.3%). Resistance to carbapenems (21.0% in 2003-2005 and 47.9% in 2009-2012) and colistin (2.8% in 2006-2008 to 6.9% in 2009-2012) more than doubled. Prevalence of MDR AB rose from 21.4% in 2003 to 2005 to 33.7% in 2006 to 2008, and remained stable at 35.2% in 2009 to 2012. In contrast, resistance to minocycline diminished from 56.5% (2003-2005) to 30.5% (2009-2012). MDR organisms were most frequent in nursing homes (46.5%), followed by general ward (29.2%), intensive care unit (28.7%), and outpatient setting (26.2%). CONCLUSIONS: Resistance rates among AB to such last-resort antimicrobials as carbapenems and colistin are on the rise, whereas that to minocycline has declined. Nursing homes are a reservoir of resistant AB. These trends should inform not only empiric treatment of serious infections, but also approaches to infection control.

The role of telavancin in hospital-acquired pneumonia and ventilator-associated pneumonia.

Hospital-acquired pneumonia (HAP) due to gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major cause of morbid conditions and death. Telavancin is a lipoglycopeptide antibiotic with potent in vitro activity against a range of gram-positive pathogens, including MRSA, methicillin-susceptible S. aureus, and Streptococcus species. In 2 phase 3 clinical trials, telavancin was noninferior to vancomycin in patients with HAP due to gram-positive pathogens. Clinically evaluable patients with S. aureus as the sole pathogen or S. aureus with a vancomycin minimum inhibitory concentration >1 µg/mL, however, had higher cure rates with telavancin than with vancomycin. In patients with bacteremic HAP, telavancin resulted in clearance of blood cultures. It was associated with increased serum creatinine levels and higher mortality rates in patients with moderate to severe renal impairment at baseline; however, on subsequent analysis, the outcomes seemed to have been at least partially affected by the adequacy of empiric gram-negative antimicrobial therapy. Thus, clinicians need to consider the risk-benefit balance when choosing telavancin in patients with severe renal impairment at baseline. Overall, these data support the use of telavancin in the treatment of HAP due to S. aureus, including MRSA and strains with elevated vancomycin minimum inhibitory concentrations, but clinicians should always weigh the risks and benefits of various treatment options.

Using the number needed to treat to assess appropriate antimicrobial therapy as a determinant of outcome in severe sepsis and septic shock.

OBJECTIVE: To assess appropriate antimicrobial therapy as an outcome determinant in severe sepsis and septic shock using the number needed to treat. DESIGN: Single-center cohort study (January 2008 to December 2012). SETTING: One thousand two hundred fifty-bed academic hospital. PATIENTS: Two thousand five hundred ninety-four patients with positive blood culture. INTERVENTIONS: We retrospectively identified patients with severe sepsis or septic shock. Inappropriate antimicrobial treatment was defined as an antimicrobial regimen that lacked in vitro activity against the isolated pathogen. Information regarding demographics, severity of illness, comorbidities, microbiology, and antimicrobial treatment was recorded. Logistic regression was used to identify risk factors for hospital mortality and inappropriate treatment. MEASUREMENTS AND MAIN RESULTS: Seven hundred eighty-seven patients (30.3%) were nonsurvivors. Inappropriate antimicrobial treatment had the greatest adjusted odds ratio for hospital mortality (adjusted odds ratio, 3.4; 95% CI, 2.8-4.1; p < 0.001). Multivariate logistic regression analysis identified resistance to cefepime, resistance to meropenem, presence of multidrug resistance, nonabdominal surgery, and prior antibiotic use as being independently associated with the administration of inappropriate antimicrobial treatment. For the entire cohort, the number needed to treat with appropriate antimicrobial therapy to prevent one patient death was 4.0 (95% CI, 3.7-4.3). The prevalence-adjusted pathogen-specific number needed to treat (PNNT) with appropriate antimicrobial therapy to prevent one patient death was lowest for multidrug-resistant bacteria (PNNT = 20) followed by Candida species (PNNT = 34), methicillin-resistant Staphylococcus aureus (PNNT = 38), Pseudomonas aeruginosa (PNNT = 38), Escherichia coli (PNNT = 40), and methicillin-susceptible S. aureus (PNNT = 47). CONCLUSIONS: Our results support the importance of appropriate antimicrobial treatment as a determinant of outcome in patients with severe sepsis and septic shock. Our analyses suggest that improved targeting of empiric antimicrobials for multidrug-resistant bacteria, Candida species, methicillin-resistant S. aureus, and P. aeruginosa would have the greatest impact in reducing mortality from inappropriate antimicrobial treatment in patients with severe sepsis and septic shock.

Assessment of ceftaroline fosamil in the treatment of community-acquired bacterial pneumonia due to Streptococcus pneumoniae: insights from two randomized trials.

Ceftaroline fosamil resulted in higher cure rates than ceftriaxone in patients with community-acquired bacterial pneumonia in 2 randomized trials (FOCUS 1 and FOCUS 2). The present analysis examines the subgroup of patients with Streptococcus pneumoniae infection to determine whether the apparent difference in cure rates persists after adjusting for potential covariates. We retrospectively pooled subjects with S. pneumoniae isolated at baseline in the original studies and employed logistic regression to evaluate the independent relationship between clinical cure and treatment with ceftaroline. Covariates evaluated included demographics, severity of illness, bacteremia, and pathogen characteristics. The final cohort included 139 subjects (69 ceftaroline, 70 ceftriaxone). Unadjusted cure rates were 85.5% and 68.6% (P = 0.009) in the ceftaroline and ceftriaxone groups, respectively. After logistic regression, ceftaroline remained associated with higher cure rates. Our findings indicate that ceftaroline may result in improved outcomes of S. pneumoniae pneumonia. Formal clinical trials are warranted to confirm this hypothesis.

Impact of vancomycin minimum inhibitory concentration on mortality among critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia.

We retrospectively evaluated 99 intensive care unit patients with methicillin-resistant Staphylococcus aureus bacteremia to determine whether having a vancomycin minimum inhibitory concentration (MIC) of 2 mg/L affected mortality. This MIC was found in 5.1% of patients and was associated with the probability of death (adjusted odds ratio, 13.9 [95% confidence interval, 1.1-171.2]) independent of other factors.

The adequacy of timely empiric antibiotic therapy for ventilator-associated pneumonia: an important determinant of outcome.

OBJECTIVE: The individual impact of timeliness vs adequacy of empiric antibiotic therapy for a clinical suspicion of ventilator-associated pneumonia (CSVAP) is unknown. Accordingly, in patients with CSVAP and timely initiation of empiric antibiotic therapy, we determined the impact of inadequate therapy (IT). METHODS: Analysis of a randomized trial of CSVAP treated empirically with meropenem or meropenem plus ciprofloxacin was done. Adequate therapy (AT) was considered present if all pathogens in the index culture were sensitive to the empiric antibiotics; IT was defined as the presence of pathogens resistant to the empiric antibiotics. A priori, for Pseudomonas sp, 2 antibiotics with activity against the organisms were required for AT to be considered present. RESULTS: Of 739 patients with CSVAP, 350 had positive cultures: 313 (89.4%) had AT, and 37 (10.6%), IT. The IT group had higher intensive care unit (35.1% vs 11.8%, P = .0001) and hospital mortalities (48.7% vs 19.5%, P < .0001), increased mechanical ventilation (15.8 vs 6.8 days, P = .0005), intensive care unit stay (13.5 vs 8.4 days, P = .02), and hospital stay (42.2 vs 27.9 days, P = .04). In multivariate analysis and a separate case control analysis, the odds ratio of hospital mortality with IT was 3.05 (95% confidence interval, 1.25-7.45; P = .01) and 3.00 (95% confidence interval, 1.24-7.24; P = .01), respectively. CONCLUSION: In the context of early administration of empiric broad spectrum antibiotics for CSVAP, IT is associated with higher morbidity and mortality.

Inappropriate antibiotic therapy in Gram-negative sepsis increases hospital length of stay.

OBJECTIVES: To describe the impact of initially inappropriate antibiotic therapy on hospital length of stay in Gram-negative severe sepsis and septic shock. DESIGN: Retrospective cohort. SETTING: Academic urban hospital. PATIENTS: Patients with Gram-negative bacteremia (primary or secondary, nosocomial or non-nosocomial) and severe sepsis or septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We defined initially inappropriate antibiotic therapy as occurring when the patient either was not administered an antibiotic within 24 hrs of sepsis onset or was treated with an antibiotic to which the culprit pathogen was resistant in vitro. The cohort included 760 subjects (mean age 59.3 ± 16.3 yrs, mean Acute Physiology and Chronic Health Evaluation II score 23.7 ± 6.7). More than half of infections were nosocomial (55.1%), and Escherichia coli represented the most common pathogen (n = 225). Pseudomonas species were isolated in 17.4% of patients. Nearly one-third of patients (31.3%) received initially inappropriate antibiotic therapy. Patients administered initially inappropriate antibiotic therapy were more likely to have a nosocomial infection, to have underlying cancer or diabetes or both, to require chronic hemodialysis, and to undergo mechanical ventilation. Those administered initially inappropriate antibiotic therapy also faced higher inhospital mortality. The unadjusted median length of stay after sepsis onset in those administered initially inappropriate antibiotic therapy was 11 days compared to 9 days in those treated appropriately (p = .028 by log-rank test). In a Cox model controlling for the multiple confounders noted, initially inappropriate antibiotic therapy independently correlated with continued hospitalization (adjusted hazard ratio 1.19, 95% confidence interval 1.01-1.40, p = .044). Adjusting for these covariates indicated that initially inappropriate antibiotic therapy independently increased the median attributable length of stay by 2 days. CONCLUSIONS: Initially inappropriate antibiotic therapy occurs in one-third of persons with severe sepsis and septic shock attributable to Gram-negative organisms. Beyond its impact on mortality, initially inappropriate antibiotic therapy is significantly associated with length of stay in this population. Efforts to decrease rates of initially inappropriate antibiotic therapy may serve to improve hospital resource use by leading to shorter overall hospital stays.

Correlates of clinical failure in ventilator-associated pneumonia: insights from a large, randomized trial.

PURPOSE: Our objective was to determine clinical variables measured at baseline and day 3 that may relate to failure of resolution of ventilator-associated pneumonia (VAP). MATERIALS AND METHODS: In patients with confirmed VAP derived from a large, randomized controlled trial comparing different modalities for the diagnosis and treatment of VAP, we identified risk factors associated with clinical failure. Clinical failure was prospectively defined in this trial as death, persistence of clinical and radiographic features of infection throughout the study period requiring additional antibiotics, superinfection, or relapsing infection. We examined the relationship between VAP resolution and clinical characteristics measured both at study enrollment and at day 3. We used logistic regression to identify independent factors associated with clinical failure and conducted a sensitivity analysis focusing only on patients who met the definition for clinical failure but who nonetheless survived until day 28. RESULTS: Of 563 subjects with VAP, 179 (31.8%) were classified as clinical failures. Death was the most common reason for clinical failure. At baseline, clinical failure patients were older, more severely ill, had been on mechanical ventilation for a longer period, and had higher Clinical Pulmonary Infection Score values and lower Pao2/Fio2 ratios. By day 3, patients defined as clinical failures remained more severely ill and continued to have worse oxygenation. In multivariate analysis, 4 factors were independently associated with clinical failure: older age, duration of ventilation before enrollment, presence of neurologic disease at admission, and failure of the Pao2/Fio2 ratio to improve by day 3. Repeating this multivariable model in only surviving patients suggested that persistence of fever was the only variable associated with clinical failure. CONCLUSIONS: Clinical characteristics correlate with eventual outcomes in VAP. Failure of the Pao2/Fio2 ratio and fever to improve are independently associated with clinical failure. We suggest that clinicians follow these measures and consider integrating them in their decisions as to when to reevaluate persons with VAP who are not improving.

Quinolones for treatment of nosocomial pneumonia: a meta-analysis.

Although quinolones are often used to treat nosocomial pneumonia (NP), there have been few trials documenting their efficacy in treating NP. Given the growing use of quinolones and issues regarding resistance, we conducted a meta-analysis of all trials of quinolones for treatment of NP. We identified 5 randomized trials comparing quinolones with other agents used to treat NP. The studies varied in both quality and sample size and included a total of nearly 1200 subjects. Four of the 5 trials used ciprofloxacin, administered every 8 h, whereas the fifth used levofloxacin administered daily. In 3 trials, the comparator agent was imipenem-cilistatin, whereas, in 2 trials, ceftazadime was the comparator agent. The efficacy of quinolones and comparator antibiotics was similar, with a pooled odds ratio for clinical cure of 1.12 (95% confidence interval, 0.80-1.55). Neither microbiological eradication rates nor mortality rates varied on the basis of antimicrobial selection.