Higher MICs (>2 mg/L) Predict 30-Day Mortality in Patients With Lower Respiratory Tract Infections Caused by Multidrug- and Extensively Drug-Resistant Pseudomonas aeruginosa Treated With Ceftolozane/Tazobactam

Abstract

BackgroundCeftolozane/tazobactam (C/T) efficacy and safety in ventilator-associated pneumonia (VAP) is being evaluated at a double dose by several trials. This dosing is based on a pharmacokinetic (PK) model that demonstrated that 3 g q8h achieved ≥90% probability of target attainment (50% ƒT > minimal inhibitory concentration [MIC]) in plasma and epithelial lining fluid against C/T-susceptible P. aeruginosa. The aim of this study was to evaluate the efficacy of different C/T doses in patients with lower respiratory infection (LRI) due to MDR- or XDR-P. aeruginosa considering the C/T MIC.MethodsThis was a multicenter retrospective study of 90 patients with LRI caused by resistant P. aeruginosa who received a standard or high dose (HDo) of C/T. Univariable and multivariable analyses were performed to identify independent predictors of 30-day mortality.ResultsThe median age (interquartile range) was 65 (51–74) years. Sixty-three (70%) patients had pneumonia, and 27 (30%) had tracheobronchitis. Thirty-three (36.7%) were ventilator-associated respiratory infections. The median C/T MIC (range) was 2 (0.5–4) mg/L. Fifty-four (60%) patients received HDo. Thirty-day mortality was 27.8% (25/90). Mortality was significantly lower in patients with P. aeruginosa strains with MIC ≤2 mg/L and receiving HDo compared with the groups with the same or higher MIC and dosage (16.2% vs 35.8%; P = .041). Multivariate analysis identified septic shock (P < .001), C/T MIC >2 mg/L (P = .045), and increasing Charlson Comorbidity Index (P = .019) as independent predictors of mortality.ConclusionsThe effectiveness of C/T in P. aeruginosa LRI was associated with an MIC ≤2 mg/L, and the lowest mortality was observed when HDo was administered for strains with C/T MIC ≤2 mg/L. HDo was not statistically associated with a better outcome.

Pulmonary infections complicating ARDS

“…Similar worrisome trends for bacterial susceptibility to available antimicrobials have been reported by other investigators as well [ 60 , 61 ]. Most worrisome is the increasingly recognized presence of resistance to new antibiotics specifically developed to treat VAP [ 62 ].

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High minimum inhibitory concentrations among derepressed AmpC-beta-lactamase–producing Enterobacter cloacae complex isolates for ceftolozane with tazobactam

“…Third, high inactivation of C/T by derepressed AmpC organisms justifies strict monitoring of its resistance level in both Enterobacterales and Pseudomonas, particularly those associated with poor outcomes when high MICs (>2 g/mL) are observed. 10 In conclusion, in this study, we identified a mechanism that seems to be predictive of high C/T resistance levels. More prominent among bacteria that are capable of derepressing AmpC β-lactamases, mainly the E. cloacae complex (but also Pseudomonas on a minor scale), this resistance to C/T should lead to stricter use and monitoring of this drug.…”

“…Some other points should also be considered. First, C/T was primarily designed to treat Pseudomonas infections, and because this bacterium is highly susceptible to this drug, 10 it is reasonable to conclude that Pseudomonas usually does not derepress chromosomal AmpC enzymes, even those with an extensively drug-resistant phenotype. Second, C/T is an inappropriate drug for use in empirical therapeutic approaches; it should be preserved for the specific niche for Pseudomonas infection.…”

Real-world Use of Ceftolozane/tazobactam: a Systematic Literature Review

“…Including studies that recruited patients from multiple countries, the most common study locations were the US (N = 50), (21, 22, 24, 27-29, 33, 34, 39-41, 43-45, 50, 51, 54, 56, 57, 59, 61, 62, 68-71, 73-77, 79-85, 87-92, 94, 95, 97-100) Spain (N = 15), (26, 28, 30-32, 35-37, 42, 47, 49, 58, 66, 79, 96) and Italy (N = 13). (18,20,23,25,48,52,53,55,64,67,72,79,86) A variety of study designs were captured: 27 were non-comparative retrospective studies, (18,19,22,24,25,28,32,33,40,41,79,81,(84)(85)(86)(87)(88)(89)(90)(91)(92)(94)(95)(96)(97)(98)(99) 14 were case series, (20, 21, 29, 31, 34-39, 42, 43, 82, 100) ve were comparative (including two cohort studies, (80,83) and three case-control studies, (23,…”

“…Five studies found mixed evidence that a delay in receipt of C/T led to worse outcomes. (18,28,30,33,39) Bassetti et al 2020 found that a signi cantly higher proportion of patients who achieved clinical success received empiric C/T and had a signi cantly shorter latency between infection onset and C/T administration (both p < 0.001). (18) Similarly, Gallagher et al 2018 found that starting C/T less than four days after positive culture was associated with signi cantly higher clinical and microbiological cure rates, and that starting C/T more than four days after positive culture was associated with signi cantly higher mortality.…”