Is Renal-Adjusted Ceftazidime/Avibactam in Patients With KPC-Producing Klebsiella Pneumoniae Bloodstream Infection Associated With Increased Mortality?
Image credit: Adobe stock
Carbapenem-resistant Enterobacterales (CRE) are gram-negative bacteria resistant to at least 1 carbapenem. Although CRE isolates can pass multiple mechanisms of resistance, a recent cohort of 261 clinical CRE isolates (defined as resistant to meropenem or imipenem) from 2019 to 2021 in the United States found that of isolates that were carbapenemase producing, 80% expressed Klebsiella pneumoniae carbapenemase (KPC).1 For CRE infections outside of the urinary tract, ceftazidime/avibactam is currently recommended as a firstline agent by the most recent Infectious Diseases Society of America Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections.1 In patients with renal dysfunction, dose reduction in renally cleared medications aims to minimize the risk of toxicity without impairing efficacy in the setting of reduced drug clearance. In the setting of critical illness, patient-specific pharmacokinetics/pharmacodynamics can become difficult to predict, with changes ranging from hyperdynamic renal clearance to acute kidney injury (AKI). As a result, serum creatinine may not be a true reflection of renal function among patients undergoing rapid changes in renal function.2,3
A recent meta-analysis by Gatti et al suggested that renally adjusting ceftazidime/avibactam for carbapenem-resistant gram-negative infections may be associated with greater mortality.4 However, this meta-analysis was limited by heterogeneity in mechanism of resistance and inconsistency in reported etiology of renal dysfunction. Given these previous findings, Oliva and colleagues conducted a retrospective single-center study to further explore the impact of renal adjustment of ceftazidime/avibactam on mortality in K pneumoniae bacteremia. This study analyzed adults with KPC-producing K pneumoniae treated with a ceftazidime/avibactam based regimen between 2018 and 2021. Patients were excluded if they received ceftazidime/avibactam for less than 48 hours, had carbapenem resistance due to a mechanism other than KPC, or had a polymicrobial bloodstream infection. The primary outcome was mortality at 7, 14, and 30 days after the start of ceftazidime/avibactam definitive therapy. In addition, clinical cure was assessed, defined as the resolution of symptoms after the end of antibiotic treatment. Finally, a subgroup analysis compared patients with AKI with those with chronic kidney disease (CKD) to control for the impact of worsening renal function on infection outcome. Using estimated glomerular filtration rate calculated via the CKD-EPI equation, patients were stratified into 2 groups: patients who received renally unadjusted ceftazidime/avibactam and those who received renally adjusted ceftazidime/avibactam. Dose adjustments for renal dysfunction were in accordance with the package insert. Overall, the study included 110 adults with 82 receiving full-dose (75%) and 28 (25%) receiving renally adjusted ceftazidime/avibactam. Both cohorts had a similar proportion of patients in the intensive care unit (30.9%) or with septic shock (25.5%) at the time of bacteremia onset. Both groups were well matched in terms of nonrenal comorbidities, with overall 10.9% with chronic liver disease and 25.5% being classified as immunodeficient.
However, patients who required dose adjustment were more likely to have baseline CKD (64.4% vs 18.3%) and require hemodialysis (17.9% vs 0%). As a result, patients who received renal dose adjustment had a higher Charlson Comorbidity Index (CCI) score of 8.0 (IQR, 6.0-10.8) compared with 6.0 (IQR, 5.0-7.3) for patients who did not require dose adjustment. There was no significant difference in Pitt Bacteraemia Scores between both arms. However, patients who received a renal dose reduction had a higher median increment-clinical progression evaluation (CPE) score of 8 (IQR, 6-11) vs 6 (IQR, 3-8), indicating a greater risk of CRE-related mortality. Overall, there was no difference in treatment regimens between groups, with the majority of patients receiving combination therapy, intravenous fosfomycin (41.8%) or meropenem (39.1%) being the most common combination agents. Only 11.8% of patients received ceftazidime/avibactam monotherapy. The overall rate of clinical cure and development of resistance was similar between both groups. There was significantly reduced survival in patients who received renal dose adjustment (P = .006), with mortality over time summarized in the TABLE.
A multivariate analysis evaluating risk factors for 30-day mortality found that dose reduction was independently associated with increased mortality (HR, 4.47; 95% CI, 1.09-18.03; P = .037). However, after excluding patients with CKD from the multivariate analysis, renal dose reduction was no longer associated with increased 30-day mortality (HR, 4.07; 95% CI, 0.5927.74; P = .152). After excluding patients with AKI (including those receiving a reduced dosage of ceftazidime/avibactam due to CKD), there was also no association with mortality (HR, 5.16; 95% CI, 0.87-30.56; P = .071). In addition, this multivariate analysis also found that septic shock, COVID-19 coinfection, and source of bacteremia of either pneumonia or intra-abdominal infections were predictors of 30-day mortality. These results suggest that renal dose reduction of ceftazidime/avibactam may be associated with a higher risk of mortality, with the authors concluding that given the cohorts of patients were reasonably well matched in terms of severity of illness and nonrenal commodities, renal dose adjustment may not provide adequate drug exposure in patients, potentially driving mortality differences. However, if drug exposure was inadequate in the renally adjusted cohort, it is incongruous with the similarly low rates of the development of resistance between groups as well as the similar rates of clinical cure. Furthermore, in the absence of therapeutic drug monitoring, it was not possible to verify whether renal dose adjustment correlated to underexposure. With this in mind, another possible factor influencing the disparity in mortality is that the renal adjustment group had significantly greater CCI and increment-CPE scores at baseline. Given these limitations, further studies, namely prospective randomized trials with larger sample sizes, are needed to explore this phenomenon.
