Population pharmacokinetics and pharmacodynamics of cefazolin using total and unbound serum concentrations in patients with high body weight.

The objective of this study was to evaluate the steady state pharmacokinetics and pharmacodynamics of cefazolin in patients with a high body weight. Cefazolin was administered by 0.5-h infusions to 11 patients with total body weight (TBW) ≥120 kg receiving 3 g q8h, and 12 patients with TBW <120 kg receiving 2 g q8h. Total and unbound serum concentration-time data obtained from serial blood samples were analysed simultaneously by population pharmacokinetic modelling using NONMEM. Probability of target attainment (PTA) was calculated for various dosing regimens through Monte Carlo simulations based on the cumulative percentage of the dosing interval that the unbound concentration exceeds the minimum inhibitory concentration (MIC) value for the pathogen at steady state (fTMIC) ≥40%, ≥60% and 100%. A two-compartment model with non-linear protein binding and allometric scaling of the central volume of distribution using TBW best characterized both total and unbound concentration-time data. Unbound clearance was significantly associated with creatinine clearance, and maximum protein binding constant was significantly associated with serum albumin concentration and body mass index (P <0.05). Based on unbound concentration-time profiles, all simulated regimens achieved PTA >90% at MIC values ≤2 mg/L using fTMIC ≥40%, at MIC values ≤1 mg/L using fTMIC ≥60%, and at MIC values ≤0.5 mg/L using fTMIC of 100%. At fTMIC ≥60%, 0.5-h infusion of cefazolin 1 g q8h achieved PTA <90% at MIC values ≥2 mg/L in patients with TBW≥120 kg; however, prolonged-infusion and higher-dose regimens improved PTA to >90%. Overall, cefazolin pharmacokinetics are altered considerably in obese patients. Higher-dose and/or prolonged-infusion cefazolin regimens should be considered in patients with TBW ≥120 kg, particularly those with less-susceptible Gram-negative infections.

Interplay of Immunosuppression and Immunotherapy Among Patients With Cancer and COVID-19.

Importance: Cytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation. Objective: To determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer. Design, Setting, and Participants: This registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings. Exposures: Immunosuppression due to therapy; systemic anticancer therapy (IO or non-IO). Main Outcomes and Measures: The primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm. Results: The median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79). Conclusions and Relevance: This cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm. Trial Registration: ClinicalTrials.gov Identifier: NCT04354701.