Comparison of Doxycycline or Minocycline to Sulfamethoxazole-Trimethoprim for Treatment of Stenotrophomonas maltophilia Pneumonia.

BACKGROUND: Stenotrophomonas maltophilia is a multidrug-resistant organism with limited antibiotic treatment options. Minocycline and doxycycline may be appropriate, but clinical data are limited. OBJECTIVE: To compare tetracyclines (minocycline and doxycycline [TCN]) with standard of care, sulfamethoxazole-trimethoprim (TMP-SMZ), in S. maltophilia pneumonia treatment. METHODS: This retrospective, 2-center study evaluated patients treated for S. maltophilia pneumonia with TCN or TMP-SMZ for clinical success, defined as resolution of leukocytosis, fever, and tachypnea. Patients were classified as treatment with TCN or TMP-SMZ based on definitive agent used for ≥50% of the treatment course and ≥4 days. Inclusion criteria were age ≥18 years, S. maltophilia confirmed on respiratory culture from January 2013 to November 2020, and appropriate definitive antibiotic dosing. Pregnancy, incarceration, S. maltophilia-resistant or intermediate to definitive therapy, and combination therapy for treatment of S. maltophilia pneumonia were exclusion criteria. Secondary outcomes were microbiologic success and recurrence or reinfection within 30 days requiring treatment. RESULTS: A total of 80 patients were included (21 TCN [15 minocycline, 6 doxycycline], 59 TMP-SMZ). There was no difference in clinical success (28.6% vs 25.4%; P = 0.994), microbiologic success (n = 28, 55.6% vs 66.4%; P = 0.677), or recurrence or reinfection (n = 24, 66.7% vs 26.7%; P = 0.092) between TCN and TMP-SMZ, respectively. CONCLUSION AND RELEVANCE: Clinical and microbiologic success rates were similar in patients treated with TCN compared with TMP-SMZ for S. maltophilia pneumonia. These data suggest minocycline and doxycycline may be options to treat S. maltophilia pneumonia, but conclusive clinical data continue to be lacking.

Cefepime Population Pharmacokinetics and Target Attainment in Critically Ill Patients on Continuous Renal Replacement Therapy.

Sepsis causes half of acute kidney injuries in the intensive care unit (ICU). ICU patients may need continuous renal replacement therapy (CRRT), which will affect their antimicrobial exposure. We aimed to build a cefepime population pharmacokinetic (PK) model in CRRT ICU patients and perform simulations to assess target attainment. Patients who were ≥18 years old, were admitted to the ICU, and received cefepime 2 g every 8 h as a 4-h infusion while on CRRT were enrolled prospectively. Samples were collected from the predialyzer ports, postdialyzer ports, and effluent fluid at 1, 2, 3, 4, and 8 h after the first dose and at steady state. Age, sex, weight, urine output, and CRRT parameters were recorded. Pmetrics was used for population PK and simulations. The target exposure was 100% of the dosing interval during which the free beta-lactam concentration is above the MIC (fT>MIC). Ten patients were included; their mean age was 53 years, and mean weight was 119 kg. Seventy percent were males. Cefepime was described by a five-compartment model. The downtime was applied to the CRRT flow rates, which were used to describe the rates of transfer between the compartments. At MICs of ≤8 mg/liter, intermittent infusion of 2 g cefepime every 8 h achieved good target attainment both early in therapy and at steady state. Only extended- and continuous-infusion regimens achieved good target attainment at MICs of 16 mg/liter. In conclusion, 2 g cefepime infused over 30 min followed by extended infusion of 2 g every 8 h achieved good target attainment at MICs of ≤16 mg/liter with different CRRT flow rates and may be considered in resistant bacterial infections.

Pharmacokinetics and Pharmacodynamics of Extended-Infusion Cefepime in Critically Ill Patients Receiving Continuous Renal Replacement Therapy: A Prospective, Open-Label Study.

STUDY OBJECTIVE: To evaluate extended-infusion (EI) cefepime pharmacokinetics (PK) and pharmacodynamic target attainment in critically ill patients receiving continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodialysis (CVVHD). DESIGN: Prospective, open-label, PK study. SETTING: Intensive care units at a large, academic, tertiary-care medical center. PATIENTS: Ten critically ill adults who were receiving cefepime 2 g intravenously every 8 hours as a 4-hour infusion while receiving CVVH (eight patients) or CVVHD (two patients). INTERVENTION: Two sets of five serum cefepime concentrations were collected for each patient to assess pharmacokinetics before and during presumed steady state. Concurrent serum and CRRT effluent samples were collected at hours 1, 2, 3, 4, and 8 after the first cefepime dose and after either the fourth, fifth, or sixth (steady-state) cefepime doses. MEASUREMENTS AND MAIN RESULTS: Reversed-phase high-performance liquid chromatography was used to determine free cefepime concentrations. PK analyses included CRRT clearance, half-life, and sieving coefficient or saturation coefficient. Cefepime peak (4 hrs) concentrations, trough (8 hrs) concentrations (Cmin ), and minimum inhibitory concentration breakpoint of 8 µg/ml for the pathogen (MIC8 ) were used to evaluate attainment of pharmacodynamic targets: 100% of the dosing interval that free drug remains above MIC8 (100% fT > MIC8 ), 100% fT > 4 × MIC8 (optimal), percentage of time fT > 4 × MIC8 (%fT > 4 × MIC8 ) at steady state, and ratio of Cmin to MIC8 (fCmin /MIC8 ). Total CRRT effluent flow rate was a mean ± SD of 30.1 ± 5.4 ml/kg/hr, CRRT clearance was 39.6 ± 9.9 ml/min, and half-life was 5.3 ± 1.7 hours. Sieving coefficient or saturation coefficient were 0.83 ± 0.13 and 0.69 ± 0.22, respectively. First and steady-state dose Cmin were 23.4 ± 10.1 µg/ml and 45.2 ± 14.6 µg/ml, respectively. All patients achieved 100% fT > MIC8 on first and steady-state doses. First and steady-state dose 100% fT > 4 × MIC8 were achieved in 22% (2/9 patients) and 87.5% (7/8 patients) of patients, respectively. The mean %fT > 4 × MIC8 at steady state was 97.5%. The fCmin /MIC8 was 2.92 ± 1.26 for the first dose and 5.65 ± 1.83 at steady state. CONCLUSION: Extended-infusion cefepime dosing in critically ill patients receiving CRRT successfully attained 100% fT > MIC8 in all patients and an appropriate fCmin /MIC8 for both first and steady-state doses. All but one patient achieved 100% fT > 4 × MIC8 at steady state. No significant differences were observed in PK properties between first and steady-state doses among or between patients. It may be reasonable to initiate an empiric or definitive regimen of EI cefepime in critically ill patients receiving concurrent CRRT who are at risk for resistant organisms. Further research is needed to identify the optimal dosing regimen of EI cefepime in this patient population.

Impact of Early Sodium Supplementation on Hyponatremia and Growth in Premature Infants: A Randomized Controlled Trial.

BACKGROUND: We tested the hypothesis that sodium supplementation in early preterm infants prevents late-onset hyponatremia and improves growth without increasing common morbidities during birth hospitalization. MATERIALS AND METHODS: This was a randomized, masked controlled trial of 4 mEq/kg/d of sodium (intervention) versus sterile water (placebo) from days-of-life 7 to 35 in infants born at <32 weeks corrected gestational age. The primary outcome was weight gain in the first 6 weeks of life. Secondary outcomes included weekly serum sodium concentrations, growth in body length and head circumference, and complications of prematurity during birth hospitalization. RESULTS: Fifty-three infants with an average corrected gestational age of 28.5 ± 2.4 weeks were randomized. Infants receiving the intervention had fewer (P = .012) reports of serum sodium concentrations <135 mmol/L and greater velocity of weight gain during the study period, mean (SD) 26.9 (3.1) vs 22.9 (4.7) g/kg/day, P = .012. At 6 weeks of age, infants <28 weeks' gestation who received sodium supplementation had greater percentage weight change from birth, mean (SD) 193% (22%) vs 173% (10%), P = .041, and maintained fetal reference birth percentile for body weight more often (P = .002) compared with infants receiving placebo. Growth in length and head circumference was not significantly different between study arms. No increase in common prematurity-related morbidities was detected in infants who received supplemental sodium chloride. CONCLUSION: Sodium supplementation of enteral feedings in very premature infants averts hyponatremia and enhances weight gain.

Evaluation of a clinical pathway for ventilator-associated pneumonia: changes in bacterial flora and the adequacy of empiric antibiotics over a three-year period.

BACKGROUND: Evaluation of causative pathogens is vital for optimizing empiric antibiotic therapy of ventilator-associated pneumonia (VAP). Based on previous data (Ann Surg 1998;227:743-755), empiric antibiotics for our VAP clinical pathway were modified to target early and late occurring pathogens (ampicillin/sulbactam during the first week of hospitalization; cefepime plus vancomycin afterwards). The objectives of this study were to compare organisms causing VAP over a three-year period to previous data, and to determine the adequacy of the empiric antibiotic regimens. METHODS: A total of 299 critically ill trauma patients with VAP over a three-year period were studied retrospectively. The incidence of pathogens causing VAP in the study period were compared to a previously published study of a two-year period in our intensive care unit (ICU). Sensitivities of Pseudomonas aeruginosa and Acinetobacter baumannii were evaluated over the study period. The adequacy of empiric antibiotic therapy for each episode of VAP was determined. Therapy was considered to be adequate if one or more antibiotics had in vitro activity against the organism causing VAP. RESULTS: Statistically significant changes in pathogens included increased Staphylococcus aureus (incidence 17% vs. 11%, p = 0.024) and decreased Acinetobacter baumannii (11% vs. 22%, p < 0.001). Susceptibility patterns were statistically unchanged except for increased resistance of P. aeruginosa to extended-spectrum penicillins (p = 0.016). Empiric therapy was adequate in 76% of VAP episodes. CONCLUSIONS: The clinical pathway's empiric antibiotic regimen was associated with only modest changes in organisms causing VAP and provided a high rate of adequate empiric coverage.