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.

Clinical Experience, Characteristics, and Performance of an Acetaminophen Absorption Test in Critically Ill Patients.

BACKGROUND: Altered drug and nutrient absorption presents a unique challenge in critically ill patients. Performing an acetaminophen absorption test (AAT) has been used as a marker for gastric motility and upper small bowel absorption; thus, it may provide objective data regarding enteral absorptive ability in critically ill patients. STUDY QUESTION: What is the clinical experience with AAT when used as a surrogate marker for enteral absorption in critically ill patients? STUDY DESIGN: This single-center, retrospective, cohort study evaluated serum acetaminophen concentrations within 180 minutes following 1-time enteral administration of an AAT. Patients admitted to the surgical and medical intensive care units and medical intensive care units over a 7-year period were evaluated. Groups were defined as positive (acetaminophen concentration of ≥10 mg/L) or negative (acetaminophen concentration of <10 mg/L) AAT. MEASURES AND OUTCOMES: The outcomes were to describe the clinical experience, characteristics, and performance of AAT. RESULTS: Forty-eight patients were included. Patients were 58.5 ± 14 years of age, mostly male (58.3%), and admitted to the surgical intensive care unit (66.7%). Median hospital length of stay was 47.5 (27-78.8) days. Thirty-four patients (70.8%) had a positive AAT [median concentration, 14 (12-18) mg/L]. Median time to first detectable concentration was 37 (33-64) minutes. AAT characteristics were similar between the groups including total dose, weight-based dose, time to first and second assays, drug formulation, and site of administration between groups. There were no independent risk factors identified on regression analysis for negative AAT. CONCLUSIONS: An acetaminophen dose of 15 mg/kg with 2 coordinated serum concentrations approximately 30 and 60 minutes after administration is a reasonable construct for AAT. Future research is needed to assess AAT utility, safety, and clinical outcomes for predicting patient ability to absorb enteral feeds and medications.

Pharmacokinetics of Levetiracetam Seizure Prophylaxis in Severe Traumatic Brain Injury.

BACKGROUND: Drug pharmacokinetics (PK) are altered in neurocritically ill patients, and optimal levetiracetam dosing for seizure prophylaxis is unknown. OBJECTIVE: This study evaluates levetiracetam PK in critically ill patients with severe traumatic brain injury (sTBI) receiving intravenous levetiracetam 1000 mg every 8 (LEV8) to 12 (LEV12) hours for seizure prophylaxis. METHODS: This prospective, open-label study was conducted at a level 1 trauma, academic, quaternary care center. Patients with sTBI receiving seizure prophylaxis with LEV8 or LEV12 were eligible for enrollment. Five sequential, steady-state, postdose serum levetiracetam concentrations were obtained. Non-compartmental analysis (NCA) and compartmental approaches were employed for estimating pharmacokinetic parameters and projecting steady-state trough concentrations. Pharmacokinetic parameters were compared between LEV8 and LEV12 patients. Monte Carlo simulations (MCS) were performed to determine probability of target trough attainment (PTA) of 6 to 20 mg/L. A secondary analysis evaluated PTA for weight-tiered levetiracetam dosing. RESULTS: Ten male patients (5 LEV8; 5 LEV12) were included. The NCA-based systemic clearance and elimination half-life were 5.3 ± 1.2 L/h and 4.8 ± 0.64 hours. A one-compartment model provided a higher steady-state trough concentration for the LEV8 group compared with the LEV12 group (13.7 ± 4.3 mg/L vs 6.3 ± 1.7 mg/L; P = 0.008). Monte Carlo simulations predicted regimens of 500 mg every 6 hours, 1000 mg every 8 hours, and 2000 mg every 12 hours achieved therapeutic target attainment. Weight-tiered dosing regimens achieved therapeutic target attainment using a 75 kg breakpoint. CONCLUSION AND RELEVANCE: Neurocritically ill patients exhibit rapid levetiracetam clearance resulting in a short elimination half-life. Findings of this study suggest regimens of levetiracetam 500 mg every 6 hours, 1000 mg every 8 hours, or 2000 mg every 12 hours may be required for optimal therapeutic target attainment. Patient weight of 75 kg may serve as a breakpoint for weight-guided dosing to optimize levetiracetam therapeutic target attainment for seizure prophylaxis.

Applying Cefepime Population Pharmacokinetics to Critically Ill Patients Receiving Continuous Renal Replacement Therapy.

Patients admitted to the intensive care unit (ICU) may need continuous renal replacement therapy (CRRT) due to acute kidney injury or worsening of underlying chronic kidney disease. This will affect their antimicrobial exposure and may have a significant impact on the treatment. We aim to develop a cefepime pharmacokinetic (PK) model in CRRT ICU patients and generate the posterior predictions for a group and assess their therapy outcomes. Adult patients, who were admitted to the ICU, received cefepime, and had its concentration measured while on CRRT were included from three different data sets. In two data sets, samples were collected from the predialyzer, postdialyzer ports, and effluent fluid at different times within the same dosing interval. The third data set had only cefepime plasma concentration measured as part of clinical service. Patients' demographics, cefepime regimens and concentration, CRRT parameters, and therapy outcomes were recorded. NPAG was used for population PK and posterior predictions. A total of 125 patients were included. Cefepime was described by a five-compartment model, and the CRRT flow rates described the rates of cefepime transfer between compartments. The posterior predictions were generated for the third data set and the median (range) fT>MIC was 100% (27%-100%) and fT>4×MIC was 64% (0%-100%). The mortality rate was 53%. There was no difference in target attainment in terms of clinical cure and 30-day mortality. This model can be used as a precision dosing tool in CRRT patients. Future studies may address other PK/PD targets in a larger population.

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.

Sustained Virologic Response of Patients Hospitalized Compared With Those Not Hospitalized During Treatment for Hepatitis C Virus With Direct-Acting Antivirals.

BACKGROUND: Direct-acting antivirals (DAAs) for treatment of hepatitis C virus (HCV) have resulted in great success through high attainment of sustained virologic response (SVR). Risk factors for DAA treatment failure are important to identify because of worsened outcomes with failure and high treatment cost. OBJECTIVE: We sought to identify whether hospitalization during treatment affects SVR. The primary outcome was the difference in SVR at 12 weeks after treatment. METHODS: This multicenter, single health system retrospective cohort review compared achievement of SVR between patients hospitalized during DAA treatment for HCV with those not hospitalized during treatment. RESULTS: Patients in the hospitalized cohort (n = 94) had more severe disease at baseline than nonhospitalized patients (n = 167) as indicated through higher Model for End-Stage Liver Disease (MELD) scores, Fibrosis-4 scores, and imaging-suggested or biopsy-confirmed cirrhosis. Patients hospitalized during treatment had lower SVR rates compared with those not hospitalized (87.2% vs 95.2%; P = 0.043) but failed to reach significance when inpatient mortality was excluded on secondary analysis (91.1% vs 95.2%; P = 0.195). Patients who were hospitalized and did not achieve SVR had higher MELD scores, were more likely to have intensive care unit stay, and had longer hospital stay compared with those who achieved SVR. Of 94 patients, 93 provided home supply of DAAs during hospitalization. CONCLUSION AND RELEVANCE: Patients hospitalized during DAA treatment for HCV had reduced rates of SVR. This reduced SVR rate may be driven by inpatient mortality and severity of liver disease. Patient education to bring home supply of medication for use during admission is an effective intervention.

Retrospective Evaluation of Venous Thromboembolism Prophylaxis in Elderly, High-Risk Trauma Patients.

BACKGROUND: Venous thromboembolism (VTE) risk increases with age. Scarce data exist for patients age ≥65 y. This study evaluated VTE incidence in elderly, high-risk trauma patients receiving unfractionated heparin (UFH) or enoxaparin chemoprophylaxis. MATERIALS AND METHODS: This retrospective, single-center, cohort study included trauma patients age ≥ 65 y with risk assessment profile (RAP) ≥ 5 who received UFH or enoxaparin chemoprophylaxis. The primary outcome was VTE incidence requiring therapeutic anticoagulation. An age-modified RAP (RAP-AM) was calculated as RAP without age distribution points. Logistic regression analyses were performed to identify independent predictors for VTE development and chemoprophylactic agent selection. Bleeding incidence compared packed red blood cells utilized. RESULTS: A total of 1090 patients were included (UFH, n = 655; enoxaparin, n = 435). VTE occurred in 39 (3.6%) patients with no difference between groups in proximal deep vein thrombosis (2.1% versus 3.0%, P = 0.52) or pulmonary embolism (1.2% versus 1.4%, P = 0.96). Weight ≥125 kg (OR 4.12, 95% CI 1.06-16.11) and RAP-AM ≥ 5 (OR 6.52, 95% CI 2.65-16.03) were independently associated with VTE development. Increasing age (OR 1.04, 95% CI 1.03-1.06), initiation ≤ 24 h (OR 2.17, 95% CI 1.66-2.84) and creatinine clearance ≤ 30 mL/min (OR 1.61, 95% CI 1.17-2.21) were independent predictors of receiving UFH whereas increasing ISS (OR 0.97, 95% CI 0.95-0.99) was associated with receiving enoxaparin. CONCLUSIONS: VTE incidence may be similar for high-risk, elderly trauma patients receiving UFH and enoxaparin chemoprophylaxis. Further research is necessary to determine noninferiority of UFH to enoxaparin in this patient population.

Ketamine versus hydromorphone patient-controlled analgesia for acute pain in trauma patients.

BACKGROUND: It is unknown whether ketamine administered via patient-controlled analgesia (PCA) provides adequate analgesia while reducing opioid consumption in the traumatically injured patient. Differences in opioid consumption, pain scores, and adverse effects between ketamine and hydromorphone PCA were studied. MATERIALS AND METHODS: This is an investigator-initiated, single-center, double-blinded, randomized, pilot trial conducted from 2014 to 2016 at a level 1 trauma center. Nonintubated trauma patients in intensive care, who were receiving PCA, were randomized to ketamine or hydromorphone PCA plus opioid analgesics for breakthrough pain. RESULTS: Twenty subjects were randomized. There was no difference in median daily breakthrough opioid use (10 [0.63-19.38] mg versus 10 [4.38-22.5] mg, P = 0.55). Subjects in the ketamine group had lower median cumulative opioid use on therapy day 1 than the hydromorphone group (4.6 [2.5-15] mg versus 41.8 [31.8-50] mg, P < 0.001), as well as in the first 48 h (10 [3.3-15] mg versus 48.5 [32.1-67.5] mg, P < 0.001) and first 72 h (10 [4.2-15] mg versus 42.5 [31.7-65.2] mg, P < 0.001) of therapy. Daily oxygen supplementation requirements were lower in the ketamine group (0.5 [0-1.5] L/min versus 2 [0.5-3] L/min, P = 0.020). Hallucinations occurred more frequently in the ketamine group (40% versus 0%, P = 0.090). CONCLUSIONS: Ketamine PCA led to lower cumulative opioid consumption and lower oxygen supplementation requirements, though hallucinations occurred more frequently with use of ketamine. Additional studies are needed to investigate the tolerability of ketamine as an alternative to traditional opioid-based PCA.

Evaluation of Thrombocytopenia in Critically Ill Patients Receiving Continuous Renal Replacement Therapy.

BACKGROUND: Continuous renal replacement therapy (CRRT) may be associated with thrombocytopenia in critically ill patients. A confounding factor is concomitant use of unfractionated heparin (UFH) and suspicion for heparin-induced thrombocytopenia (HIT). OBJECTIVE: To determine the impact of CRRT on platelet count and development of thrombocytopenia. METHODS: Retrospective analyses evaluated the intrapatient change in platelet count following CRRT initiation. Critically ill adult patients who received CRRT for at least 48 hours were included. The primary outcome was intrapatient change in platelet count from CRRT initiation through the first 5 days of therapy. Secondary outcomes included thrombocytopenia incidence, identification of concomitant factors associated with thrombocytopenia, and frequency of HIT. RESULTS: 80 patients were included. Median platelet count at CRRT initiation (D0) was 128000/µL (81500-212500/µL), which was higher than those on subsequent post-CRRT days (D1: 104500/µL [63000-166750/µL]; D2: 88500/µL [53500-136750/µL]; D3: 91000/µL [49000-138000/µL]; D4: 93000/µL [46000-134000/µL]; and D5: 76000/µL [45500-151000/µL]; P < 0.05 for all). Twenty-five (35%) patients had thrombocytopenia on CRRT D0 compared with D2 (56.3%), D3 (58.7%), and D5 (59.1%); P < 0.05 for all. Controlling for potential confounders, Sequential Organ Failure Assessment score at the time of CRRT initiation was the only independent factor associated with thrombocytopenia. One (1.3%) patient had confirmed HIT. Conclusion and Relevance: This study is the first to demonstrate serial decreases in platelet count across multiple days after CRRT initiation. These data may provide additional insight to thrombocytopenia development in critically ill patients receiving heparin while on CRRT that is not associated with HIT.

Adjunctive intraventricular antibiotic therapy for bacterial central nervous system infections in critically ill patients with traumatic brain injury.

BACKGROUND: Limited data exist on the role of adjunctive intraventricular (IVT) antibiotics for the treatment of central nervous system (CNS) infections in traumatic brain injury (TBI) patients. OBJECTIVE: To evaluate differences in CNS infection cure rates for TBI patients who received adjunctive IVT antibiotics compared with intravenous (IV) antibiotics alone. METHODS: We retrospectively identified patients with TBI and bacterial CNS infections admitted to the trauma intensive care unit (ICU) from 1997 to 2013. Study patients received IV and IVT antibiotics, and control patients received IV antibiotics alone. Clinical and microbiological cure rates were determined from patient records, in addition to ICU and hospital lengths of stay (LOSs), ventilator days, and hospital mortality. RESULTS: A total of 83 patients were enrolled (32 study and 51 control). The duration of IV antibiotics was similar in both groups (10 vs 12 days, P = 0.14), and the study group received IVT antibiotics for a median of 9 days. Microbiological cure rates were 84% and 82% in study and control groups, respectively (P = 0.95). Clinical cure rates were similar at all time points. No significant differences were seen in days of mechanical ventilation, ICU or hospital LOS, or hospital mortality. When only patients with external ventricular drains were compared, cure rates remained similar between groups. CONCLUSIONS: TBI patients with CNS infections had similar microbiological and clinical cure rates whether they were treated with adjunctive IVT antibiotics or IV antibiotics alone. Shorter than recommended durations of antibiotic therapy still resulted in acceptable cure rates and similar clinically relevant outcomes.

Case Report: Extended Duration Andexanet Alfa Infusion in a Surgical Trauma Patient.

Background: Andexanet alfa (andexanet) is the only FDA-approved medication for reversal of apixaban and rivaroxaban anticoagulation for life-threatening or uncontrolled bleeding. Infusion modifications may be required in surgical patients undergoing prolonged operative intervention but have not previously been described. Case Report: A 78-year-old woman on rivaroxaban for atrial fibrillation was admitted to the trauma service for a mechanical fall, sustaining a T4 burst fracture with severe canal stenosis and spinal cord edema resulting in loss of strength and sensation in her legs. Clinically relevant rivaroxaban activity was verified with an elevated low molecular weight heparin anti-factor Xa assay, and laboratory confirmed coagulopathy was demonstrated by a prolonged prothrombin time, thromboelastography (TEG) R-time, and activated clotting time (ACT). The patient required urgent surgical intervention for spinal fixation. Given the expected prolonged duration of the procedure, standard dose andexanet was initiated with a prolonged infusion at half the standard rate during the operation. The procedure was successful and intraoperative TEGs demonstrated normalization of R-time and ACT throughout the procedure. The patient did not experience any complications postoperatively and successfully discharged to inpatient rehabilitation. Conclusion: Modifications to the andexanet infusion may be required in surgical patients requiring rivaroxaban reversal for a prolonged procedure. Further data are needed to determine the optimal approach to infusion modification.

Assessment of Detectable Serum Tobramycin Concentrations in Patients Receiving Inhaled Tobramycin for Ventilator-Associated Pneumonia.

BACKGROUND: Inhaled tobramycin can be used for empiric or definitive therapy of ventilator-associated pneumonia (VAP) in mechanically ventilated patients. This is believed to minimize systemic exposure and potential adverse drug toxicities including acute kidney injury (AKI). However, detectable serum tobramycin concentrations have been reported after inhaled tobramycin therapy with AKI. METHODS: This retrospective, observational study evaluated mechanically ventilated adult subjects admitted to ICUs at a large, urban academic medical center that received empiric inhaled tobramycin for VAP. Subjects were separated into detectable (ie, ≥ 0.6 mg/L) or undetectable serum tobramycin concentration groups, and characteristics were compared. Independent predictors for detectable serum tobramycin concentration and new onset AKI during or within 48 h of therapy discontinuation were assessed. RESULTS: Fifty-nine inhaled tobramycin courses in 53 subjects were included in the analysis, of which 39 (66.1%) courses administered to 35 (66.0%) subjects had detectable serum tobramycin concentrations. Subjects with detectable serum tobramycin concentrations were older (57.1 y ± 11.4 vs 45.9 ±15.0, P = .004), had higher PEEP (9.2 cm H2O [7.0-11.0] vs 8.0 [5.6-8.9], P = .049), chronic kidney disease stage ≥ 2 (10 [29.4%] vs 0 [0%], P = .009), and higher serum creatinine before inhaled tobramycin therapy (1.26 mg/dL [0.84-2.18] vs 0.76 [0.47-1.28], P = .004). Age (odds ratio 1.09 [95% CI 1.02-1.16], P = .009) and PEEP (odds ratio 1.47 [95% CI 1.08-2.0], P =.01) were independent predictors for detectable serum tobramycin concentration. Thirty-seven subjects had no previous renal disease or injury, of which 9 (24.3%) developed an AKI. Sequential Organ Failure Assessment score (odds ratio 1.72 [95% CI 1.07-2.76], P = .03) was the only independent predictor for AKI. CONCLUSIONS: Detectable serum tobramycin concentrations were frequently observed in critically ill, mechanically ventilated subjects receiving empiric inhaled tobramycin for VAP. Subject age and PEEP were independent predictors for detectable serum tobramycin concentration. Serum monitoring and empiric dose reductions should be considered in older patients and those requiring higher PEEP.

Multidisciplinary Team Utilizing Pharmacists in Multimodal, Bundled Care Reduce Chronic Obstructive Pulmonary Disease Hospital Readmission Rates.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major contributor of morbidity and mortality in the United States resulting in high hospitalization and readmission rates. For health systems, identifying an effective strategy to reduce COPD readmissions has remained difficult. Multiple COPD care bundles have been developed with varying degrees of success. Bundles that were multidisciplinary and included pharmacists were successful in reducing readmissions. OBJECTIVE: To describe and assess a multidisciplinary, 5-element, COPD care bundle that was implemented in an academic, urban safety-net hospital to reduce COPD readmissions and the role of pharmacists in bundle implementation. METHODS: A multidisciplinary team collaborated to develop a 5-element COPD care bundle that met unmet patient needs. The bundle elements included the following, with pharmacy responsible for the first two: optimization of COPD inhalers, 30-day supply of insurance-compatible inhalers, individualized patient inhaler teaching, provision of standardized discharge instructions, and scheduling of a 15-day discharge follow-up appointment. Bundle was implemented with multiple Plan-Do-Study-Act (PDSA) cycles to develop intra- and interdepartment processes. RESULTS: Prior to bundle implementation, the health system COPD readmission rates were 22.7%. Reliable implementation of the bundle reduced readmissions to 14.7% over a 6-month period. Pharmacy adherence to completion of the bundle was over 95% over 2 years of bundle use. CONCLUSION: Pharmacists have a crucial role in hospital-based transitions of care to reduce COPD readmissions.

High-dose ciprofloxacin for serious gram-negative infection in an obese, critically ill patient receiving continuous venovenous hemodiafiltration.

OBJECTIVE: To describe the pharmacokinetic profile and clinical outcome associated with high-dose ciprofloxacin therapy in a patient with the triad of extreme obesity, multiple organ failure, and deep-seated infection. CASE SUMMARY: A 45-year-old, class 3 obese (185 kg; body mass index 53.7), critically ill trauma patient receiving continuous venovenous hemodiafiltration (CVVHDF) was treated with ciprofloxacin 800 mg intravenously every 12 hours for presumed Enterobacter aerogenes (ciprofloxacin minimum inhibitory concentration [MIC] ≤1 µg/mL) lumbar spine osteomyelitis. Four sequential plasma ciprofloxacin samples were obtained and analyzed to determine the steady-state pharmacokinetic profile. The observed steady-state maximum (C(max)) and calculated minimum (C(min)) ciprofloxacin plasma concentrations measured on treatment day 8 were 13 µg/mL and 4.8 µg/mL, respectively, corresponding to an estimated half-life, area under the curve (AUC(0-24)), total systemic clearance, and clearance by CVVHDF of 7.6 hours, 192 µg·h/mL, 139 mL/min, and 26 mL/min, respectively. These concentrations produced AUC(0-24)/MIC ratios >125 and plasma C(max)/MIC ratios >10 for MICs ≤1 µg/mL. Intravenous colistin and polymyxin B lumbar wound irrigation were initiated on ciprofloxacin days 12 and 15, respectively, for concomitant multidrug-resistant Acinetobacter baumannii infection. Lumbar tissue cultures on day 24 of ciprofloxacin therapy demonstrated no growth, coinciding with overall improvement of the invasive wound. A week later, the patient developed worsening septic shock and died secondary to an occult subdiaphragmatic abscess. DISCUSSION: Pharmacodynamic outcome studies suggest that AUC(0-24)/MIC ratios >125 and plasma C(max)/MIC ratios >10 are good predictors of clinical and microbiologic success of ciprofloxacin against gram-negative pathogens. These pharmacodynamic goals were achieved in the plasma with high-dose ciprofloxacin for MICs ≤1 µg/mL. CONCLUSIONS: Critically ill obese patients with deep-seated infection involving organisms with MICs >0.5 µg/mL likely require ciprofloxacin dosages greater than traditional daily doses of 400-800 mg during CVVHDF to achieve optimal pharmacodynamic targets.

COPD Care Bundle in Emergency Department Observation Unit Reduces Emergency Department Revisits.

BACKGROUND: COPD exacerbations lead to accelerated decline in lung function, poor quality of life, and increased mortality and cost. Emergency department (ED) observation units provide short-term care to reduce hospitalizations and cost. Strategies to improve outcomes in ED observation units following COPD exacerbations are needed. We sought to reduce 30-d ED revisits for COPD exacerbations managed in ED observation units through implementation of a COPD care bundle. The study setting was an 800-bed, academic, safety-net hospital with 700 annual ED encounters for COPD exacerbations. Among those discharged from ED observation unit, the 30-d all-cause ED revisit rate (ie, the outcome measure) was 49% (baseline period: August 2014 through September 2016). METHODS: All patients admitted to the ED observation unit with COPD exacerbations were included. A multidisciplinary team implemented the COPD bundle using iterative plan-do-study-act cycles with a goal adherence of 90% (process measure). The bundle, adopted from our inpatient program, was developed using care-delivery failures and unmet subject needs. It included 5 components: appropriate inhaler regimen, 30-d inhaler supply, education on devices available after discharge, standardized discharge instructions, and a scheduled 15-d appointment. We used statistical process-control charts for process and outcome measures. To compare subject characteristics and process features, we sampled consecutive patients from the baseline (n = 50) and postbundle (n = 83) period over 5-month and 7-month intervals, respectively. Comparisons were made using t tests and chi-square tests with P < .05 significance. RESULTS: During baseline and postbundle periods, 410 and 165 subjects were admitted to the ED observation unit, respectively. After iterative plan-do-study-act cycles, bundle adherence reached 90% in 6 months, and the 30-d ED revisit rate declined from 49% to 30% (P = .003) with a system shift on statistical process-control charts. There was no difference in hospitalization rate from ED observation unit (45% vs 51%, P = .16). Subject characteristics were similar in the baseline and postbundle periods. CONCLUSIONS: Reliable adherence to a COPD care bundle reduced 30-d ED revisits among those treated in the ED observation unit.

Effects of critical illness and organ failure on therapeutic argatroban dosage requirements in patients with suspected or confirmed heparin-induced thrombocytopenia.

BACKGROUND: Critically ill patients often require therapeutic argatroban dosages lower than those recommended in package labeling. The magnitude of dosage alteration in relation to severity of organ failure is unknown. OBJECTIVE: To compare therapeutic argatroban dosages between critically ill and noncritically ill patients with confirmed or suspected heparin-induced thrombocytopenia and investigate the relationship between total Sequential Organ Failure Assessment (SOFA) score and therapeutic argatroban dosage. METHODS: This retrospective cohort study was conducted at an urban academic medical center. Adults without Child-Pugh class C hepatic dysfunction who received argatroban for more than 24 hours over a 3-year period were included. Therapeutic argatroban dosage was that resulting in 2 consecutive activated partial thromboplastin time (aPTT) values 1.5-3 times the patient-specific baseline obtained at least 4 hours apart. Initial argatroban dosages were at the discretion of the managing service. RESULTS: Fifty-three patients (critically ill, n = 34; noncritically ill, n = 19) were included. Critically ill patients had higher median [interquartile range] Acute Physiology and Chronic Health Evaluation (APACHE II) (17 [12-21] vs 10 [3.25-17.75]; p = 0.007) and SOFA (11 [7-13] vs 2 [0-2.75]; p < 0.001) scores. Critically ill patients required lower mean +/- SD therapeutic argatroban dosage (0.6 +/- 0.5 vs 1.4 +/- 0.9 microg/kg/min; p < 0.001). There was no significant difference in time to therapeutic aPTT or proportion of aPTTs within therapeutic range. Argatroban dosage was inversely related to SOFA score tertiles (<6: 1.34 +/- 0.82 microg/kg/min; 6-9: 0.93 +/- 0.54; > or =10: 0.40 +/- 0.27; p < 0.001). Total SOFA score at the time of argatroban initiation was independently associated with an argatroban dosage less than 0.75 microg/kg/min (OR 1.5, 95% CI 1.2 to 1.8; p < 0.001). Adverse events were similar between groups. CONCLUSIONS: Critically ill patients with single or multiple organ failure require lower therapeutic argatroban dosages compared with noncritically ill patients. Because of an inverse relationship with SOFA score, initial argatroban dosage in critically ill patients should be based on the presence and magnitude of organ failure.

Continuous Infusion Ketamine for Adjunctive Analgosedation in Mechanically Ventilated, Critically Ill Patients.

OBJECTIVE: Ketamine is an N-methyl-D-aspartate antagonist with emerging evidence assessing its use as a continuous infusion agent to provide concomitant analgesia and sedation. The role of ketamine as adjunctive therapy in mechanically ventilated patients is unclear. This study sought to investigate the impact of adjunctive continuous infusion ketamine on concomitant analgesic and sedative dosing while providing goal comfort in mechanically ventilated patients. METHODS: This retrospective two-center intrapatient comparison study included mechanically ventilated adult ICU patients who received continuous infusion ketamine with at least one other analgesic or sedative infusion. The primary outcome assessed percent relative change in concomitant analgesic-sedative doses 24 hours after ketamine initiation. Secondary outcomes included percent of Richmond Agitation and Sedation Score (RASS) assessments at goal, adverse effects, and delirium incidence. Exploratory evaluation of independent factors associated with ketamine responders (50% or more relative reduction in analgesic-sedative dosing requirements at 24 hrs) and nonresponders (less than 50% relative reduction) was performed using multivariate logistic regression. RESULTS: Overall, 104 patients were included. A total of 160 concomitant analgesic-sedative infusions were used in combination with ketamine, most commonly fentanyl (98 [61.3%]) and propofol (46 [28.8%]). A 20% (interquartile range [IQR] -63.6 to 0.0, p<0.001) relative reduction in total analgesic-sedative infusion pharmacotherapy was achieved at 24 hours after ketamine initiation. Analgesic and sedative infusion doses decreased at 24 hours (fentanyl: pre, 175 µg/hr [IQR 100-200 µg/hr] vs post, 125 µg/hr [IQR 50-200 µg/hr], p<0.001; propofol: pre, 42.5 µg/kg/min [IQR 20.0-60.0 µg/kg/min] vs post, 20.0 µg/kg/min [IQR 3.8-31.3 µg/kg/min], p<0.001). Median percent time within goal RASS improved after ketamine initiation (pre, 7.1% [0-40%] vs post, 25% [0-66.7%], p=0.005). No differences were observed in secondary outcomes between responders and nonresponders, except a longer non-ICU hospital length of stay in responders. Independent factors associated with ketamine response included a lower body mass index, higher starting dose of ketamine, lower severity of illness, and need for multiple concomitant analgesic-sedative infusions before initiation of ketamine. CONCLUSIONS: Adjunctive continuous infusion ketamine promotes analgesic and sedative dose-sparing effects in mechanically ventilated patients while improving time spent within goal sedation range. Further prospective research is warranted.

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.

Sunitinib-related fulminant hepatic failure: case report and review of the literature.

Drug-induced hepatotoxicity is an infrequent but life-threatening complication. Sunitinib is a multitargeted receptor tyrosine kinase inhibitor approved for treatment of renal cell carcinoma and gastrointestinal stromal tumor. However, results from preapproval clinical trials suggest an equivocal hepatic risk profile for sunitinib. We describe a 75-year-old woman with renal cell carcinoma who was admitted to the intensive care unit after experiencing fulminant hepatic failure during sunitinib therapy. The patient's hepatic and renal chemistries had been within normal limits throughout four previous cycles of sunitinib therapy spanning 9 months. After the fifth cycle, she complained of a 3-day history of severe diarrhea and dehydration. Her abnormal laboratory test results included the following: total bilirubin level 5.9 mg/dl, aspartate aminotransferase level 3872 U/L, alanine aminotransferase level 3332 U/L, ammonia level 897 microg/dl, and an international normalized ratio of 4.8. Use of the Naranjo adverse drug reaction probability scale indicated a possible relationship between sunitinib and hepatotoxicity. Supportive care including aggressive intravenous hydration and reversal of coagulopathy was successful. The patient was discharged home on hospital day 7 without apparent longstanding sequelae. Clinicians should be aware of this possible adverse effect of sunitinib, and continued pharmacovigilance is imperative to accurately quantify the possible risk of sunitinib-related hepatotoxicity.