Craig Whitman

Fidaxomicin for the Treatment of Clostridium difficile Infections

Objective: To evaluate the pharmacology, microbiology, safety, and efficacy of fidaxomicin for treatment of Clostridium difficile infections (CDI). Data Sources: Literature was identified through Ovid MEDLINE (1940-December 2011) and International Pharmaceutical Abstracts (1970-December 2011) using the search terms fidaxomicin, OPT-80, PAR-101, OP-118, difimicin, tiacumicin, lipiarmycin, Clostridium difficile, Clostridium difficile infection, Clostridium difficile-associated diarrhea, and cost. Drug monographs were retrieved from manufacturers’ Web pages, and the Red Book component of Micromedex was used for cost Information. Study Selection and Data Extraction: All pertinent Phase 1,2, and 3 studies published in English were included. Data Synthesis: Fidaxomicin is a macrocyclic compound bactericidal against C. difficile and inhibits toxin and spore production. It has poor oral absorption with high fecal concentrations. Available Phase 2 and 3 data with fidaxomicin 200 mg orally every 12 hours demonstrate similar effectiveness in treating CDI compared to oral vancomycin. Fidaxomicin was shown to have less frequency of recurrent infections. Adverse effects are uncommon and occur at similar rates as with oral vancomycin. The most frequently reported adverse effects are gastrointestinal, hematologic, and electrolyte disorders. Available data are lacking in several areas, including the efficacy and safety of fidaxomicin compared to established regimens for mild-to-moderate, life-threatening, and recurrent CDIs. The cost of a 10-day course of fidaxomicin is significantly more than that of metronidazole and vancomycin for treatment of mild-to-moderate CDI. Conclusions: Fidaxomicin appears to be an effective and safe alternative to oral vancomycin for treatment of mild-to-moderate and severe CDI. Data on its use compared to guideline-recommended therapies for mild-to-moderate and life-threatening CDI are needed. Further data assessing the cost-effectiveness of fidaxomicin are needed. Currently, it cannot be recommended over vancomycin for treatment of CDI. However, it may be considered for treatment of recurrent infections.

Efficacy of Aminophylline for Treatment of Recurrent Symptomatic Bradycardia After Spinal Cord Injury

Cardiac dysrhythmias and cardiac arrest can occur after acute spinal cord injury (SCI). Disrupted sympathetic innervation after SCI results in unopposed parasympathetic activity leading to baseline bradycardia. Hence, vagal stimulation can result in episodes of exaggerated symptomatic bradycardia. Data supporting pharmacologic intervention for treatment of symptomatic bradycardia after SCI are limited. We describe a patient who sustained a high cervical SCI and subsequently developed episodic symptomatic bradycardia. The addition of aminophylline to the patients therapeutic regimen was associated with resolution of the bradycardia. Throughout her treatment course, the patients serum theophylline concentrations were 1.9‐3.4 mg/L. These levels were consistent with those identified in other case reports describing treatment with methylxanthines to prevent episodic bradycardia after SCI. Our understanding of drug pharmacokinetics and pharmacodynamics in patients with acute SCI is limited and provides an ideal opportunity for further study in this area.

Possible case of nafcillin-induced acute interstitial nephritis.

PURPOSE To report a case of acute interstitial nephritis (AIN) secondary to nafcillin. SUMMARY A 55-year-old Hispanic man (height, 63 in.; weight, 61.2 kg) with a history of deep vein thrombosis in the right lower extremity, hypertension, hyperlipidemia, and hepatitis C infection was admitted to the hospital with right-sided chest pain that radiated down his right arm and leg. The patient was diagnosed with methicillin-sensitive Staphylococcus aureus endocarditis. A renal ultrasound was performed on hospital day 9 after the patient developed acute renal failure and showed diffusely increasing echogenicity of the renal parenchymal bilaterally with an interpolar cyst in the left kidney. A urine analysis, serum chemistry panels, and complete blood counts were consistent with AIN. The patient received a total of seven days of nafcillin, and cefazolin was initiated. A renal ultrasound and renal biopsy were performed, which confirmed the diagnosis of AIN. The patient received short-term hemodialysis, after which his renal function slowly returned to baseline. He then underwent an aortic valve replacement and tricuspid valve repair. His antibiotics were changed to rifampin and vancomycin after methicillin-resistant S. aureus was found in an aortic valve culture on hospital day 26. Cefazolin was discontinued 3 days after rifampin and vancomycin were added. The patient received 18 more days of antibiotics and was discharged on the last day of therapy (hospital day 45). CONCLUSION A 55-year-old, critically ill man developed a possible case of nafcillin-induced AIN after receiving a 7-day course of treatment with the drug.

Cephalosporin-Induced Leukopenia Following Rechallenge with Cefoxitin

Objective To describe a case of cefazolin-induced leukopenia in a critically ill patient who developed this adverse reaction upon rechallenge with cefoxitin. Case Summary: A 22-year-old male was admitted after a motor vehicle crash. β-Lactam therapy was initiated with vancomycin, cefepime, and metronidazole and, upon identification of methicillin-sensitive Staphylococcus aureus bacteremia 4 days later, therapy was narrowed to cefazolin 1 g every 12 hours. The dose was adjusted to 1 g every 12 hours during continuous venovenous hemodialysis. Imipenem was given for 2 days, resulting in a total of 18 days of β-lactam treatment, at which time he developed significant leukopenia (white blood celt [WBC] count 0.9 × 103/μL). Antimicrobial treatment was changed to tigecycline and continued for suspected pleural space infection. The patients WBC count recovered within 4 days after the change in therapy. He was taken to surgery 8 days after cefazolin was discontinued and received perioperative prophylaxis with cefoxitin (total dose 3 g). Subsequently, the patient again became severely leukopenic (WBC count 2.4 × 103/μL). Within a week after surgery, the patient developed septic shock secondary to multidrug-resistant Escherichia coli bacteremia and died. Discussion: β-Lactam–induced leukopenia is a rare but well-described adverse drug reaction. It is a cumulative dose-dependent phenomenon reported to occur most often after 2 weeks of therapy. The mechanism of leukopenia is thought to be secondary to either an immune-mediated response or direct bone marrow toxicity. Rechallenge with a different β-lactam antibiotic has not been shown to consistently cause recurrent leukopenia. The case described here suggests an immune-related mechanism for the development of leukopenia. Use of the Naranjo probability scale determined the association between cephalosporin use and leukopenia to be probable. Conclusions: Cefazolin was a probable cause of this patients leukopenia. It is important for clinicians to recognize β-lactam–induced leukopenia and maybe recommend use of a drug from a different antibiotic class if continued treatment is indicated.

Nalbuphine-induced psychosis treated with naloxone

PURPOSE A case of nalbuphine-induced psychosis, which resolved after the administration of naloxone, is described. SUMMARY A 25-year-old African-American woman with a history of systemic lupus erythematosus was admitted to the hospital for management of cholecystitis. A laparoscopic cholecystectomy was performed, and the patient received multiple doses of i.v. hydromorphone for postoperative pain management. Four days later, shortly after receiving a dose of i.v. nalbuphine for opioid-induced pruritus, she experienced an acute psychotic event, with symptoms including intense headache, akathisia, altered mental status, and formication (a hallucinatory sensation of insects crawling on the skin). The neuropsychiatric symptoms abated within 5 minutes of two consecutively administered doses of i.v. naloxone. During this event, which lasted 25-30 minutes, there was no evidence of metabolic abnormalities and were no signs of infection. The patient did not have a history of mental illness or substance abuse. The patient did not receive further doses of nalbuphine and did not experience similar events during her hospital stay; she was discharged home 10 days later without further complications. According to the algorithm of Naranjo et al., the case was assigned a score of 6, indicating a probable adverse reaction to nalbuphine. CONCLUSION A patient developed an acute psychotic reaction that was probably secondary to administration of i.v. nalbuphine for opioid-induced pruritus. Evidence supporting this diagnosis included correlation between the timing of administration of nalbuphine and symptom onset and the marked improvement in mentation following the administration of naloxone.

Methylprednisolone Sodium Succinate–Associated Macroglossia in a Critically Ill Patient

Allergic hypersensitivity reactions are a rare adverse effect of corticosteroids. Previous reports have identified patients who developed symptoms of urticaria, dyspnea, hypotension, bronchospasm, and angioedema occurring within minutes to an hour after corticosteroid administration. A 35‐year‐old woman is described who developed an atypical reaction of isolated macroglossia after receiving intravenous methylprednisolone sodium succinate for myasthenic crisis. Macroglossia was identified on day 2 of therapy and worsened through day 5. On day 5, she was transitioned to prednisone 50 mg daily administered by feeding tube. Tongue swelling improved by day 7 and on day 10, the patient was extubated. The patient required reintubation due to stridor, but received a tracheostomy and was weaned off mechanical ventilation by day 15. The reaction was not confirmed with skin‐prick tests, intradermal tests, or a drug rechallenge; however, she had previously received and tolerated all other drugs administered during this time. Due to the timing of administration and onset of symptoms, we feel this adverse drug reaction was likely due to administration of methylprednisolone. Applying the Naranjo adverse drug reaction probability scale to this case, a score of six was obtained, indicating a probable association between the administration of methylprednisolone and the development of macroglossia. As intravenous corticosteroids are often used in the treatment of allergic reactions, they may be overlooked as a cause of macroglossia and other allergic reactions; therefore, practitioners need to be aware of the possibility of this adverse effect secondary to corticosteroid administration. In the event of methylprednisolone sodium succinate–induced macroglossia, alternative nonesterified corticosteroids, such as dexamethasone or prednisone, should be considered if continuation of therapy is required.

945: SAFETY AND TOLERABILITY OF RAPID TITRATION INTRAVENOUS TREPROSTINIL

www.ccmjournal.org Critical Care Medicine • Volume 46 • Number 1 (Supplement) Learning Objectives: Treprostinil is increasingly used to treat pulmonary hypertension (PH) due to its ease of use and stability profile. Approved dose initiation and titration by weekly increments may result in delays in dose optimization. Titration beyond the approved frequency is used with little supporting data. The purpose of this study is to evaluate safety and tolerability of rapid titration of treprostinil. Methods: Single-center, retrospective, chart-review study including subjects ≥18 years old with pulmonary hypertension diagnosis, initiating intravenous treprostinil with dose titrations more frequently than once weekly. Exclusion criteria < 18 years old, transition from parenteral epoprostenol, pregnancy, or imprisonment. Subjects were identified using Pharmacy Informatics database and evaluated for inclusion upon chart review. Descriptive statistics were used for analysis. Results: 26 subjects were included with 11 PH Group 1 and all Class IV. Mean pulmonary artery pressure was 54 mmHg. Medications prior to treprostinil included phosphodiesterase inhibitors (69.2%), endothelin receptor antagonists (19.2%), and inhaled prostacyclin (26.9%). Most common starting doses of treprostinil were 1 and 2 ng/kg/min (8 subjects each). Titration frequency was every 24 hours in 18 subjects. Doses were titrated mostly by 1 ng/ kg/min (80.8%). Median maximum dose and time to maximum dose of treprostinil was 7 ng/kg/min and 8.1 days. Durations of intensive care unit stay and hospital stay were 9.15 days and 23.1 days, respectively. 18 subjects experienced an adverse drug event (ADE) in this study, with a total of 27 ADEs. 8 subjects experienced > 1 event. Most common ADEs were hypotension (14), headache (5), and nausea/vomiting (4). 6 ADEs required analgesia or antiemetics, and 6 episodes of hypotension required intervention (2 fluids, 4 vasopressors). Hypotension requiring dose reduction and cessation of dose titration occurred in 4 and 1 subjects. Discontinuation of therapy occurred secondary to hypotension in one subject. Conclusions: Rapid titration of treprostinil varies and appears to be safe and tolerable.

1023: Impact of patient location on time to antimicrobial administration in severe sepsis and septic shock

Introduction: No study has examined the differences in time to antimicrobials between patient locations at the time of severe sepsis and septic shock onset and its impact on outcomes. This study aimed to compare the time from onset of severe sepsis or septic shock to antimicrobial administration bet