Paul Juang

Prolonged Infusion Antibiotics for Suspected Gram-Negative Infections in the ICU: A Before-After Study

BACKGROUND: β-Lactam antibiotics demonstrate time-dependent killing. Prolonged infusion of these agents is commonly performed to optimize the time the unbound concentration of an antibiotic remains greater than the minimum inhibitory concentration and decrease costs, despite limited evidence suggesting improved clinical results. OBJECTIVE: To determine whether prolonged infusion of β-lactam antibiotics improves outcomes in critically ill patients with suspected gram-negative infection. METHODS: We conducted a single-center, before-after, comparative effectiveness trial between January 2010 and January 2011 in the intensive care units at Barnes-Jewish Hospital, an urban teaching hospital affiliated with the Washington University School of Medicine in St. Louis, MO. Outcomes were compared between patients who received standardized dosing of meropenem, piperacillin-tazobactam, or cefepime as an intermittent infusion over 30 minutes (January 1, 2010, to June 30, 2010) and patients who received prolonged infusion over 3 hours (August 1, 2010, to January 31, 2011). RESULTS: A total of 503 patients (intermittent infusion, n = 242; prolonged infusion, n = 261) treated for gram-negative infection were included in the clinically evaluable population. Approximately 50% of patients in each group received cefepime and 20% received piperacillin-tazobactam. More patients in the intermittent infusion group received meropenem (35.5% vs 24.5%; p = 0.007). Baseline characteristics were similar between groups, with the exception of a greater occurrence of chronic obstructive pulmonary disease (COPD) in the intermittent infusion group. Treatment success rates in the clinically evaluable group were 56.6% for intermittent infusion and 51.0% for prolonged infusion (p = 0.204), and in the microbiologically evaluable population, 55.2% for intermittent infusion and 49.5% for prolonged infusion (p = 0.486). Fourteen-day, 30-day, and inhospital mortality rates in the clinically evaluable population for the intermittent and prolonged infusion groups were 13.2% versus 18.0% (p = 0.141), 23.6% versus 25.7% (p = 0.582), and 19.4% versus 23.0% (p = 0.329). CONCLUSIONS: Routine use of prolonged infusion of time-dependent antibiotics for the empiric treatment of gram-negative bacterial infections offers no advantage over intermittent infusion antibiotic therapy with regard to treatment success, mortality, or hospital length of stay. These results were confirmed after controlling for potential confounders in a multivariate analysis.

WSES guidelines for management of Clostridium difficile infection in surgical patients

In the last two decades there have been dramatic changes in the epidemiology of Clostridium difficile infection (CDI), with increases in incidence and severity of disease in many countries worldwide. The incidence of CDI has also increased in surgical patients. Optimization of management of C difficile, has therefore become increasingly urgent. An international multidisciplinary panel of experts prepared evidenced-based World Society of Emergency Surgery (WSES) guidelines for management of CDI in surgical patients.

Fidaxomicin: A Macrocyclic Antibiotic for the Treatment of Clostridium difficile Infection

Clostridium difficile is an emerging pathogen in certain health care systems and community‐based populations that is associated with high rates of morbidity and mortality as well as increased costs for the health care system. As recurrence rates increase, new pharmacologic agents to treat C. difficile infection are needed. Fidaxomicin, a novel macrocyclic antibiotic, was recently approved by the United States Food and Drug Administration for the treatment of C. difficile‐associated diarrhea. Originally isolated from fermentation broth of Dactylosporangium aurantiacum subspecies hamdenensis, the drug has a selective spectrum, distinctive pharmacokinetic and pharmacodynamic properties, and a favorable adverse‐effect profile. Fidaxomicin has demonstrated similar clinical cure rates (i.e., resolution of diarrhea) compared with vancomycin, with lower recurrence rates and higher global cure rates (i.e., resolution of diarrhea without recurrence) in non‐restriction endonuclease analysis type BI, North American Pulsed Field type 1 (NAP1), polymerase chain reaction ribotype 027 (or non‐BI/NAP1/027) strains. Overall, fidaxomicin has been generally well tolerated, with the most common adverse effects reported as mild gastrointestinal complaints. Fidaxomicin appears to be a useful agent in the treatment of severe C. difficile infection, demonstrating decreased rates of recurrence.

Probable Loop Diuretic–Induced Pancreatitis in a Sulfonamide-Allergic Patient

Objective: To report the case of a patient with a prior allergy to a sulfonamide antibiotic who subsequently developed the same reaction when administered various loop diuretics. Case Summary: A 57-year-old female with cardiomyopathy and “sulfa” (trimethoprim/sulfamethoxazole) allergy documented as pancreatitis presented with symptoms consistent with pancreatitis after use of furosemide. She subsequently developed similar symptoms after multiple rechallenges with various loop diuretics including furosemide, bumetanide, and torsemide. The patient was placed on ethacrynic acid until she was desensitized to furosemide. She had been receiving oral furosemide for 5 months at the time of this report, with no complications. According to the Naranjo probability scale, this reaction was probable. Discussion: Reactions associated with arylamine sulfonamide–containing antibiotics have been commonly reported; however, cross-reactions with non-arylamine sulfonamide–containing medications have been rare. The time delay by which symptoms of pancreatitis presented following administration of loop diuretics suggests an immunologic pathway. In addition, while cases of loop diuretic–induced pancreatitis, including furosemide, have been published, the allergic manifestations with both sulfonamide antibiotics and non-antibiotics in our patient suggest possible cross-reactivity between these 2 drug classes. Conclusions: The mechanism by which loop diuretics induce pancreatitis appears to be via an immunologic pathway. While the true correlation remains unknown, allergic cross-reactivity may occur between sulfonamide antibiotics and non-antibiotics, such as loop diuretics. Torsemide appears to also be a part of a long list of agents that can cause pancreatitis.

Role of Fidaxomicin for the Treatment of Clostridium difficile Infection

Clostridium difficile is a gram-negative, anaerobic, spore-forming emerging pathogen within health care systems and community-based populations that has a high associated morbidity and mortality as well as cost for the health care system. Recent studies reported high rates of recurrence thus a need for new pharmacological agents to treat C difficile infections (CDIs). Fidaxomicin is a novel macrocyclic antibiotic, originally isolated from fermentation broth of Dactylosporangium aurantiacum spp Hamdenensis, with selective spectrum, unique pharmacokinetic and pharmacodynamics profile, adverse effect profile, efficacy, and role in the treatment of and time to recurrent CDI. Fidaxomicin data have similar clinical cure, when compared to vancomycin, with lower recurrence rates and higher global cure rates in non-BI/NAP1/027 strains. Fidaxomicin also lacks activity against gram-negative bacteria; hence, its potential effect on resistance development among enteric bacteria appears to be low. It appears to have minimal need for renal or hepatic adjustments and minimal concerns for drug–drug interactions. Overall, fidaxomicin has been generally well tolerated with the most common adverse effects reported as mild gastrointestinal complaints. Fidaxomicin appears to have a role in the treatment of CDI with potential lower rates of recurrence, especially in patients with severe disease or risk factors for recurrent CDI.

Update on New Antifungal Therapy

Increases in rates as well as morbidity and mortality associated with fungal infections have necessitated the need for additional antifungal agents. Recent research has resulted in the introduction of 3 new antifungal agents: micafungin, anidulafungin, and posaconazole. Micafungin and anidulafungin, both potent inhibitor of 1,3-beta-D-glucan synthase, are the second and third available agents in the echinocandins class that are available in clinical practice. Posaconazale, a potent inhibitor of ergosterol synthesis, is a new agent in the triazole class that has shown promising clinical efficacy in the treatment and prophylaxis of invasive fungal infections due to Candida as well as molds. This article reviews the clinical efficacy as well as the approved uses and dosages associated with the use of these new antifungal agents. Other considerations, such as precautions, administration techniques, potential drug interactions, and common adverse effects associated with the use of these agents, are also reviewed.

Perceived Motivating Factors and Barriers for the Completion of Postgraduate Training Among American Pharmacy Students Prior to Beginning Advanced Pharmacy Practice Experiences

Objective. To examine perceived motivating factors and barriers (MFB) to postgraduate training (PGT) pursuit among pharmacy students. Methods. Third-year pharmacy students at 13 schools of pharmacy provided demographics and their plan and perceived MFBs for pursuing PGT. Responses were characterized using descriptive statistics. Kruskal-Wallis equality-of-proportions rank tests determined if differences in perceived MFBs existed between students based on plan to pursue PGT. Results. Among 1218 (69.5%) respondents, 37.1% planned to pursue PGT (32.9% did not, 30% were undecided). Students introduced to PGT prior to beginning pharmacy school more frequently planned to pursue PGT. More students who planned to pursue PGT had hospital work experience. The primary PGT rationale was, “I desire to gain more knowledge and experience.” Student debt was the most commonly cited barrier. Conclusion. Introducing pharmacy students early to PGT options and establishing work experiences in the hospital setting may increase students’ desire to pursue PGT.

Design and Validation of Patient-Centered Communication Tools (PaCT) to Measure Students' Communication Skills

Objective. To develop a comprehensive instrument specific to student pharmacist-patient communication skills, and to determine face, content, construct, concurrent, and predictive validity and reliability of the instrument. Methods. A multi-step approach was used to create and validate an instrument, including the use of external experts for face and content validity, students for construct validity, comparisons to other rubrics for concurrent validity, comparisons to other coursework for predictive validity, and extensive reliability and inter-rater reliability testing with trained faculty assessors. Results. Patient-centered Communication Tools (PaCT) achieved face and content validity and performed well with multiple correlation tests with significant findings for reliability testing and when compared to an alternate rubric. Conclusion. PaCT is a useful instrument for assessing student pharmacist communication skills with patients.

Effects of Empiric Antifungal Therapy for Septic Shock on Time to Appropriate Therapy for Candida Infection: A Pilot Study

PURPOSE Inappropriate initial therapy for Candida-related septic shock is common and associated with a high mortality rate. This before-after pilot study was conducted to determine the feasibility of using empiric therapy for reducing the time to appropriate antifungal therapy in patients with Candida-related septic shock. METHODS Patients aged 18-99 years with septic shock presenting to Barnes-Jewish Hospital, St. Louis, Missouri, in 2012-2013 were assigned to 1 of 2 groups. Patients presenting between January 1, 2012, and December 31, 2012, were managed according to local standard of care for patients with septic shock, to include antifungal therapy at the discretion of the treating physician (standard therapy group). Patients presenting between January 1, 2013, and December 31, 2013, received empiric antifungal therapy (primarily micafungin 100 mg/d or fluconazole 800 mg on day 1, followed by 400 mg/d), facilitated by a clinical pharmacist in the medical intensive care unit, until microbiologic cultures were available to determine the cause of septic shock (empiric therapy group). The primary outcome was time to appropriate therapy after shock onset. FINDINGS A total of 28 patients were enrolled (mean age, 56.3 [15.1] years [range, 30-92 years]; 16 [57.1%] men). The time to appropriate therapy after shock onset was statistically shorter with empiric therapy (n = 13) compared with standard therapy (n = 15) (10.6 [15.8] vs 40.5 [26.0] hours; P = 0.001). Patients receiving empiric therapy were more likely to have received appropriate therapy within 12 hours (69.2% vs 6.7%; P = 0.001) and within 24 hours (76.9% vs 40.0%; P = NS) of shock onset. In an analysis to determine the number of septic shock patients needed to be treated with empiric antifungal therapy for 1 patient with Candida-related septic shock to receive appropriate treatment, 256 patients without Candida infection received a total of 687 doses of empiric antifungal therapy (mean, 2.7 doses per patient) compared with 136 patients who received 382 doses of standard antifungal therapy (mean, 2.8 doses per patient); the number needed to treat was 19.6. IMPLICATIONS The present pilot study demonstrated that the use of empiric antifungal therapy for Candida-related septic shock was associated with a statistically shorter time to administration of appropriate treatment. ClinicalTrials.gov identifier.

Controversies and advances in the management of ventilator associated pneumonia

ABSTRACT Introduction: Although national surveillance data suggests that the incidence of ventilator associated pneumonia (VAP) is down-trending, it remains one of the most commonly encountered hospital acquired infections in the United States and worldwide. Its association with increased healthcare costs and worsened patient outcomes warrants continued effort to improve the care of patients with VAP. Areas covered: The increasing prevalence of multi-drug resistant bacteria further drives the need to explore advances in diagnostic and treatment options. In this review, controversies pertaining to the definition and diagnosis of VAP as well as empiric treatment strategies will be discussed along with several developments related to rapid microbiologic testing methods and the use of non-traditional antimicrobial agents. Expert commentary: The application of rapid diagnostic techniques to identify microbial pathogens is perhaps one of the most impactful advancements in the treatment of serious nosocomial infections. This technology has the potential to reduce inappropriate initial antimicrobial therapy, unnecessary antimicrobial exposure, and mortality in patients with VAP. In addition, the anticipated approval of new antimicrobial agents within the next several years will provide a much-needed expansion of available treatment options in an era of growing antimicrobial resistance.