Paul O. Lewis

Pathophysiologic studies in human rabies

Six patients with proved rabies were studied with a combination of clinical, physiologic and pathologic technics. Three were given a type of intensive care but died with evidence of respiratory failure. Although circulatory failure did not develop in any of the six patients, three had supraventricular arrhythmias: interstitial myocarditis was found in one of these and rabies virus was isolated from the myocardium of another. Inspiratory muscle spasm was the dominant clinical feature in all cases. This occurred as part of the hydrophobic response and followed stimulation of the upper respiratory tract and skin. Hydrophobia may represent an exaggerated respiratory tract irritant reflex with associated arousal. Later in the course of the disease, various patterns of periodic and ataxic breathing were observed. Widespread brain stem encephalitis was discovered at autopsy, with particular involvement of the neighborhood of the nucleus ambiguous in two of three patients examined. In one patient cerebral metabolism was grossly abnormal, with greatly reduced cerebral oxygen consumption suggesting irreversible brain damage. Respiratory and circulatory disturbances may well be immediate causes of death in patients with rabies, but the present studies reemphasize the severity of the encephalitis which remains the ultimate barrier to survival. In the developing countries in which rabies is still a major problem and in which the cost precludes intensive care, the clinical management of rabies can aim only to reduce suffering by heavy sedation.

Risk and Severity of Hospital‐Acquired Clostridium difficile Infection in Patients Taking Proton Pump Inhibitors

To compare the rates and severity of hospital‐acquired Clostridium difficile infection (CDI) among patients taking proton pump inhibitors (PPIs) versus those not taking PPIs.

Ceftolozane–tazobactam: A new-generation cephalosporin

PURPOSE The chemistry, pharmacokinetic and pharmacodynamic properties, efficacy, and safety of the recently introduced combination antimicrobial agent ceftolozane-tazobactam are reviewed. SUMMARY Ceftolozane-tazobactam (Zerbaxa, Cubist Pharmaceuticals) is a cephalosporin β-lactam and β-lactamase inhibitor marketed as a fixed-dose combination agent for the treatment of complicated urinary tract and intraabdominal infections. Its dosing and chemistry provide expansive antimicrobial coverage of gram-negative organisms, including Pseudomonas aeruginosa, and stable activity against many β-lactamases, as well as coverage of most extended-spectrum β-lactamase-producing organisms and some anaerobes. Ceftolozane-tazobactam is susceptible to hydrolysis by carbapenemase enzymes but is not affected by other resistance mechanisms such as efflux pumps and porin loss. Clinical trials demonstrated that combination treatment with ceftolozane-tazobactam plus metronidazole had efficacy comparable to that of levofloxacin in patients with complicated urinary tract infections, including pyelonephritis, and comparable to that of meropenem against complicated intraabdominal infections. A Phase III trial of ceftolozane-tazobactam versus meropenem for treatment of bacterial pneumonia, including ventilator-associated pneumonia, is underway. Adverse effects reported with ceftolozane-tazobactam use are comparable to those seen with other β-lactams (e.g., hypersensitivity, nausea, diarrhea, headache). Initially, ceftolozane-tazobactam may be reserved for targeted therapy against multidrug-resistant pathogens. CONCLUSION Ceftolozane-tazobactam is a new cephalosporin with enhanced activity against multidrug-resistant P. aeruginosa and other gram-negative pathogens.

Comparison of three generic vancomycin products using liquid chromatography–mass spectrometry and an online tool

PURPOSE Three different generic vancomycin products were compared using liquid chromatography-mass spectrometry (LC-MS) and open-access metabolomic tools. METHODS Single-lot samples of vancomycin hydrochloride from three different manufacturers (Hospira, APP Pharmaceuticals, and Pfizer) were reconstituted and injected into a high-resolution LC-MS system. The mass spectral fingerprints were compared for similarity of nonvancomycin B components using the XCMS Online system through Scripps University. Significance was defined as a p of ≤0.01 and a fold change of ≥1.5. The concentration of vancomycin B in each product was also measured using LC-MS on days 0, 1, 2, 4, 7, 10, and 14. RESULTS Qualitative comparisons of the products using the XCMS Online interface indicated the presence of significant differences among the products at the time of reconstitution; however, these variations seemed to converge after 14 days of storage. The concentration profiles of vancomycin B during refrigerated storage did not differ significantly among the three products. XCMS Online analyses revealed that the Pfizer and Hospira products were the most similar to each other. CONCLUSION While there were no significant differences found in the concentration of vancomycin B among Pfizer, APP, and Hospira products, there were differences in their initial mass spectral analysis after reconstitution. Liquid chromatography-tandem mass spectrometry profiles of the ions or isotopes present in the three products showed significant differences in impurities such as crystalline degradation product (CDP)-1 and CDP intermediate. After 14 days of refrigerated storage, the differences among the products converged, and fewer distinct features could be detected.

Implementation of Global Strategies to Prevent Hospital-Onset Clostridium difficile Infection: Targeting Proton Pump Inhibitors and Probiotics

Background: Proton pump inhibitors (PPIs) have been identified as a significant risk factor for the development of Clostridium difficile infection (CDI). Probiotics given concurrently with antibiotics have been shown to have a moderate impact on preventing CDI. Objective: To evaluate the effectiveness of hospital-wide interventions designed to reduce PPI use and increase probiotics and whether these interventions were associated with a change in the incidence of hospital onset (HO)-CDI. Methods: This retrospective cohort study compared 2 fiscal years: July 2013 to June 2014 (FY14) and July 2014 to June 2015 (FY15). In July of FY15, global educational initiatives were launched targeting PPIs. Additionally, a HO-CDI prevention bundle was added to antibiotic-containing order sets targeting probiotics. Overall PPI use, probiotic use, and incidence of HO-CDI were recorded and compared for each cohort. Charts were also reviewed for patients who developed HO-CDI for the presence and appropriateness of a PPI and presence of probiotics. Results: The interventions resulted in a decrease in PPI use by 14% or 96 doses/1000 patient days (TPD; P = 0.0002) and a reduction in IV PPI use by 31% or 71 doses/TPD (P = 0.0008). Probiotic use increased by 130% or 126 doses/TPD (P = 0.0006). The incidence of HO-CDI decreased by 20% or 0.1 cases/TPD (P = 0.04). Conclusions: A collaborative, multifaceted educational initiative directed at highlighting the risks associated with PPI use was effective in reducing PPI prescribing. The implementation of a probiotic bundle added to antibiotic order sets was effective in increasing probiotic use. These interventions were associated with a decrease in incidence of HO-CDI.

Successful stepdown treatment of pulmonary histoplasmosis with thrice-weekly liposomal amphotericin B in a hospital-associated, outpatient infusion centre: A case report

Amphotericin is the preferred treatment for pulmonary histoplasmosis during pregnancy. The long half‐life of amphotericin supports less than daily administration.

Rifampin-Resistant Staphylococcus aureus Bacteremia in a Patient on Chronic Rifaximin

We present a case of a 61-year-old man with a history of type 2 diabetes mellitus, hypertension, nonalcoholic cirrhosis (Child Pugh Class C), and hepatic encephalopathy, for which he was receiving chronic rifaximin for approximately 14 months. The patient initially presented with worsening confusion and fevers. Blood cultures were drawn, and computed tomography of the abdomen was performed, revealing a lumbosacral abscess. Subsequent magnetic resonance imaging demonstrated L2-3 diskitis with osteomyelitis. Culture and sensitivities revealed methicillin-resistant Staphylococcus aureus. Rifampin resistance was observed without prior exposure. The patient was initially treated with vancomycin. However, because of declining renal function, he was switched to daptomycin. Ultimately, the patient was put under comfort care because of lack of clinical response, worsening multiorgan failure, and overall declining status. Our 2016 hospital antibiogram demonstrates that less than 1% of 1550 S aureus isolates tested were resistant to rifampin. After reviewing our 2016 rifampin-resistant isolates, 3 additional patients who received chronic rifaximin for hepatic encephalopathy were identified (see Table 1). These patients had not previously received rifampin. Rifamycins, including rifampin and its semisynthetic derivative rifaximin, bind to bacterial DNA-dependent RNA polymerase, blocking transcription, leading to protein synthesis termination and bacterial growth inhibition. Rifamycins are most notably used in combination for treatment of mycobacterial infections, including tuberculosis. Additionally, rifampin is well described for biofilm penetration and synergy with other antimicrobials in treating staphylococcal prosthetic valve endocarditis and prosthetic joint infections. However, monotherapy with rifampin is not recommended because of the high propensity for resistance. Rifaximin was introduced in 2004 as monotherapy for the indication of traveler’s diarrhea. Subsequent indications include hepatic encephalopathy and irritable bowel syndrome. Resistance to this class is mediated by mutations in the rpoB gene, resulting in reduced binding affinity on RNA polymerase. The prescribing information states that rifaximin is poorly absorbed, achieving average steady-state maximum concentrations of 3.4 ± 1.6 ng/mL in healthy individuals and 39.7 ± 13.4 ng/mL in Child-Pugh Class C; also, crossresistance between rifaximin and other classes of antimicrobials has not been well observed. As rifaximin use continues to increase, the concern for rifaximin-induced rifamycin resistance to S aureus, Clostridium difficile, Mycobacterium tuberculosis, and Neisseria meningitidis continues to increase. Valentin et al demonstrated the emergence of rifampin-resistant staphylococci on the skin after ingesting rifaximin in 7 out of 11 healthy volunteers. Another case similar to ours describes rifampin-resistant S aureus bacteremia in a patient who had been treated with rifaximin 400 mg 3 times daily for hepatic encephalopathy for the previous 6 weeks, supporting the potential for cross-resistance. A compelling argument against rifaximin cross-resistance is its low systemic absorption. However, absorption increases a minimum of 10-fold in patients with liver failure, a commonly targeted population and the indication for our 4 patients. Absorption is also possible in patients without liver failure and at high enough concentrations to cause drug interactions. One case describes increased warfarin metabolism as a result of rifaximin in a patient being treated for small intestine bacterial overgrowth, another condition potentially resulting in increased absorption. Even without absorption, staphylococci still colonize the gastrointestinal tract and perianal area, which may harbor rifaximin-exposed, rifampin-resistant isolates. Although we are unable to definitively state that the rifampin resistance is caused by rifaximin, rifampin resistance at our institution is extremely uncommon, and a rise in rates raises concern. Further studies are needed to examine causality and evaluate the relative risk of rifaximin use on resistance. Given these concerns, prescribers should use caution when selecting rifaximin for chronic use and 701221 AOPXXX10.1177/1060028017701221Annals of PharmacotherapyLewis et al letter2017

Stability of a pyrimethamine suspension compounded from bulk powder

Purpose. Development of a stability‐indicating high‐performance liquid chromatography (HPLC) method for pyrimethamine analysis, with subsequent application of that method to assess the 90‐day stability of a pyrimethamine suspension compounded from bulk USP‐grade pyrimethamine powder, is described. Methods. A stability‐indicating method of HPLC with ultraviolet detection specific to pyrimethamine was developed according to pharmacopeial recommendations and validated. The method was applied to investigate the stability of a 2‐mg/mL pyrimethamine suspension in a vehicle consisting of Ora‐Plus and Ora‐Sweet (Perrigo) over a period of 90 days. Three replicate test preparations were stored at room temperature or refrigerated at 4.3–5.2 °C, and samples were analyzed in duplicate immediately after preparation and on study days 1, 2, 4, 7, 10, 14, 21, 30, 48, 60, 75, and 90. Results. The 2‐mg/mL suspension of pyrimethamine in Ora‐Plus and Ora‐Sweet retained 90–110% of the labeled potency to 90 days at both temperature ranges. However, color changes in the samples stored at room temperature observed at day 60 indicated that a beyond‐use date less than 90 days from the preparation date should be specified when the suspension is to be stored at room temperature. Conclusion. The study demonstrated that USP‐grade pyrimethamine powder can be formulated as a 2‐mg/mL suspension in a vehicle of Ora‐Plus and Ora‐Sweet and is stable when stored at room temperature and when refrigerated, in amber plastic bottles, for 48 and 90 days, respectively.

Antibiotic Use in Home Health A Primer

Cost containment measures within hospital systems push for earlier discharges on stable patients. Due to patient placement difficulties and costs associated with skilled facilities, antibiotic use in home health care settings is becoming a common occurrence. This trend will likely increase as care continues to shift to outpatient areas. Lack of sufficient serum drug concentrations needed in severe infections and increasing resistance to many of the oral options often necessitates the use of the intravenous (IV) route. Home health care practitioners may have minimal information on patients or limited experience with IV antibiotics that may impact quality of care. This review summarizes key points relevant to IV antibiotics routinely used by home health prescribers, nurses, technicians, and care managers. This review will focus on antibacterial agents including vancomycin, aminoglycosides, beta-lactams, daptomycin, tigecycline, and telavancin. Appropriate dosing, indications, adverse events, monitoring parameters, and feasibility of using IV antibiotics are discussed.

Vancomycin plus nafcillin salvage for the treatment of persistent methicillin-resistant Staphylococcus aureus bacteremia following daptomycin failure: a case report and literature review

Background: Evidence supporting beta-lactam plus vancomycin synergy for methicillin-resistant Staphylococcus aureus (MRSA) continues to grow. Current in vivo evidence demonstrates that combination therapy is associated with shorter time to blood sterilization than vancomycin monotherapy. However, this combination has not been reported as salvage therapy for persistent MRSA bacteremia. Case report: We report a case of an 81-year-old male who was successfully treated with vancomycin plus nafcillin after failing vancomycin monotherapy, daptomycin monotherapy, and daptomycin plus gentamicin combination therapy. The patient originally presented with sepsis from a suspected urinary tract infection. Blood cultures drawn on days 1, 3, 5, 15, 19, 23, and 28 remained positive for MRSA despite multiple antimicrobial therapy changes. On day 29, therapy was changed to vancomycin plus nafcillin. Blood cultures drawn on day 32 remained negative. After 11 days, nafcillin was changed to piperacillin–tazobactam due to an infected decubitus ulcer. The combination was continued for 42 days after achieving blood sterility, 71 days after the patient originally presented. Evidence regarding salvage therapy for persistent bacteremia is sparse and is limited to case reports and case series. Conclusion: This case report supports that vancomycin plus an anti-staphylococcal beta-lactam combination should be further studied as salvage therapy for persistent MRSA bacteremia.