Omar Abu Saleh

Efficacy of Antitoxin Therapy in Treating Patients With Foodborne Botulism: A Systematic Review and Meta-analysis of Cases, 1923–2016

Background Botulism is a rare, potentially severe illness, often fatal if not appropriately treated. Data on treatment are sparse. We systematically evaluated the literature on botulinum antitoxin and other treatments. Methods We conducted a systematic literature review of published articles in PubMed via Medline, Web of Science, Embase, Ovid, and Cumulative Index to Nursing and Allied Health Literature, and included all studies that reported on the clinical course and treatment for foodborne botulism. Articles were reviewed by 2 independent reviewers and independently abstracted for treatment type and toxin exposure. We conducted a meta-analysis on the effect of timing of antitoxin administration, antitoxin type, and toxin exposure type. Results We identified 235 articles that met the inclusion criteria, published between 1923 and 2016. Study quality was variable. Few (27%) case series reported sufficient data for inclusion in meta-analysis. Reduced mortality was associated with any antitoxin treatment (odds ratio [OR], 0.16; 95% confidence interval [CI], .09-.30) and antitoxin treatment within 48 hours of illness onset (OR, 0.12; 95% CI, .03-.41). Data did not allow assessment of critical care impact, including ventilator support, on survival. Therapeutic agents other than antitoxin offered no clear benefit. Patient characteristics did not predict poor outcomes. We did not identify an interval beyond which antitoxin was not beneficial. Conclusions Published studies on botulism treatment are relatively sparse and of low quality. Timely administration of antitoxin reduces mortality; despite appropriate treatment with antitoxin, some patients suffer respiratory failure. Prompt antitoxin administration and meticulous intensive care are essential for optimal outcome.

Hypokalemia and hypertension associated with supratherapeutic posaconazole levels

We report a case of posaconazole toxicity in a 44-year-old man with a history of diffuse large B cell lymphoma. He achieved disease remission following 4 cycles of chemotherapy, with the last cycle administered over a year prior to presentation. He presented with several weeks of fatigue, nonproductive cough, fever, and night sweats. 18F-fluoro-deoxyglucose (FDG) positron emission computed tomography demonstrated numerous FDG-avid pulmonary nodules and mediastinal and bilateral hilar adenopathy without evidence of recurrent lymphoma at the site of prior nasal involvement. Granulomatous inflammation was present upon mediastinal lymph node biopsy. Histoplasma antibody complement fixation and histoplasma urine antigen levels were consistent with pulmonary histoplasmosis. The patient was initially started on itraconazole. However, he developed generalized pruritus and an urticarial rash 5 days after starting itraconazole. The rash resolved after itraconazole was stopped. Skin testing was negative for posaconazole, fluconazole, and voriconazole. Therefore, the patient was switched to posaconazole delayed-release tablets (300 mg daily), which he tolerated without issues. A serum posaconazole level measured 2 weeks after initiation of therapy was 7,980 ng/ml; therefore, the posaconazole dose was decreased to 200 mg daily. Two months after initiating antifungal therapy, he developed fatigue, polyuria, and hypertension, with a blood pressure of 154/98 mm Hg. Serum chemistries were notable for potassium at 2.2 mmol/liter and a posaconazole level of 5,180 ng/ml. Laboratory studies were notable for mild metabolic alkalosis and a urine transtubular potassium excretion gradient of 6.3%, suggestive of inappropriate renal potassium wasting. In addition, early-morning plasma renin ( 0.7 ng/ml) and aldosterone ( 4.0 ng/dl) levels were undetectable, with a normal early-morning serum cortisol level (17 g/dl). No gastrointestinal or other source of potassium loss could be identified, and the patient was on no other medications. An echocardiogram (ECG) demonstrated sinus bradycardia and a prominent U wave, prompting admission for cardiac monitoring and intravenous potassium repletion. He received 290 meq of potassium and was started on oral potassium supplementation. The posaconazole dose was further decreased to 100 mg daily. A subsequent posaconazole level was measured at 2,160 ng/ml, with resolution of the alkalosis, hypokalemia, and hypertension. Posaconazole is a potent, extended-spectrum triazole antifungal approved for the treatment and prophylaxis of serious fungal infections. Use of the oral-suspension formulation of posaconazole is often hindered by subtherapeutic levels due to poor absorption, and high drug levels are rarely achieved. However, with the newer delayedrelease tablet formulation, more patients achieve high serum drug concentrations (1, 2). At our institution, we usually obtain posaconazole trough levels at least once after initiation, with a general goal of at least 1,000 to 1,250 ng/ml for treatment of fungal infections, based on improved response rates with higher serum drug levels in a study of salvage therapy for invasive aspergillosis. Dose adjustment is not typically required Accepted manuscript posted online 6 February 2017 Citation Mahmood M, Abu Saleh O, Sohail MR. 2017. Hypokalemia and hypertension associated with supratherapeutic posaconazole levels. Antimicrob Agents Chemother 61:e00019-17. https://doi.org/ 10.1128/AAC.00019-17. Copyright

Infectious complications in patients on treatment with Ruxolitinib: case report and review of the literature

Abstract Background: Primary myelofibrosis is a chronic myeloproliferative neoplasm that may cause debilitating symptoms, which can be improved with the use of Ruxolitinib, a Janus kinase 2 inhibitor. However, this agent has significant immunomodulatory effects which may increase the risk for infections. Methods: We searched the literature and our institutional electronic medical record for reported cases of infections in adult patients on ruxolitinib treatment. Results: We found 28 cases in our literature search and 4 cases from our Institution for a total of 32 cases. The most common infection was tuberculosis in 11/32 cases (34%), followed by cryptococcal infection in 3/32 (9%) and hepatitis B virus reactivation in 3/32 (9%). Conclusion: Opportunistic infections associated with ruxolitinib use are increasingly reported in the literature; further studies should investigate the role of systematic screening and prophylaxis against infections in this subset of patients.

Development of high-grade daptomycin resistance in Corynebacterium striatum while on therapy

We report a case of a 62-year-old male with ischemic cardiomyopathy complicated by cardiogenic shock who underwent placement of a left-ventricular assist device (LVAD; HeartMate II) in July 2013 as destination therapy. This was complicated by a sternal infection with Candida albicans and Staphylococcus epidermidis in October 2013, which was managed conservatively with chronic suppression with fluconazole and minocycline. In December 2016, he presented with a febrile illness without localizing signs and was diagnosed with a Corynebacterium striatum bloodstream infection, which cleared within 24 h of vancomycin initiation. Computed tomography (CT) of the chest, abdomen, and pelvis noted a tiny amount of retrosternal fluid adjacent to the LVAD cannula. Transesophageal echocardiography (TEE) was not suggestive of endocarditis. Susceptibility testing revealed resistance to ciprofloxacin (MIC of 2 g/ml), clindamycin (MIC of 2 g/ml), ceftriaxone (MIC of 2 g/ml), and trimethoprim-sulfamethoxazole (MICs of 2/38 g/ml). The isolate was susceptible to meropenem (MIC of 0.25 g/ml), vancomycin (MIC of 1 g/ml), linezolid (MIC of 2 g/ml), and doxycycline (MIC of 4 g/ml) and intermediately susceptible to penicillin (MIC of 1 g/ml). Daptomycin susceptibility testing was performed by the concentration gradient diffusion method Etest on Mueller-Hinton agar containing 5% sheep blood and revealed a MIC of 0.12 g/ml. He was switched to intravenous daptomycin (6 mg/kg/day) for outpatient therapy for 7 weeks with plans for chronic suppression. About 6 weeks into therapy, the patient was readmitted with recurrence of fevers and chills. Blood cultures grew a C. striatum strain that had developed high-grade daptomycin resistance (MIC of 256 g/ml) but retained susceptibility to vancomycin (MIC of 1 g/ml). His intravenous line was removed, a tip culture was negative, and TEE and CT results were unchanged. He was switched to intravenous vancomycin, and his blood cultures cleared within 24 h. He is currently undergoing 6 weeks of vancomycin therapy without a relapse of bacteremia. An increase in the number of clinically significant infections due to Corynebacterium sp. is reported as more complex patients are managed with immunosuppression and long-term prosthetic devices. Daptomycin inhibits bacterial replication by multiple mechanisms, including membrane targeting and interruption of cell wall synthesis, resulting in disruption of the bacterial cell wall and leakage of cellular components and cell death. Data are limited regarding the development of high-grade daptomycin resistance during therapy. We performed a literature search and identified three similar cases of patients with LVAD-associated infections with C. striatum that developed high-grade daptomycin resistance during therapy, resulting in relapsed infection (1, 2). The genetic basis of daptomycin resistance in Corynebacterium sp. is not fully understood. It is proposed that a large bacterial burden with large prosthetic devices and/or prolonged exposure to daptomycin may be causative factors. In other Grampositive pathogens, such as Staphylococcus aureus and Enterococcus sp., mutations Accepted manuscript posted online 8 May 2017 Citation Ajmal S, Saleh OA, Beam E. 2017. Development of high-grade daptomycin resistance in a patient being treated for Corynebacterium striatum infection. Antimicrob Agents Chemother 61:e00705-17. https://doi .org/10.1128/AAC.00705-17. Copyright

Coadministration of liposomal amphotericin B and contrast medium does not increase risk of kidney injury

ABSTRACT Intravenous radiographic contrast medium and amphotericin B are commonly required in the care of patients with fungal infections. Both interventions have proposed nephrotoxicity through similar mechanisms. We systematically examined patients who received coadministration of liposomal amphotericin B (AmBisome; GE Healthcare) and intravenous contrast medium within a 24-h period and compared the results for those patients with the results for patients who underwent non-contrast medium studies. We found 114 cases and 85 controls during our study period. Overall, no increased risk of renal injury was seen with coadministration of these 2 agents. Adjustment for age, baseline kidney function, and other clinical factors through propensity score adjustment did not change this result. Our observations suggest that, when clinically indicated, coadministration of contrast medium and liposomal amphotericin B does not present excess risk compared with that from the administration of liposomal amphotericin B alone.

Unrecognized pre-transplant disseminated Coxiella burnetti infection diagnosed in a post-transplant heart-kidney recipient

To the best of our knowledge, we report the first case of pre‐transplant unrecognized disseminated Coxiella burnetii infection, unmasked in the post‐transplant period leading to both heart and kidney allograft dysfunction. A 59 year old man with a history of simultaneous heart‐kidney transplantation due to end stage heart failure from severe aortic regurgitation (AR) and cryoglobulinemic immune complex mediated concentric necrotizing glomerulonephritis (GN), presents with a history of intermittent fevers and fatigue. Prior to transplantation he was treated for multiple episodes of culture negative endocarditis requiring bio‐prosthetic valve replacement. Evaluation of fever included a transesophageal echocardiogram (TEE) that revealed a large hyperechoic mass on the anterior mitral leaflet with perforation, severe mitral regurgitation and moderate AR. Blood cultures were negative at that time. Owing to development of allograft mitral and aortic valve insufficiency, he underwent allograft bio‐prosthetic mitral valve (MV) replacement and aortic valvuloplasty 2 years following his transplantation. Pathologic examination of the allograft mitral valve demonstrated fibrinopurulent exudate with degenerating bacterial organisms, consistent with vegetation and myxoid degenerative changes. Due to a high suspicion for native heart C. burnetii prosthetic valve endocarditis prior to transplantation, we re‐evaluated the native explanted heart histopathology, as well as the explanted allograft MV. Cardiac allograft and native MV were positive for C. burnetii by real‐time PCR. C. burnetii serology was consistent with persistent infection as well.

Disseminated blastomycosis in a transplant patient

A 51‐year‐old woman from Wisconsin with past medical history of kidney transplantation from her sibling 8 weeks prior, presented with symptoms of shortness of breath, cough, and a new skin rash over a 2‐week period.

Diagnostic evaluation and management of culture-negative cardiovascular implantable electronic device infections

Culture‐negative (CN) cardiovascular implantable electronic device (CIED) infections represent a significant management challenge for clinicians with no specific guidelines addressing this subgroup of patients. The aim of the current investigation is to report our institutional experience of CN CIED infections and propose a systematic approach to diagnostic evaluation and management of these complicated cases based on our observations.

Clinical Manifestations and Outcomes of Fluoroquinolone-Related Acute Interstitial Nephritis

Objective: To describe the clinical presentation, diagnosis, and outcomes of patients with biopsy‐proven acute interstitial nephritis (AIN) related to fluoroquinolone (FQ) therapy. Patient and Methods: We conducted a retrospective review of biopsy‐proven AIN attributed to FQ use at Mayo Clinics campus in Rochester, Minnesota, from January 1, 1993, through December 31, 2016. Cases were reviewed by a renal pathologist and attributed to FQ use by an expert nephrologist. We also reviewed and summarized all published case reports of biopsy‐proven AIN that were attributed to FQ use. Results: We identified 24 patients with FQ‐related biopsy‐proven AIN at our institution. The most commonly prescribed FQ was ciprofloxacin in 17 patients (71%), and the median antibiotic treatment duration was 7 days (interquartile range [IQR], 5‐12 days). The median time from the initiation of FQ to the diagnosis of AIN was 8.5 days (IQR, 3.75‐20.75 days). Common clinical manifestations included fever (12; 50%), skin rash (5; 21%), and flank pain (2; 8%), and 9 (38%) had peripheral eosinophilia. However, 4 (17%) of the patients were asymptomatic at the time of diagnosis and AIN was suspected on the basis of routine laboratory monitoring. Most patients (17; 71%) recovered after the discontinuation of antibiotic therapy, and renal function returned to baseline at a median of 20.5 days (IQR, 11.75‐27.25 days). Six patients (25%) required temporary hemodialysis, and 14 patients (58%) received corticosteroid therapy. Conclusion: The onset of FQ‐related AIN can be delayed, and a high index of suspicion is needed by physicians evaluating these patients. Overall outcomes are favorable, with recovery to baseline renal function within 3 weeks of discontinuing the offending drug.

Mycobacterium genavense infections in non-HIV immunocompromised hosts: a systematic review

Abstract Background: Mycobacterium genavense is a non-tuberculous mycobacterium which can rarely cause disease in non-HIV immunocompromised hosts. We describe our experience with this unusual infection and perform a systematic review of the literature to describe the features of M. genavense infection in non-HIV immunocompromised hosts. Methods: All cases of Mycobacterium genavense infection in non-HIV patients at our institution were reviewed. In addition, we conducted a systematic review of the literature to identify previously published cases of M. genavense infections in non-HIV hosts. Findings: Two cases of M. genavense were identified at our center; a 51-year-old renal transplant recipient with a prosthetic knee joint infection and a 66-year-old woman with idiopathic CD4 lymphocytopenia with gastrointestinal tract disease. The systematic review identified 44 cases of M. genavense infection in non-HIV hosts. The most common underlying conditions were solid organ transplantation (40%), sarcoidosis (14%) and hematopoietic stem cell transplantation (7%). Disease most commonly involved the gastrointestinal tract, spleen, liver or bone marrow. Diagnosis was challenging with PCR required for identification in nearly all cases. Over one-third of patients died, which may reflect the combination of infection and underlying comorbidities. Overall cure was achieved in 61% with a mean duration of antimycobacterial therapy of 15.5 months (range 10–24). Conclusion: M. genavense infection is a rare mycobacterial infection in non-HIV immunocompromised hosts. It should be suspected in immunocompromised patients presenting with disseminated mycobacterial infection, acid fast bacilli on smear or histopathologic examination, with poor or no growth in mycobacterial cultures.