Jason N. Barreto

Emerging Issues in Gram-Negative Bacterial Resistance: An Update for the Practicing Clinician

The rapid and global spread of antimicrobial-resistant organisms in recent years has been unprecedented. Although resistant gram-positive infections have been concerning to clinicians, the increasing incidence of antibiotic-resistant gram-negative infections has become the most pressing issue in bacterial resistance. Indiscriminate antimicrobial use in humans and animals coupled with increased global connectivity facilitated the transmission of gram-negative infections harboring extended-spectrum β-lactamases in the 1990s. Carbapenemase-producing Enterobacteriaceae, such as those containing Klebsiella pneumoniae carbapenemases and New Delhi metallo-β-lactamases, have been the latest scourge since the late 1990s to 2000s. Besides β-lactam resistance, these gram-negative infections are often resistant to multiple drug classes, including fluoroquinolones, which are commonly used to treat community-onset infections. In certain geographic locales, these pathogens, which have been typically associated with health care-associated infections, are disseminating into the community, posing a significant dilemma for clinicians treating community-onset infections. In this Concise Review, we summarize emerging trends in antimicrobial resistance. We also review the current knowledge on the detection, treatment, and prevention of infection with these organisms, with a focus on the carbapenemase-producing gram-negative bacilli. Finally, we discuss emerging therapies and areas that need further research and effort to stem the spread of antimicrobial resistance.

Therapeutic review: Antiretroviral drugs

The first antiretroviral drug to be licensed, zidovudine, became available in 1987. Until December 1995, the antiretroviral drugs available and approved for clinical use in the United States consisted of only 5 individual drugs belonging to a single class of antiretroviral agents, nucleoside analog reverse transcriptase inhibitors. Since then, numerous other antiretroviral drugs and classes of antiretroviral drugs have been introduced. Additional drugs and newer classes of antiretrovirals are in various stages of development. Currently, there are 22 Food and Drug Administration (FDA)‐approved antiretroviral agents categorized in 4 classes of drugs: nucleoside/nucleotide analog reverse transcriptase inhibitors, nonnucleoside analog reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors. The authors review the general characteristics of each class of antiretroviral drugs, including mechanism of action, pharmacologic properties, adverse effects, and drug interactions. A synopsis of current antiretroviral treatment guidelines is also provided.

Retrospective Comparison of Posaconazole Levels in Patients Taking the Delayed-Release Tablet versus the Oral Suspension

ABSTRACT While posaconazole prophylaxis decreases the risk of invasive fungal infection compared to fluconazole, low bioavailability of the oral-suspension formulation limits its efficacy. A new delayed-release tablet formulation demonstrated an improved pharmacokinetic profile in healthy volunteers. However, serum levels for the two formulations have not been compared in clinical practice. This study compared achievement of therapeutic posaconazole levels in patients taking the delayed-release tablet to those taking the oral suspension. This retrospective cohort study included 93 patients initiated on posaconazole between 2012 and 2014 and had at least one serum posaconazole level measured. The primary measure was the proportion of patients achieving an initial therapeutic level (>700 ng/ml). An initial therapeutic posaconazole level was seen in 29 of 32 (91%) patients receiving tablets and 37 of 61 (61%) patients receiving suspension (P = 0.003). Among patients with a steady-state level measured 5 to 14 days after initiation, a therapeutic level was observed in 18 of 20 (90%) patients receiving tablets and 25 of 43 (58%) patients receiving suspension (P = 0.01). In these patients, the median posaconazole level of the tablet cohort (1655 ng/ml) was twice that of the suspension cohort (798 ng/ml) (P = 0.004). In this cohort study, the improved bioavailability of delayed-release posaconazole tablets translates into a significantly higher proportion of patients achieving therapeutic serum levels than in the cohort receiving the oral suspension. The results of this study strongly support the use of delayed-release tablets over suspension in patients at risk for invasive fungal infection.

Rothia Bacteremia: a 10-Year Experience at Mayo Clinic, Rochester, Minnesota

ABSTRACT Rothia spp. are Gram-positive cocco-bacilli that cause a wide range of serious infections, especially in immunocompromised hosts. Risk factors for Rothia mucilaginosa (previously known as Stomatococcus mucilaginosus) bacteremia include prolonged and profound neutropenia, malignancy, and an indwelling vascular foreign body. Here, we describe 67 adults at the Mayo Clinic in Rochester, MN, from 2002 to 2012 with blood cultures positive for Rothia. Twenty-five of these patients had multiple positive blood cultures, indicating true clinical infection. Among these, 88% (22/25) were neutropenic, and 76% (19/25) had leukemia. Common sources of bacteremia were presumed gut translocation, mucositis, and catheter-related infection. One patient died with Rothia infection. Neutropenic patients were less likely to have a single positive blood culture than were nonneutropenic patients. Antimicrobial susceptibility testing was performed on 21% of the isolates. All of the tested isolates were susceptible to vancomycin and most beta-lactams; however, four of six tested isolates were resistant to oxacillin. There was no difference between the neutropenic and nonneutropenic patients in need of intensive care unit care, mortality, or attributable mortality.

The incidence of invasive fungal infections in neutropenic patients with acute leukemia and myelodysplastic syndromes receiving primary antifungal prophylaxis with voriconazole

The objective of this study is to characterize the outcomes of primary antifungal prophylaxis with voriconazole in patients receiving intensive chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS). We conducted a single center, retrospective, cohort study of consecutive adult patients with AML or MDS at Mayo Clinic between January 1, 2006 and July 1, 2010. The study included patients undergoing induction or first relapse combination chemotherapy who received voriconazole 200 mg orally twice daily as prophylaxis during the neutropenic phase. Patient records were evaluated until 30 days after neutrophil recovery for development of invasive fungal infection (IFI) as defined per EORTC/MSG 2008 criteria with computed tomography scans independently reviewed by a radiologist. Therapeutic drug monitoring and reasons for voriconazole discontinuation were documented. Twenty four episodes of IFI were detected among 165 consecutive patients for an overall incidence of 145 per 1000 patients. The incidence of IFI was 24, 42, and 78 per 1000 patients for proven, probable, and possible infection, respectively. Four patients developed proven IFI (n = 2 Aspergillus spp., n = 2 Rhizopus spp.). Serum voriconazole trough concentrations were available in 39 patients, and no statistically significant difference in voriconazole trough level was observed between those with versus without an IFI. Voriconazole prophylaxis was discontinued in 81 patients due to suspected IFI (n = 24), fever of unknown origin (n = 19), adverse events (n = 23), and other causes (n = 17). Voriconazole as primary IFI prophylaxis is safe and may be beneficial in AML/MDS patients receiving intensive chemotherapy. Am. J. Hematol. 88:283–288, 2013.

Antineoplastic Agents and the Associated Myelosuppressive Effects A Review

Bone marrow is a complex organ responsible for the regulation of hematopoietic cell distribution throughout the human body. Patients receiving antineoplastic agents as a therapeutic intervention for hematologic malignancy often experience varying degrees of myelotoxicity. Antineoplastic agents cause hypocellularity in marrow resulting in a reduction in hematopoietic tissue activity and a corresponding decline in cell production. Quantifying the adverse effects on hematopoiesis is based on the properties of a single agent, the use of individual drugs within a combination chemotherapy regimen, and the course, or courses, of chemotherapy designed to treat cancer. The direct or indirect suppression of erythrocytes, granulocytes, and megakaryocytes has potential for multiple negative clinical consequences ranging from increased monitoring of blood counts to life-threatening infection and death. This review will provide an overview of the structure and function of competent adult bone marrow, describe the process of hematopoiesis, and characterize the myelotoxicities associated with common antineoplastic agents currently used in the treatment of cancer.

Cystatin C–Guided Vancomycin Dosing in Critically Ill Patients: A Quality Improvement Project

BACKGROUND The aim of the study was to determine whether a vancomycin dosing algorithm based on estimated glomerular filtration rate from creatinine and cystatin C levels (eGFRcr-cys) improves target trough concentration achievement compared to an algorithm based on estimated creatinine clearance (eCLcr) in critically ill patients. STUDY DESIGN This prospective quality improvement project evaluated intensive care unit (ICU) patients started on intravenous vancomycin using one of 2 different strategies. Dosing regimens were selected and implemented after an individualized goal trough range was established (10-15 or 15-20mg/L). Steady-state goal trough achievement was compared between treatment arms with and without adjustment for potential confounders. SETTING & PARTICIPANTS 3 medical and surgical ICUs at a single tertiary medical center. QUALITY IMPROVEMENT PLAN During January 2012 to October 2013, vancomycin was dosed according to eCLcr using the Cockcroft-Gault formula (control arm). During December 2013 to May 2015, a multidisciplinary quality improvement team implemented a novel vancomycin dosing algorithm according to eGFRcr-cys using the CKD-EPI equation (intervention arm). OUTCOME Steady-state initial goal vancomycin trough concentration achievement. MEASUREMENTS & RESULTS More patients in the intervention arm (67 of 135 [50%]) achieved therapeutic trough vancomycin levels than in the control arm (74 of 264 [28%]; OR, 2.53; 95% CI, 1.65-3.90; P<0.001). Improved trough achievement was maintained even after adjustment for age, sex, APACHE (Acute Physiology and Chronic Health Evaluation) III score, fluid balance, baseline CLcr, surgical admission diagnosis, presence of sepsis, and goal trough concentration range (adjusted OR, 2.79; 95% CI, 1.76-4.44; P<0.001). Clinical outcomes were similar between groups. LIMITATIONS Nonrandomized, incomplete algorithm compliance. CONCLUSIONS A vancomycin dosing nomogram based on eGFRcr-cys significantly improved goal trough achievement compared to eCLcr among ICU patients with stable kidney function. Further studies are warranted to characterize the relationship between use of cystatin C-guided dosing and clinical outcomes.

Serum Peak Sulfamethoxazole Concentrations Demonstrate Difficulty in Achieving a Target Range: A Retrospective Cohort Study

Objectives Trimethoprim (TMP)/sulfamethoxazole (SMX) has consistently demonstrated great interindividual variability. Therapeutic drug monitoring may be used to optimize dosing. Optimal peak SMX concentration has been proposed as 100 to 150 μg/mL. The objective of our work was to determine the success rate of a TMP/SMX dosing guideline in achieving a targeted serum peak SMX concentration range. Methods Our retrospective cohort study enrolled 305 adult hospitalized patients who received treatment with TMP/SMX and underwent serum peak SMX concentration monitoring from January 2003 to November 2011. Patients receiving low-dose TMP/SMX therapy (TMP <15 mg/kg/d) were compared with those receiving high-dose therapy (TMP >15 mg/kg/d). Results Patients were classified into peak and modified peak SMX concentration cohorts based on time between TMP/SMX dose and SMX quantification. The association between dosing group and the outcome of the SMX level within the goal range was measured using logistic regression models. The primary outcome measured was serum peak SMX concentration 100 to 150 μg/mL. Serum peak SMX concentrations were attained within range for the peak and modified peak cohort 29% and 26% of the time, respectively. The median peak SMX concentration was 144 μg/mL (range 25–471 μg/mL). The low daily dose cohort demonstrated a trend toward improvement in the odds of target peak concentration range attainment. The results were similar regardless of the method used to adjust for baseline characteristics. The pure peak and modified peak cohorts had 44% and 46% of patients with above-target SMX peak concentrations, respectively. Conclusions Attainment of the intended target concentration range was low with no difference in attainment between the low-dose and high-dose cohorts. Higher proportions of patients had an above-target SMX peak, which may indicate that the dosing algorithm is overly aggressive in obtaining the therapeutic goal.

Characterization of Admission Types in Medically Hospitalized Patients Prescribed Clozapine

BACKGROUND Clozapine is the antipsychotic of choice for treatment-resistant schizophrenia; however, rigorous monitoring is required to prevent or detect adverse drug events that contribute to morbidity and mortality. In addition to the Food and Drug Administration (FDA) boxed safety warnings specific to clozapine (agranulocytosis, hypotension, seizures, and cardiomyopathy/myocarditis), other adverse events such as pneumonia and gastrointestinal hypomotility have been reported in the literature to result in hospitalization. OBJECTIVE To explore the reasons for medical hospitalization in patients prescribed clozapine, a retrospective chart review was completed. METHODS Adults with schizophrenia or schizoaffective disorder prescribed clozapine were identified if they had a nonpsychiatric medical admission between 1/1/2003 and 8/1/2015. Demographics, admitting diagnosis, admitting service type, psychiatric consult information, clozapine dosing, and drug interactions were collected. RESULTS Overall, 104 patients, representing 248 hospitalizations, were admitted to a medical unit during the study period. The predominant admission types were for the management of either pulmonary (32.2%) or gastrointestinal (19.8%) illnesses. The most common pulmonary diagnosis was pneumonia, accounting for 58% of pulmonary admissions. Further, 61.2% of the gastrointestinal admissions were related to hypomotility, ranging from constipation to death. Clozapine was discontinued owing to neutropenia in 2 patients; however, in both cases concomitant chemotherapy had been given. CONCLUSION In patients prescribed clozapine admitted to nonpsychiatric medical settings, gastrointestinal and pulmonary illnesses were common, but not illnesses related to boxed warnings. Additional research is needed to better assess the causality and true incidence of gastrointestinal or pulmonary events associated with clozapine. Furthermore, clinicians must be prepared to prevent, detect, and manage potentially life-threatening events associated with clozapine.

Low incidence of Pneumocystis pneumonia utilizing PCR-based diagnosis in patients with B-cell lymphoma receiving Rituximab-containing combination chemotherapy

Recent literature has demonstrated concern over the risk of Pneumocystis jirovecii pneumonia (PJP) when administering rituximab with combination chemotherapy such as in R‐CHOP; however, the exact risk and potential need for prophylaxis is unknown. We sought to determine the incidence of PJP infection following R‐CHOP administration in patients with B‐cell lymphoma. Consecutive patients diagnosed with B‐cell lymphoma receiving R‐CHOP were evaluated from chemotherapy initiation until 180 days after the last administration. The primary outcome was cumulative incidence of PJP infection. Secondary endpoints included the association of rituximab, prednisone and subsequent chemotherapy with PJP infection risk. A total of 689 patients (53% male, median age 66 years) were included. Seventy‐three percent of patients completed at least 6 cycles of R‐CHOP treatment. Median rituximab and prednisone cumulative doses were 3950 mg and 5325 mg, respectively. Median daily prednisone dose through end of treatment was 45 mg (range 7.6 mg to 119 mg). The cumulative incidence of PJP was 1.51% (95% CI 0.57–2.43, at maximum follow‐up of 330 days), below 3.5%, the conventional threshold for prophylaxis. Univariate analysis did not detect a statistically significant association between PJP and rituximab, steroids, or receipt of additional chemotherapy in this patient population. Our results demonstrate a low occurrence of Pneumocystis pneumonia during R‐CHOP treatment of B‐cell lymphoma and argue against universal anti‐Pneumocystis prophylaxis in this setting. Further investigations should focus on targeted anti‐Pneumocystis prophylaxis for patients presenting with high‐risk baseline characteristics or when receiving rituximab‐inclusive intensive combination chemotherapy regimens as treatment for other aggressive lymphoma subtypes. Am. J. Hematol. 91:1113–1117, 2016.