Computing antimicrobial use/antimicrobial resistance ratios: A novel way to assess inpatient antimicrobial utilization using current National Healthcare Safety Network metrics.

BACKGROUND: Current methods for benchmarking inpatient antimicrobial use (AU) could benefit from combining AU with antimicrobial resistance (AR) information to provide metrics benchmarked to microbiological data; this may yield more instructive and better risk-adjusted measurements than AU and AR in isolation. METHODS: In this retrospective single-center study, we computed facility-wide AU/AR ratios from 2019 to 2020 for specific antimicrobial agents and corresponding AR events, and compared median monthly AU/AR ratios between March 2019 through December 2019 (pre-COVID period) and March 2020 through December 2020 (COVID period). Aggregate AU was expressed as a ratio to aggregate AR events for antimicrobials that typically have activity against the AR organism and are frequently used to treat the AR organism in clinical practice. We also computed AU/AR ratios in our surgical intensive care unit in the pre-COVID period. RESULTS: High-median facility-wide monthly AU/AR ratios were observed for intravenous vancomycin/methicillin-resistant Staphylococcus aureus, with 130.0 in the pre-COVID period and 121.3 in the COVID period (p =.520). Decreases in facility-wide median monthly AU/AR ratios were observed between periods for meropenem/ESBL Enterobacterales (20.9 vs. 7.9, p < .001), linezolid/vancomycin-resistant Enterococcus (48.5 vs. 15.8, p =.004), and daptomycin/vancomycin-resistant Enterococcus (32.2 vs. 4.8, p = .002). Increases in facility-wide median monthly AU/AR ratios were observed between periods for ceftazidime-avibactam/carbapenem-resistant Enterobacterales (0.0 vs. 3.2, p = .020) and ceftazidime-avibactam/multidrug-resistant Pseudomonas aeruginosa (0.0 vs. 4.0, p = .017). The AU/AR ratio for intravenous vancomycin/methicillin-resistant S. aureus in the surgical intensive care unit was 191.5 in the pre-COVID period. CONCLUSIONS: AU/AR ratios may be used to supplement current AU and AR metrics. Future directions should include the development of more AU metrics benchmarked to microbiological information. AU metrics more specific to transplant infectious diseases should be developed.

Long-term risk of hepatocellular carcinoma mortality in 23220 hospitalized patients treated with micafungin or other parenteral antifungals.

BACKGROUND: Liver tumours observed in rats exposed to micafungin led to a black box warning upon approval in Europe in 2008. Micafungin's risk for liver carcinogenicity in humans has not been investigated. We sought to describe the risk of fatal hepatocellular carcinoma (HCC) among persons who received micafungin and other parenteral antifungals (PAFs) with up to 12 years of follow-up. METHODS: We assembled a US multicentre cohort of hospitalized patients who received micafungin or other PAFs between 2005 and 2012. We used propensity score (PS) matching on patient characteristics from electronic medical records to compare rates of HCC mortality identified through the National Death Index though to the end of December 2016. We computed HRs and 95% CIs. RESULTS: A total of 40110 patients who received a PAF were identified; 6903 micafungin recipients (87% of those identified) were successfully matched to 16317 comparator PAF users. Ten incident HCC deaths, one in the micafungin-exposed group and nine among comparator PAF users, occurred in 71285 person-years of follow-up. The HCC mortality rate was 0.05 per 1000 person-years in micafungin patients and 0.17 per 1000 person-years in comparator PAF patients. The PS-matched HR for micafungin versus comparator PAF was 0.29 (95% CI 0.04-2.24). CONCLUSIONS: Both micafungin and comparator PAFs were associated with HCC mortality rates of <0.2 per 1000 person-years. Given the very low event rates, any potential risk for HCC should not play a role in clinical decisions regarding treatment with micafungin or other PAFs investigated in this study.

High incidence of neutropenia in patients with prolonged ceftaroline exposure.

OBJECTIVES: We sought to determine the rate of incident neutropenia and identify potential clinical factors associated with incident neutropenia among patients treated with long courses of ceftaroline. METHODS: We retrospectively identified adult patients who received ceftaroline for ≥7 days consecutively at two large academic medical centres in Boston, USA between November 2010 and March 2015. Clinical characteristics (age, gender, medication allergies, baseline renal function, duration of ceftaroline exposure, total daily ceftaroline dose, body mass-adjusted ceftaroline dose and development of rash and neutropenia) were recorded and the rate of incident neutropenia was calculated. The Naranjo probability scale was used to assess whether ceftaroline exposure was associated with neutropenia. We assessed whether clinical factors were associated with neutropenia. RESULTS: The overall rate of incident neutropenia was 10%-14% with ≥2 weeks and 21% with ≥3 weeks of ceftaroline exposure. The median duration of ceftaroline exposure [26 days (IQR 22-44; range 13-68) in patients who developed neutropenia and 15 days (IQR 9-29; range 7-64) in patients without neutropenia] was associated with incident neutropenia (P = 0.048). The median total number of ceftaroline doses received [63 (IQR 44-126; range 36-198) by neutropenic patients and 32 (IQR 22-63; range 14-180) by non-neutropenic patients] was also associated with incident neutropenia (P = 0.023). CONCLUSIONS: The overall rate of neutropenia was high and associated with duration of ceftaroline exposure and total number of doses received. Close laboratory monitoring is warranted with long-term ceftaroline use.

Short-term risk of liver and renal injury in hospitalized patients using micafungin: a multicentre cohort study.

BACKGROUND: Although echinocandins are generally well tolerated, there is little information on the frequency with which renal and hepatic adverse effects occur during use of micafungin or other parenteral antifungal (PAF) agents in clinical practice. METHODS: MYCOS is a multicentre cohort study of adult and paediatric patients who received micafungin or other PAFs between 2005 and 2012 at seven tertiary care hospitals from six centres in the USA. PAF cohort controls were selected through propensity score (PS) matching to micafungin recipients using clinical characteristics, other treatments, procedures and hospital service where PAF treatment was initiated. Analysis was restricted to patients without chronic liver and kidney conditions at the time of cohort entry. Treatment-emergent hepatic and renal injury was documented by changes in liver enzymes or estimated glomerular filtration rate through 30 days following completion of PAF treatment. Comparisons were quantified using the HR from a proportional hazards analysis. RESULTS: There were 2970 micafungin recipients PS matched to 6726 recipients of comparator PAFs. Balance was achieved in all baseline covariates between treatment groups. There were similar rates of hepatic injury (micafungin, 13 events per 100 patients and other PAF, 12 per 100; HR = 0.99; 95% CI 0.86-1.14) and lower rates of renal injury (micafungin, 63 events per 100 patients and other PAF, 65 per 100; HR = 0.93; 95% CI 0.87-0.99) for micafungin recipients versus PAF comparators. CONCLUSION: For a wide spectrum of underlying conditions, we observed no increase in liver injury by micafungin and possibly a reduced risk of renal dysfunction in comparison with other PAF medications.

Tracking colistin-treated patients to monitor the incidence and outcome of carbapenem-resistant Gram-negative infections.

BACKGROUND: Existing surveillance mechanisms may underestimate the incidence of carbapenem-resistant gram-negative infections (CRGNIs). Although carbapenem resistance increases the risk of death, the trend in mortality over time is unknown. METHODS: A retrospective cohort study was conducted at 40 academic medical centers using a discharge database to identify adult hospital admissions without cystic fibrosis in 2006-2012 and received intravenous colistin for >3 consecutive days or died during therapy (termed colistin cases). The primary outcomes were the number of colistin cases per 100,000 admissions per year and change in the hospital mortality rate over time compared with the rate of discharges to home. Secondary outcomes included median overall and intensive care unit lengths of stay. RESULTS: From 2006 to 2012, a total of 5011 unique patients were identified as colistin cases. The number per 100,000 admissions per year increased from 35.56 to 92.98 during the 7-year study (P < .001). The odds of in-hospital death among colistin cases (compared with discharge to home) decreased by a mean of 5.2%/y (P = .04), whereas discharge to an institution (P = .24) or hospice (P = .89) remained steady over time. The median overall and intensive care unit lengths of stay decreased by 7.5 and 6 days, respectively (P < .001). In a 4-hospital chart review, 81.6% of colistin cases were found to have culture-positive CRGNIs. Conversely, 53% of extensively drug-resistant bloodstream CRGNIs at 2 of these hospitals met colistin case criteria. CONCLUSIONS: Colistin cases represent a severely ill population with a high probability of having culture-confirmed CRGNIs. Colistin tracking is a novel strategy for monitoring the incidence and mortality of CRGNIs, particularly those caused by extensively drug-resistant bacteria. Although the incidence of colistin cases nearly tripled within 7 years, more of these patients are surviving hospitalization and going home.

Impact of a clinical guideline for prescribing antibiotics to inpatients reporting penicillin or cephalosporin allergy.

BACKGROUND: Self-reported penicillin allergy infrequently reflects an inability to tolerate penicillins. Inpatients reporting penicillin allergy receive alternative antibiotics that might be broader spectrum, more toxic, or less effective. OBJECTIVE: To develop and assess a clinical guideline for the general inpatient provider that directs taking a history and prescribing antibiotics for patients with penicillin or cephalosporin allergy. METHODS: A guideline was implemented to assist providers with assessing allergy history and prescribing antibiotics for patients with reported penicillin or cephalosporin allergy. The guideline used a standard 2-step graded challenge or test dose. A quasi-experimental study was performed to assess safety, feasibility, and impact on antibiotic use by comparing treatment 21 months before guideline implementation with 12 months after guideline implementation. RESULTS: Significantly more test doses to ß-lactam antibiotics were performed monthly after vs before guideline implementation (median 14.5, interquartile range 13-16.25, vs 2, interquartile range 1-3.25, P < .001). Seven adverse drug reactions occurred during guideline-driven test doses, with no significant difference in rate (3.9% vs 6.1%, P = .44) or severity (P > .5) between periods. Guideline-driven test doses decreased alternative antimicrobial therapy after the test dose, including vancomycin (68.3% vs 37.2%, P < .001), aztreonam (11.5% vs 0.5%, P < .001), aminoglycosides (6.0% vs 1.1%, P = .004), and fluoro quinolones (15.3% vs 3.3%, P < .001). CONCLUSION: The implementation of an inpatient antibiotic prescribing guideline for patients with penicillin or cephalosporin allergy was associated with an almost 7-fold increase in the number of test doses to ß-lactams without increased adverse drug reactions. Patients assessed with guideline-driven test doses were observed to have significantly decreased alternative antibiotic exposure.

Effect of Cefepime on Neurotoxicity Development in Critically Ill Adults With Renal Dysfunction.

BACKGROUND: Pharmacodynamic and pathophysiologic changes in critically ill adults receiving cefepime may increase the risk of adverse events. RESEARCH QUESTION: What is the impact of cefepime exposure on neurotoxicity development in critically ill adults with renal dysfunction? STUDY DESIGN AND METHODS: Critically ill adults with creatinine clearance < 60 mL/min who received cefepime for ≥ 48 hours between January 1, 2014 and July 31, 2018 were evaluated for cefepime-associated neurotoxicity (CAN) development. Higher- and lower-dose cefepime exposure groups stratified by moderate (≥ 8 g vs < 8 g in first 48 hours) or severe (≥ 4 g vs < 4 g in first 48 hours) renal dysfunction were compared. Between-group comparisons were performed using Fisher exact tests. CAN-free survival was evaluated using Kaplan-Meier curves and log-rank tests. RESULTS: Cefepime total dose in the first 48 hours was greater in the higher-dose cefepime group (3.7 ± 1.6 g vs 7.7 ± 2.2 g; P < .001). Cefepime-associated neurotoxicity occurred infrequently in both lower- (n = 108) and higher-dose (n = 92) cefepime groups (4% vs 10%, OR 2.82, 95% CI, 0.84-9.48, P = .093). The frequencies of cefepime-associated neurotoxicity were similar between lower- and higher-dose cefepime groups when moderate renal dysfunction subgroups were compared (5% vs 7%, OR 1.42, 95% CI, 0.34-5.92, P = .72) and numerically greater in the higher-dose cefepime group in the severe renal dysfunction subgroup (0 vs 16%, P = .064). Times to cefepime-associated neurotoxicity development and resolution were similar between lower- and higher-dose groups. Durations of CAN-free survival were similar between lower- and higher-dose groups. Most patients who developed cefepime-associated neurotoxicity displayed altered mental status (n = 12, 92%). INTERPRETATION: Cefepime-associated neurotoxicity is an uncommon occurrence in critically ill adults. Patients with severe renal dysfunction receiving higher-dose cefepime may be at greater risk of cefepime-associated neurotoxicity, although this requires additional investigation.

A Case of Linezolid Induced Toxicity.

Adverse effects of linezolid are typically limited to diarrhea, nausea, and headache when shorter durations are used; however, as extended durations of linezolid therapy are increasingly more common, additional monitoring parameters should be considered in these patients. We describe a unique case of hypoglycemia, lactic acidosis, and pancreatitis related to an extended duration of linezolid therapy. A 52-year-old woman presented with altered mental status, abdominal pain, and hypotension following six weeks of linezolid and ertapenem therapy. Laboratory data revealed an initial blood glucose of 40 mg/dL and metabolic acidosis secondary to lactic acidosis. Finally, her abdominal pain on admission was likely related to an enlarged pancreas noted on computed tomography of her abdomen. Due to suspected linezolid toxicity, the patient received two intermittent hemodialysis sessions to remove linezolid and correct the metabolic acidosis. Given limited data on long-term monitoring of patients receiving extended durations of linezolid therapy, we suggest periodic monitoring of lactate, arterial blood gas, and blood glucose. If patients present with this triad of symptoms secondary to linezolid therapy, adverse effects should be treated with dextrose and intravenous thiamine while reserving hemodialysis for those with metabolic acidosis refractory to thiamine.

Adverse Drug Reactions Associated with Ceftaroline Use: A 2-Center Retrospective Cohort.

BACKGROUND: Ceftaroline fosamil is a cephalosporin approved for treating skin and soft tissue infections (SSTIs), including those caused by methicillin-resistant Staphylococcus aureus and community-acquired pneumonia (CAP). OBJECTIVES: We aimed to study ceftaroline use and associated adverse drug reactions (ADRs), including hypersensitivity reactions (HSRs), among inpatients. METHODS: We performed a retrospective electronic health record review of inpatients from Massachusetts General Hospital and Brigham and Women's Hospital who received ceftaroline between May 2012 and February 2015. ADRs diagnosed by clinical providers during the course of clinical care were subsequently verified and classified. Risk factors for ADRs were identified. RESULTS: Among 96 patients (median age, 57 years; 54% females) who received a median of 28 (interquartile range, 6-63) ceftaroline doses, 54% were being treated for methicillin-resistant Staphylococcus aureus and treatment indications other than SSTI and CAP comprised 59% of care. There were 31 ADRs observed in 20 (21%) patients; hematologic (n = 15) and cutaneous (n = 9) findings were most common. Observed HSRs included rash with mucosal lesions (n = 1), rash with skin desquamation (n = 1), and possible organ-specific HSRs (n = 2). Patients who suffered an ADR received more doses of ceftaroline (median, 46 vs 21; P = .013). There was no increased risk of ceftaroline ADR among patients with reported beta-lactam allergy history (P > .5). CONCLUSIONS: Ceftaroline is used to treat a range of infections beyond SSTI and CAP. We observed a high rate of ADRs from ceftaroline, including signs of severe HSRs. More data are needed to understand the frequency and predictors of ceftaroline ADRs and HSRs.

Ceftaroline desensitization procedure in a pregnant patient with multiple drug allergies.

Validated skin testing is lacking for many drugs, including ceftaroline. The cross-reactivity between ceftaroline and other ß-lactam antibiotics is unknown. We report a case of a pregnant patient with cystic fibrosis and multiple drug allergies who required ceftaroline for methicillin-resistant Staphylococcus aureus pneumonia and underwent an uncomplicated empiric desensitization procedure.

Effect of a drug allergy educational program and antibiotic prescribing guideline on inpatient clinical providers' antibiotic prescribing knowledge.

BACKGROUND: Inpatient providers have varying levels of knowledge in managing patients with drug and/or penicillin (PCN) allergy. OBJECTIVES: Our objectives were (1) to survey inpatient providers to ascertain their baseline drug allergy knowledge and preparedness in caring for patients with PCN allergy, and (2) to assess the impact of an educational program paired with the implementation of a hospital-based clinical guideline. METHODS: We electronically surveyed 521 inpatient providers at a tertiary care medical center at baseline and again 6 weeks after an educational initiative paired with clinical guideline implementation. The guideline informed providers on drug allergy history taking and antibiotic prescribing for inpatients with PCN or cephalosporin allergy. RESULTS: Of 323 unique responders, 42% (95% CI, 37-48%) reported no prior education in drug allergy. When considering those who responded to both surveys (n = 213), we observed a significant increase in knowledge about PCN skin testing (35% vs 54%; P < .001) and loss of PCN allergy over time (54% vs 80%; P < .0001). Among those who reported attending an educational session (n = 62), preparedness to determine if an allergy was severe significantly improved (77% vs 92%; P = .03). Other areas, including understanding absolute contraindications to receiving a drug again and PCN cross-reactivity with other antimicrobials, did not improve significantly. CONCLUSIONS: Inpatient providers have drug allergy knowledge deficits but are interested in tools to help them care for inpatients with drug allergies. Our educational initiative and hospital guideline implementation were associated with increased PCN allergy knowledge in several crucial areas. To improve care of inpatients with drug allergy, more research is needed to evaluate hospital policies and sustainable educational tools.

Antibiotic-associated diarrhea: a refresher on causes and possible prevention with probiotics--continuing education article.

Antibiotic-associated diarrhea (AAD) describes any unexplained diarrhea associated with the use of an antibiotic. AAD also includes infection caused by Clostridium difficile, however this organism only accounts for a small percentage of diarrhea caused by antibiotics. AAD can be caused by multiple other organisms including C perfringens, S aureus, and Candida. Some antibiotics are more likely to cause non-C difficile AAD, such as erythromycin and the penicillin class. AAD develops through the loss of normal flora and reduced colonic bacterial carbohydrate metabolism during antibiotic administration. There is an increasing interest in the use of probiotics for the prevention of AAD. There are several meta-analyses that report a relative risk reduction of AAD with the use of probiotics during antibiotic administration. Interpretation of these studies has been challenging due to the heterogeneity and size of the patient populations, unclear probiotic regimen, and unclear safety profile. Since AAD can be a reason for a patient to become non-compliant or receive incomplete treatment, clinicians should monitor for this potential adverse effect caused by antibiotics.