Purpose The 2012 multistate fungal meningitis outbreak caused by contaminated methylprednisolone suggests that contaminated compounded drugs can pose a public health threat. The problem has not been well described. Our objective was to systematically review the literature to describe: a) features of infectious outbreaks associated with exposure to contaminated drugs produced by compounding pharmacies, b) sterile compounding procedures that caused microbial contamination, and c) outbreak features relevant for detection and investigation. Methods We searched PubMed (reviewing 850 citations) and the CDC and FDA Web sites to identify infectious outbreaks associated with compounding pharmacies outside the hospital setting between January 2000 and November 2012. We extracted information from peer-reviewed literature, FDA and CDC documents, meeting abstracts, and congressional testimony. Results Between 2000 and prior to the 2012 fungal meningitis outbreak, 11 infectious outbreaks from contaminated compounded drugs were reported involving 207 case-patients with 17 deaths (8.2% case fatality rate). The 2012 meningitis outbreak increased totals almost 5-fold. Half the outbreaks involved case-patients in more than 1 state. Three outbreaks involved ophthalmic drugs: trypan blue and Brilliant Blue-G ophthalmic solutions used during surgery, and triamcinolone and bevacizumab for intravitreal injection. Remaining outbreaks involved corticosteroids (n=2), heparin flush solutions (n=2), cardioplegia, intravenous magnesium sulfate, total parenteral nutrition, and fentanyl. The outbreaks were caused by pathogens commonly associated with healthcare associated infections (n=6), common skin commensals (n=1), and organisms that rarely cause infection (n=5). Morbidity was substantial, including vision loss; mortality rates during earlier outbreaks were similar to the 2012 meningitis outbreak. A variety of problems with sterile procedures were found. No single source reported all outbreaks. Conclusion Sporadic but serious infectious outbreaks associated with contaminated drugs from compounding pharmacies occurred before the 2012 fungal meningitis outbreak. These outbreaks illustrate root causes that could be addressed with preventive policies and practices.

Background: In patients with acute respiratory distress syndrome (ARDS), low tidal volume ventilation has been associated with reduced mortality. Driving pressure (tidal volume normalized to respiratory system compliance) may be an even stronger predictor of ARDS survival than tidal volume. We sought to study whether these associations hold true in acute respiratory failure patients without ARDS. Methods: This is a retrospectively cohort analysis of mechanically ventilated adult patients admitted to ICUs from 12 hospitals over 2 years. We used natural language processing of chest radiograph reports and data from the electronic medical record to identify patients who had ARDS. We used multivariable logistic regression and generalized linear models to estimate associations between tidal volume, driving pressure, and respiratory system compliance with adjusted 30-day mortality using covariates of Acute Physiology Score (APS), Charlson Comorbidity Index (CCI), age, and PaO 2 /FiO 2 ratio. Results: We studied 2641 patients; 48% had ARDS (n = 1273). Patients with ARDS had higher mean APS (25 vs. 23, p < .001) but similar CCI (4 vs. 3, p = 0.6) scores. For non-ARDS patients, tidal volume was associated with increased adjusted mortality (OR 1.18 per 1 mL/kg PBW increase in tidal volume, CI 1.04 to 1.35, p = 0.010). We observed no association between driving pressure or respiratory compliance and mortality in patients without ARDS. In ARDS patients, both ΔP (OR1.1, CI 1.06-1.14, p < 0.001) and tidal volume (OR 1.17, CI 1.04-1.31, p = 0.007) were associated with mortality. Conclusions: In a large retrospective analysis of critically ill non-ARDS patients receiving mechanical ventilation, we found that tidal volume was associated with 30-day mortality, while driving pressure was not.

Background SARS-CoV-2 reinfection and reactivation has mostly been described in case reports. We therefore investigated the epidemiology of recurrent COVID-19 SARS-CoV-2. Methods Among patients testing positive for SARS-CoV-2 between March 11 and July 31, 2020 within an integrated healthcare system, we identified patients with a recurrent positive SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) assay ≥60 days after an initial positive test. To assign an overall likelihood of COVID-19 recurrence, we combined quantitative data from initial and recurrent positive RT-PCR cycle thresholds—a value inversely correlated with viral RNA burden— with a clinical recurrence likelihood assigned based on independent, standardized case review by two physicians. “Probable” or “possible” recurrence by clinical assessment was confirmed as the final recurrence likelihood only if a cycle threshold value obtained ≥60 days after initial testing was lower than its preceding cycle threshold or if the patient had an interval negative RT-PCR. Results Among 23,176 patients testing positive for SARS-CoV-2, 1,301 (5.6%) had at least one additional SARS-CoV-2 RT-PCRs assay ≥60 days later. Of 122 testing positive, 114 had sufficient data for evaluation. The median interval to the recurrent positive RT-PCR was 85.5 (IQR 74–107) days. After combining clinical and RT-PCR cycle threshold data, four patients (3.5%) met criteria for probable COVID-19 recurrence. All four exhibited symptoms at recurrence and three required a higher level of medical care compared to their initial diagnosis. After including six additional patients (5.3%) with possible recurrence, recurrence incidence was 4.3 (95% CI 2.1–7.9) cases per 10,000 COVID-19 patients. Conclusions Only 0.04% of all COVID-19 patients in our health system experienced probable or possible recurrence; 90% of repeat positive SARS-CoV-2 RT-PCRs were not consistent with true recurrence. Our pragmatic approach combining clinical and quantitative RT-PCR data could aid assessment of COVID-19 reinfection or reactivation by clinicians and public health personnel.

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