ABSTRACTWe hypothesize that low-level efflux pump expression is the first step in the development of high-level drug resistance in mycobacteria. We performed 28-day azithromycin dose-effect and dose-scheduling studies in our hollow-fiber model of disseminatedMycobacterium avium-M. intracellularecomplex. Both microbial kill and resistance emergence were most closely linked to the within-macrophage area under the concentration-time curve (AUC)/MIC ratio. Quantitative PCR revealed that subtherapeutic azithromycin exposures over 3 days led to a 56-fold increase in expression of MAV_3306, which encodes a putative ABC transporter, and MAV_1406, which encodes a putative major facilitator superfamily pump, inM. avium. By day 7, a subpopulation ofM. aviumwith low-level resistance was encountered and exhibited the classic inverted U curve versus AUC/MIC ratios. The resistance was abolished by an efflux pump inhibitor. While the maximal microbial kill started to decrease after day 7, a population with high-level azithromycin resistance appeared at day 28. This resistance could not be reversed by efflux pump inhibitors. Orthologs of pumps encoded by MAV_3306 and MAV_1406 were identified inMycobacterium tuberculosis,Mycobacterium leprae,Mycobacterium marinum,Mycobacterium abscessus, andMycobacterium ulcerans. All had highly conserved protein secondary structures. We propose that induction of several efflux pumps is the first step in a general pathway to drug resistance that eventually leads to high-level chromosomal-mutation-related resistance in mycobacteria as ordered events in an “antibiotic resistance arrow of time.”

BackgroundMethicillin-susceptible Staphylococcus aureus (MSSA) infections are traditionally treated with intravenous (IV) nafcillin, oxacillin, or cefazolin, all antibiotics that require multiple doses per day. Despite theoretical limitations of using ceftriaxone in MSSA infections, some clinical studies suggest noninferiority of ceftriaxone compared with standard of care. At Parkland Memorial Hospital, many patients diagnosed with MSSA infections receive self-administered Outpatient Parenteral Antimicrobial Therapy (S-OPAT). Daily-dosed ceftriaxone is often used for convenience and feasibility of medication adherence.MethodsWe conducted a retrospective cohort study among S-OPAT patients receiving cefazolin and ceftriaxone for treatment of MSSA infections. We compared infection type and planned duration of therapy as baseline differences between the treatment cohorts. Our clinical outcomes of interest were 30-day readmission rates and treatment failure as defined by repeat positive blood culture within 6 months.ResultsWe identified 184 patients treated with cefazolin and 74 patients treated with ceftriaxone. Characteristics of treatment plan are shown in Table 1. There were no statistically significant differences in infection type or mean duration of therapy between the two treatment cohorts. Outcomes are shown in Table 2. There were no statistically significant differences in readmission rates and rate of treatment failure.ConclusionOur retrospective review suggests patients treated with ceftriaxone for MSSA bacteremia had similar clinical outcomes as those treated with cefazolin. While this study is limited in its retrospective nature, the findings suggest that ceftriaxone may be a safe and more convenient antibiotic option in certain MSSA infections.Cefazolin (n = 184)Ceftriaxone (n = 74) P-ValueInfection type0.87Bacteremia10629Osteomyelitis2330Skin and soft-tissue infection146Endocarditis142Line-related111Pulmonary92GU52Other22Mean duration of therapy30 days32 days0.26Disclosures All authors: No reported disclosures.

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BackgroundHigh rates of influenza-related hospitalizations and deaths occurred in the United States during the 2017–2018 influenza season. A record number of influenza outbreaks were reported in long-term care facilities (LTCF) in Dallas County. Public health surveillance of influenza-related intensive care unit (ICU) admissions and deaths in acute care hospitals improved early identification of outbreaks in LTCFs.MethodsA confirmed LTCF influenza outbreak was defined as at least 1 lab-confirmed influenza case plus at least 1 case of influenza-like illness among residents or staff within 72 hours. Outbreaks were self-reported by facilities or identified by the health department during investigations of ICU hospitalizations and deaths. CDC guidance for influenza outbreak management was provided and daily active surveillance was continued for at least 1 week after the last case was identified. Data collected included: numbers of ill residents and staff, vaccination rates, dates of illness and chemoprophylaxis initiation, hospitalizations and deaths. Fisher exact tests and Chi-square were performed using SAS 9.4.ResultsDuring this influenza season, 32 confirmed influenza outbreaks were identified in Dallas County LTCFs: 17 in skilled nursing facilities (SNF), 13 in assisted-living facilities (ALF) and 2 in hybrid SNF/ALF. The average attack rate in residents was 9.8% (range: 1–35%). Influenza hospitalization rates were higher in ALF compared with SNF outbreaks (OR: 2.2). Influenza-associated mortality rates were higher in ALF compared with SNF (OR: 3.1). Of the 32 outbreaks, 20 (63%) were self-reported by facilities to public health and 12 (38%) were identified through health department review of influenza-associated ICU hospitalizations. Facilities where outbreak cases were identified through public health surveillance of ICU admissions had significantly lower overall attack rates (5.9% vs. 12.1%, P = 0.01) and shorter time to initiation of facility-wide chemoprophylaxis (0.4 vs. 2.4 days, P = 0.05).ConclusionActive surveillance of influenza-associated ICU admissions in acute-care hospitals facilitated the early identification of influenza outbreaks in LTCFs, which was associated with lower overall attack rates and shorter time to initiation of facility-wide chemoprophylaxis.Disclosures All authors: No reported disclosures.

BackgroundIn the wake of Hurricane Maria, hospitals nationwide have faced a shortage of IV fluids sourced from Puerto Rico. Out of necessity to conserve IV fluids, Parkland Memorial Hospital shifted IV antibiotic administration from traditional fluid suspension via pump/gravity to “IV push” administration. The safety and potential cost savings of short infusion administration of antibiotics have been previously described; however, implementation of IV push administration among patients receiving long-term IV antibiotics has yet to be described.MethodsStarting November 2017, patients requiring long-term IV antimicrobial treatment with were transitioned to receive IV push administration from infusion. Per the Parkland self-administered Outpatient Parenteral Antimicrobial Therapy (S-OPAT), patients were screened and trained to self-administer IV antibiotics prior to hospital discharge and followed in the Parkland OPAT clinic.ResultsSince implementation November 2017, 200 patients completed antimicrobial therapy with IV push method with 100% success rate and no reported complications. The following supplies were estimated to be saved: 3,000 less IV fluid bags, 1,000 IV tubing, and 50% fewer gloves and alcohol swabs, amounting to approximately $22,000 of cost savings for a patient going home on once a day antibiotic therapy. Teaching time for the nursing team was reduced on average by 50% per patient. Preliminary patient satisfaction surveys indicate greater satisfaction due to decreased infusion time from an average of 45 minutes to 3–5 minutes with the IV push method. Patient’s reported satisfaction with the new IV Push method due to greater convenience for both storing the medication and a faster preparation time.ConclusionParkland Memorial Hospital was able to implement IV push as a safe and cost-effective alternative to traditional IV antibiotic administration in fluid suspension. Use of IV push antibiotics resulted in $22,000 of cost savings and reduced utilization of a critical resource currently facing a nationwide shortage. Though implemented at our institution in response to a national crisis, IV push is a favorable alternative to administration via a pump or gravity due to time savings, cost reduction, and convenience.Disclosures All authors: No reported disclosures.