FDA Public Workshop Summary: Advancing Animal Models for Antibacterial Drug Development.

The U.S. Food and Drug Administration (FDA) hosted a public workshop entitled "Advancing Animal Models for Antibacterial Drug Development" on 5 March 2020. The workshop mainly focused on models of pneumonia caused by Pseudomonas aeruginosa and Acinetobacter baumannii The program included discussions from academic investigators, industry, and U.S. government scientists. The potential use of mouse, rabbit, and pig models for antibacterial drug development was presented and discussed.

Community-associated methicillin-resistant Staphylococcus aureus bacteremia and endocarditis among HIV patients: a cohort study.

BACKGROUND: HIV patients are at increased risk of development of infections and infection-associated poor health outcomes. We aimed to 1) assess the prevalence of USA300 community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) among HIV-infected patients with S. aureus bloodstream infections and. 2) determine risk factors for infective endocarditis and in-hospital mortality among patients in this population. METHODS: All adult HIV-infected patients with documented S. aureus bacteremia admitted to the University of Maryland Medical Center between January 1, 2003 and December 31, 2005 were included. CA-MRSA was defined as a USA 300 MRSA isolate with the MBQBLO spa-type motif and positive for both the arginine catabolic mobile element and Panton-Valentin Leukocidin. Risk factors for S. aureus-associated infective endocarditis and mortality were determined using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). Potential risk factors included demographic variables, comorbid illnesses, and intravenous drug use. RESULTS: Among 131 episodes of S. aureus bacteremia, 85 (66%) were MRSA of which 47 (54%) were CA-MRSA. Sixty-three patients (48%) developed endocarditis and 10 patients (8%) died in the hospital on the index admission Patients with CA-MRSA were significantly more likely to develop endocarditis (OR = 2.73, 95% CI = 1.30, 5.71). No other variables including comorbid conditions, current receipt of antiretroviral therapy, pre-culture severity of illness, or CD4 count were significantly associated with endocarditis and none were associated with in-hospital mortality. CONCLUSIONS: CA-MRSA was significantly associated with an increased incidence of endocarditis in this cohort of HIV patients with MRSA bacteremia. In populations such as these, in which the prevalence of intravenous drug use and probability of endocarditis are both high, efforts must be made for early detection, which may improve treatment outcomes.

Comparison of the methicillin-resistant Staphylococcus aureus acquisition among rehabilitation and nursing home residents.

OBJECTIVE: To assess risk factors for methicillin-resistant Staphylococcus aureus (MRSA) acquisition among extended care residents focusing on level of care (residential vs rehabilitation) and room placement with an MRSA-positive resident. DESIGN: Prospective cohort study. SETTING: Extended care units at 2 healthcare systems in Maryland. PARTICIPANTS: Four hundred forty-three residents with no history of MRSA and negative MRSA surveillance cultures of the anterior nares and areas of skin breakdown at enrollment. METHODS: Follow-up cultures were collected every 4 weeks and/or at discharge for a period of 12 weeks. Study data were collected by a research nurse from the medical staff and the electronic medical records. Cox proportional hazards modeling was used to calculate adjusted hazards ratios (aHRs) and 95% confidence intervals (CIs). RESULTS: Residents in rehabilitation care had 4-fold higher risk of MRSA acquisition compared with residents in residential care (hazard ratio [HR], 4. [95% CI, 2.2-8.8]). Being bedbound was significantly associated with MRSA acquisition in both populations (residential care, aHR, 4.3 [95% CI, 1.5-12.2]; rehabilitation care, aHR, 4.8 [95% CI, 1.2-18.7]). Having an MRSA-positive roommate was not significantly associated with acquisition in either population (residential care, aHR, 1.4 [95% CI, 0.5-3.9]; rehabilitation care, aHR, 0.5 [95% CI, 0.1-2.2]); based on concordant spa typing, only 2 of 8 residents who acquired MRSA and had room placement with an MRSA-positive resident acquired their MRSA isolate from their roommate. CONCLUSION: Residents in rehabilitation care appear at higher risk and have different risk factors for MRSA acquisition compared to those in residential care.

Prolonged colonization with the methicillin-resistant Staphylococcus aureus strain USA300 among residents of extended care facilities.

We performed a retrospective cohort study (n=129) to assess whether residents of extended care facilities who were initially colonized or infected with the methicillin-resistant Staphylococcus aureus (MRSA) strain USA300 were less likely to have prolonged colonization than were residents colonized or infected with other MRSA strains. We found no difference in prolonged colonization (adjusted odds ratio, 1.1 [95% confidence interval, 0.5-2.4]).

Colonization sites of USA300 methicillin-resistant Staphylococcus aureus in residents of extended care facilities.

BACKGROUND: The anterior nares are the most sensitive single site for detecting methicillin-resistant Staphylococcus aureus (MRSA) colonization. Colonization patterns of USA300 MRSA colonization are unknown. OBJECTIVES: To assess whether residents of extended care facilities who are colonized with USA300 MRSA have different nares or skin colonization findings, compared with residents who are colonized with non-USA300 MRSA strains. METHODS: The study population included residents of 5 extended care units in 3 separate facilities who had a recent history of MRSA colonization. Specimens were obtained weekly for surveillance cultures from the anterior nares, perineum, axilla, and skin breakdown (if present) for 3 weeks. MRSA isolates were categorized as USA300 MRSA or non-USA300 MRSA. RESULTS: Of the 193 residents who tested positive for MRSA, 165 were colonized in the anterior nares, and 119 were colonized on their skin. Eighty-four percent of USA300 MRSA-colonized residents had anterior nares colonization, compared with 86% of residents colonized with non-USA300 MRSA (P= .80). Sixty-six percent of USA300 MRSA-colonized residents were colonized on the skin, compared with 59% of residents colonized with non-USA300 MRSA (P= .30). CONCLUSIONS: Colonization patterns of USA300 MRSA and non-USA300 MRSA are similar in residents of extended care facilities. Anterior nares cultures will detect most--but not all--people who are colonized with MRSA, regardless of whether it is USA300 or non-USA300 MRSA.

Skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus USA300 clone.

Until recently, methicillin-resistant Staphylococcus aureus (MRSA) has caused predominantly healthcare-associated infections. We studied MRSA infections and overall skin and soft tissue infections (SSTIs) in outpatients receiving care at the Baltimore Veterans Affairs Medical Center Emergency Care Service during 2001-2005. We found an increase in MRSA infections, from 0.2 to 5.9 per 1,000 visits (p < 0.01); most were community-associated SSTIs. Molecular typing showed that > 80% of MRSA infections were caused by USA300. In addition, SSTI visits increased from 20 to 61 per 1,000 visits (p < 0.01). The proportion of SSTI cultures that yielded MRSA increased from 4% to 42% (p < 0.01), while the proportion that yielded methicillin-sensitive S. aureus remained the same (10% to 13%, p = 0.5). The increase in community-associated MRSA infections and the overall increase in SSTIs in our population suggest that USA300 is becoming more virulent and has a greater propensity to cause SSTIs.

Staphylococcus aureus colonization in community-dwelling people with spinal cord dysfunction.

OBJECTIVES: To estimate the prevalence of and determine risk factors for Staphylococcus aureus colonization of the perineum. DESIGN: Cross-sectional study with follow-up of up to 1 year. SETTING: Multiple outpatient sites. PARTICIPANTS: Eighty-four community-dwelling adults with spinal cord dysfunction (SCD). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Colonization of perineum with S. aureus. RESULTS: Overall, 24% of the study cohort carried S. aureus on their perineal skin at enrollment, with 16% having methicillin-susceptible S. aureus and 10% having methicillin-resistant S. aureus (MRSA). Most perineal carriers were also colonized in the anterior nares. Participants with trauma as the cause of their SCD were more likely to be colonized with S. aureus than participants with SCD caused by multiple sclerosis or other causes (relative risk [RR], 2.8; 95% confidence interval [CI], 1.2-6.6; P=.01). Participants with pelvic decubiti were more likely to be colonized with S. aureus than participants without pelvic decubiti (RR=4.3; 95% CI, 2.4-7.7; P<.001). The recent use of any antibiotic was not associated with an increased risk of colonization with S. aureus (RR=1.5; 95% CI, 0.7-3.3; P=.31); however, recent fluoroquinolone use was significantly associated with perineal colonization (RR=2.8; 95% CI, 1.4-5.8; P=.02). Of the 8 participants with MRSA colonization, only 2 (25%) had a history of MRSA colonization. CONCLUSIONS: S. aureus colonization of the perineum is common in this outpatient population of people with SCD. The use of fluoroquinolones was associated with S. aureus colonization. Colonization with MRSA without a history of MRSA was common.

How important is patient-to-patient transmission in extended-spectrum beta-lactamase Escherichia coli acquisition.

BACKGROUND: Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli is an emerging pathogen. The causal role of antibiotic selective pressure versus patient-to-patient transmission has not been assessed. The objective of this study was to quantify the amount of patient-to-patient transmission among patients who acquire an ESBL-producing E coli infection using perianal surveillance cultures in an intensive care unit (ICU) population. METHODS: A prospective cohort of patients admitted between September 1, 2001, and September 1, 2004, to the medical and surgical ICUs at a tertiary care hospital was studied. Patients had perianal cultures on admission, weekly, and upon discharge. Strain typing by pulsed-field gel electrophoresis (PFGE) and epidemiologic criteria were used to quantify the amount of patient-to-patient transmission. RESULTS: There were 1806 patients admitted to the ICUs. There were 74 patients who had ESBL-producing E coli on admission to the ICU and 23 patients who acquired ESBL-producing E coli. Among these 23 patients, there were 14 PFGE types, and 3 (13%) patient acquisitions were defined as patient-to-patient transmission by similar PFGE type and overlapping time in the hospital. CONCLUSION: Our data suggest that patient-to-patient transmission is not an important cause of the acquisition of ESBL-producing E coli colonization in the ICU setting.

Comparison of mortality risk associated with bacteremia due to methicillin-resistant and methicillin-susceptible Staphylococcus aureus.

OBJECTIVE: To quantify the clinical impact of methicillin-resistance in Staphylococcus aureus causing infection complicated by bacteremia in adult patients, while controlling for the severity of patients' underlying illnesses. DESIGN: Retrospective cohort study from October 1, 1995, through December 31, 2003. PATIENTS AND SETTING: A total of 438 patients with S. aureus infection complicated by bacteremia from a single Veterans Affairs healthcare system. RESULTS: We found that 193 (44%) of the 438 patients had methicillin-resistant S. aureus (MRSA) infection and 114 (26%) died of causes attributable to S. aureus infection within 90 days after the infection was identified. Patients with MRSA infection had a higher mortality risk, compared with patients with methicillin-susceptible S. aureus (MSSA) infections (relative risk, 1.7 [95% confidence interval, 1.3-2.4]; P<.01), except for patients with pneumonia (relative risk, 0.7 [95% confidence interval, 0.4-1.3]). Patients with MRSA infections were significantly older (P<.01), had more underlying diseases (P=.02), and were more likely to have severe sepsis in response to their infection (P<.01) compared with patients with MSSA bacteremia. Patients who died within 90 days after S. aureus infection was identified were significantly older (P<.01) and more likely to have severe sepsis (P<.01) and pneumonia (P=.01), compared with patients who survived. After adjusting for age as a confounder, comorbidities, and pneumonia as an effect modifier, S. aureus infection-related mortality remained significantly higher in patients with MRSA infection than in those with MSSA infection, among those without pneumonia (hazard ratio, 1.8 [95% confidence interval, 1.2-3.0]); P<.01. CONCLUSIONS: The results of this study suggest that patients with MRSA infections other than pneumonia have a higher mortality risk than patients with MSSA infections other than pneumonia, independent of the severity of patients' underlying illnesses.

Neonatal sepsis and mortality in a regional hospital in Trinidad: aetiology and risk factors

A total of 132 neonatal deaths among 627 infants admitted to the neonatal ward of the San Fernando General Hospital, Trinidad over a 2-year period were reviewed. The most common cause of death was prematurity (43.9%). Infection was the second most common cause (21.2%). Pseudomonas aeruginosa and Staphylococcus aureus were the most frequently isolated organisms (43%). The major drugs used empirically in suspected cases of sepsis were ampicillin or ceftazidime plus gentamicin. About 85% of S. aureus were resistant to ampicillin, and P. aeruginosa resistance to ceftazidime and gentamicin was 76.7% and 72.1%, respectively. Significant risk factors in maternal history were infrequent antenatal care and prolonged rupture of membranes. The incidence of infection among low birthweight infants was 85.6%. Early-onset sepsis (86.4%) seemed to have a nosocomial origin because of the type of pathogens seen. There is an urgent need to improve the staff-to-patient ratio in the neonatal unit and for staff to be constantly reminded to employ simple infection control practices such as proper hand-washing to reduce cross-infections.