Lit Review April #1
Disclaimer: this compilation of synopses have been collected from multiple sources, including Mark Crislip's Puscast, Journal Watch Infectious Diseases, Medscape Infectious Diseases, CDC MMWR, AMA Morning Rounds, ProMED Mail, Journal of Clinical Microbiology, Antimicrobial Agents and Chemotherapy, Clinical Infectious Diseases, and more. I chose these articles based on their relevance to clinical microbiology and would be of interest to my fellows, and some other pieces that I found amusing to read. All credit goes to these original contributors. I'm just a messenger :).
Leading Photo by CDC (https://www.cdc.gov/salmonella/index.html)
Distinct fermentation and antibiotic sensitivity profiles exist in salmonellae of canine and human origin
S. enterica is pathogenic in both humans and dogs, but no evidence showing possibility of transfer between dog and owner
Looked at 88 human and 86 dog isolates (clinical)
Carbon utilization profiles between two groups was different (determined using a phenotypic array ala API
Canine isolates seemed to have higher AMP, AMX, CHL MICs compared to human isolates
Suggested separated reservoirs for disease
WGS would have given a better resolution
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Salmonella enterica Serotype 4,[5],12:i:- in Swine in the United States Midwest: An Emerging Multidrug-Resistant Clade
Examples of Kauffmann-White-Le Minor scheme (from WHO document)
"4,[5],12" = somatic O antigen
":i:-" = H antigen phase 1 is "i"
"-" = no phase 2 H antigen
Emerging globally, including in pork in the US, lacks the second-phase flagellar antigen
Compared WGS data from hundreds of 4,[5],12:i:- and Typhimurium from US and Europe, with a focus on isolates from pork in the US Midwest
4,[5],12:i:- regardless of source could be divided into two clades – B I and B II
85% of US isolates from 2014-15 in clade B II, which is emerging globally
R to AMP, STR, sulfonamides, TET
Subset of isolates R to enrofloxacin or ceftiofur associated with presence of plasmid-mediated resistance genes (qnrB19/qnrB2/qnrS1 for FQ and blaCMY-2/blaSHV-12 for ceph), with FQ resistance probably acquired in the US
Epidemiology, Microbiological Diagnosis, and Clinical Outcomes in Pyogenic Vertebral Osteomyelitis: A 10-year Retrospective Cohort Study
PVO: difficult to treat, sometimes culture-negative, pt on broad-spectrum treatment for a long time with little benefit compared to a shorter course, besides reduction of relapse in some studies
A study from Australia looking at 129 patients over 10 years
Most patients had blood culture, 44% had vertebral samples (open Bx better yield than core or FNA)
78% organism identified, MSSA or gram positive most prevalent, these patients were more likely to be febrile and had elevated CRP on admission – makes sense
22% - only 5 patients had histology results, with varying evidence of inflammation, 16s PCR in these patients was not conclusive
Overall clinical outcomes poor regardless of organism ID (only 15% complete recovery upon D/C)
However, not having org ID associated with more risk of adverse outcomes (mortality during index admission or attributable readmission within 2 years due to stuff like pain, disability, or need for more investigation)
It may be reasonable to go above and beyond to get a microbiological diagnosis to guide treatment instead of empirical
Systemic Antibiotics for the Treatment of Skin and Soft Tissue Abscesses: A Systematic Review and Meta-Analysis
To use or not to use antibiotics after I&D? Classical way of thinking is that antibiotics wouldn’t add much
Meta-analysis looking at 2400 patients
About half had MRSA
Treated with SXT or CLI
Treatment failure in antibiotic group (7.7%) less than placebo (16.1%)
Antibiotic also reduced risk of developing more lesions, while increase in adverse effects was minimal and mild (GI, rash, etc)
Mark Crislip on his podcast: DOX and LZD result in less chance of developing C. diff
Management of an Outbreak of Exophiala dermatitidis Bloodstream Infections at an Outpatient Oncology Clinic
Dematiaceous, may cause CNS infection in IC hosts, resp pathogen in CF patients
Photo: Mycology Online: https://mycology.adelaide.edu.au/descriptions/hyphomycetes/exophiala/
May 2016 NY: 4 cases of E. dermatitidis in oncology patients receiving infusion through port-a-cath at a clinic
Identified a total of 15 cases of fungemia with E. dermatitidis and 2 with Rhodotorula mucilaginosa, some positive in all cultures (peripheral, CVC-drawn blood, CVC device), most are asymptomatic
Source of contamination: IV flush solution containing saline, VAN, CAZ, heparin
Compounded in the clinic in substandard conditions, in 1 L bags, kept for 4-8 weeks with multiple access per day until bag was depleted
38 patients exposed to potentially contaminated fluids
Isolates confirmed by WGS to be the same
Pts with positive blood culture had CVC removed, treated with mainly voriconazole, 3 died
mcr-3 and mcr-4 Variants in Carbapenemase-Producing Clinical Enterobacteriaceae Do Not Confer Phenotypic Polymyxin Resistance
Fact: mcr-1 isolates don’t always have NWT CST MICs (>=4): choosing isolates to screen is challenging
Singapore: sequenced a bunch of Enterobacteriaceae
Found mcr-3-like element in E. coli
Initial assembly showed a 9kb contig with this element
Claimed to not be plasmid-associated: mapping reads onto closest reference genome and re-assemble reads that did not match, found no plasmid-associated gene on the 9kb contig containing this element
Seems to be associated with transposable elements
I have a problem with this approach
Plasmid are notoriously difficult to assemble, lots of repeated sequences
One cannot make this assumption without long read sequencing
Transposable elements can be on a plasmid too
Was PlasmidFinder used on assembled contigs? Any origin of replication?
Found mcr-4-like elements in E. cloacae
7.7kb contig with this element matched existing mcr-4 harboring plasmid
Both isolates S to CST, cloned genetic elements in E. coli did not confer resistance either
Why is this exciting?
Two Cases of Meningococcal Disease in One Family Separated by an Extended Period — Colorado, 2015–2016
Transmitted through large respiratory droplets
April 2015 in CO: 75 yo F came down with sepsis, GS CFF positive for GNDP but culture neg, BCB positive, treated and survived
7 family members were prescribed PEP, but compliance unknown
Adults CIP PO single dose
Children RIF q12 for 2 days or CRO IM one dose
15 mo later, a 3 mo grandbaby of patient came down also with meningococcemia
WGS: same bug
Treatment in patients usually eradicate organisms
Where did the bug come from?
Baby shared close unknown contact with index patient
Circulating strain
Incomplete eradication during PEP
Notes from the Field: Fatalities Associated with Human Adenovirus Type 7 at a Substance Abuse Rehabilitation Facility — New Jersey, 2017
HAdV type 4 (HAdV-4) and HAdV type 7 (HAdV-7): reported to be associated with outbreaks in communal facilities and the military
Feb 2017 in NJ: potential outbreak reported in substance abuse treatment facility
During Jan-Mar: 79 people defined as probable (respiratory illness)
4 hospitalized, 3 died
For the 3 - HAdV-7, all alcoholic with cirrhosis and/or DM
Vital Signs: Containment of Novel Multidrug-Resistant Organisms and Resistance Mechanisms — United States, 2006–2017
National Healthcare Safety Network: keep data for CLABSIs, CAUTIs
Facilities are required by CMS to report
Looked at percentage of EC and KP that were ESBLs or CREs
Antibiotic Resistance Laboratory Network (ARLN): provide testing for CRE, CRPA in PHLs
Decreased may be due to early aggressive responses: IP, reporting, testing, etc.
CRE: 25% CPO
KPC, NDM most common in CRE
VIM most common is CRPA
1,489 screening tests for asymptomatic individuals for carbapenemases performed during 70 surveys in 50 facilities in 7 large regional labs
Post-acute care facility tops the chart
Antibiotic Therapy Duration in US Adults With Sinusitis
Sinusitis: always been a problem – should or shouldn’t use antibiotic, if so, which one?
National Disease and Therapeutic Index (IQVIA): random sample of US office-based physicians in private practice, report on all patient contacts for 2 randomly selected consecutive workdays
Exclude chronic sinusitis
Findings are pretty sad
69% of patients prescribed antibiotics for more than 10 days (IDSA guidelines say 5-7 days for acute bacterial sinusitis with low risk of developing resistance, 7-10 days saved for high risk or treatment failures
20% prescribed 5 day course of AZT: NOT RECOMMENDED according to IDSA over development of resistance
If remove AZT: >90% of patients prescribe for more than 10 days
Infectious Diseases Mortality in the United States Ongoing Investment Needed for Continued Progress
National Center for Health Statistics: CDC initiative, collects data from birth and death records, medical records, interview surveys, and through direct physical exams and laboratory testing
2014: death rate from infection = 34.10 per 100,000
1980: 41.95 per 100 000 persons
18.73% overall reduction
In 2014 LRTIs most common (78%), then diarrheal diseases (7% which is a >400% increase compared to 1980, most likely due to C. diff, which has been reported to cause almost half of death from GE associated diseases in the US)
Also looked at several aspects of the data (type of infection, geological, etc)
Effect of Meropenem-Vaborbactam vs Piperacillin-Tazobactam on Clinical Cure or Improvement and Microbial Eradication in Complicated Urinary Tract Infection
Vaborbactam: cyclic boronic acid–based BLI, active against Ambler classes A (especially KPC) and C (AmpC)
Combination has trade name of Vabomere
Indicated for treatment of complicated UTI or acute pyelonephritis
Data from phase III: compared to TZP
When considering clinical improvement and microbiological: better than TZP (98.4% vs 94%)
When considering test of cure: non-inferior to TZP (66.7% vs 57.7%)
Carbapenem-Resistant Klebsiella pneumoniae Exhibiting Clinically Undetected Colistin Heteroresistance Leads to Treatment Failure in a Murine Model of Infection
Resistance to CST is on the rise in CREs
2 CRKP isolates harboring KPC, MIC by BMD = 0.5
Population analysis profile (PAP): plating serial dilutions on agar with various concentrations of
Presence of minor CST-R (actually, NWT) subpopulation (1:10^3-1:10^6) in both isolates with growth present in up 100 µg/ml CST. The colistin-resistant subpopulation was present at between 1 in 1,000 and 1 in 1,000,000 CFU at doses of colistin ranging from 2 to 100 µg/ml
Not seen in a control strain
After passaging in antibiotic-free media: MICs came down
WGS comparing between CST-WT and CST-NWT populations: genetically identical
Phenotypic changes, compatible with heteroresistance
Looked at expression of these genes
PhoPQ (two-component system pathway thought to regulate CST resistance in KP) increased in resistant cells
MgrB (negative regulator of PhoPQ) decreased in resistant cells
Peritonitis mouse model
Even in the absence of CST, enrichment in resistant population was seen: maybe due to cross-resistance with antimicrobial peptides
These strains resulted in 100% death, compared to control strain – this may also happen in vivo!
Strain with heteroresistance may result in treatment failure
Found that if incubated BMD to 48 hours: CST MIC in these strains increased to NWT level – but maybe not a great idea to do in a clinical lab
Pharmacokinetic/Pharmacodynamic Determinants of Vancomycin Efficacy in Enterococcal Bacteremia
VAN: traditionally believed to have similar PD to BL (time over MIC)
More data suggested AUC/MIC: people like to target at 400 ug*hr/mL
Correlated with serum peak of 40 and trough of 15 ug/mL, with the assumption that MIC = 1 ug/mL
Data mostly for MRSA – not much for Enterococcus
Retrospectively looked at 57 patients bacteremic with Enterococcus spp.
AUC/MIC (by Etest) ≥389 achieved within 72 hours associated with reduced 30-day mortality (from 45.5 to 10.9%)
This was only safely achievable (nephrotoxicity) if MIC Etest <= 1.5
VAN trough not significantly different between treatment success and failure
Maybe we need to calculate AUC/MIC instead
UK case of Neisseria gonorrhoeae with high-level resistance to azithromycin and resistance to
ceftriaxone acquired abroad
Public Health England reported an imported case of N. gonorrhoeae infection with treatment failure (CRO only, followed by SPT)
Not treated with double regimen (CRO+AZT)
Genital infection was cured, but throat was persistently positive
Not a surprise since throat infections are harder to get rid of, and ALL reported cases of CRO failure so far have exclusively been pharyngeal infections
Caused by a bug with:
CRO MIC > 0.125
EUCAST breakpoint for R: >0.125
CLSI breakpoint for R: >0.25
AZT MIC > 0.5
EUCAST breakpoint for R: >0.5
CLSI epidemiological cutoff (ECV) for NWT: >=2
End point MICs were not reported, so we don't know if this bug would be considered R/NWT for both drugs when using CLSI breakpoints/ECVs
Currently treated with ETP IV: based on MIC 0.032, but no breakpoint exists
Is this terrifying? Yes, but there are things to consider
Hawaii Department of Public Health has reported isolates with CRO MICs 0.125 by agar dilution and AZT MIC > 256, yet these infections were successfully treated with double regimen
Hawaii paper did not specify whether these include pharyngeal infections, and if so, whether treatment was successful
Would this UK case have been successfully treated with the double regimen? We'll never know
UK uses EUCAST BPs, which are lower than CLSIs
Let's wait and see how this turns out.......
UPDATE: they finally determined endpoint MICs
CRO = 0.5
AZT > 256
This is the real deal y'all.
Consensus Details H. pylori Testing, Treatment for US Patients
A new consensus document from 11 US experts
http://www.cghjournal.org/article/S1542-3565(18)30268-4/pdf
Testing has been kind of a problem
Between 2010-2013: 100 million people got tested
70% serology, 4.2% positive
US is a low prevalence country, and confirmatory testing (UBT, HpSAg) should be done
However, only about a third of all positive had these tests done within 14 days
Treatment is also a problem
Cure rate with standard triple regimen (AMX, CLR, a PPI) decreased below 80% since 2000, but only half of gastroenterologists reported eradication
Summary of statements that were accepted by panel and external reviewer
Everyone with H. pylori should be treated
Anybody with these following condition must be tested
Current or history of gastroduodenal ulcers
Uninvestigated dyspepsia (epigastric pain lasting longer than one month)
Gastric mucosal associated lymphoid tissue (MALT) lymphoma
Family history of gastric cancer
Some that did not reach unanimous opinion
Pt with reflux with high risk for infection
1st gen immigrant from high-prevalence countries
Latino, African-American due to reported higher prevalence
Cervical Cancer to Double Across Middle East Without Vaccines
Absence of public awareness of vaccines in conservative countries in ME and North Africa
Prevalence will double in 2035 without vaccination
That's all for now. Bug Hunters, may the odds be ever in your favor.