This document summarizes the presentation given by Dr. Robert Bonomo on new global challenges of Gram-negative resistance. It discusses the increasing issues with carbapenem and cephalosporin resistance seen in key pathogens like Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. These bacteria are acquiring numerous resistance mechanisms that render most or all antibiotic classes ineffective. The presentation highlights the expanding resistance gene content observed in these pathogens and urges the development of effective treatment strategies given the limited treatment options.
Structure of a carotenoid gene cluster from Pantoea sp. strain C1B1YArunkumar K.R.
Structure of a carotenoid gene
cluster from Pantoea sp. strain C1B1Y and characterization of β-carotene hydroxylase (crtZ) gene
by functional complementation in Escherichia coli.
Structure of a carotenoid gene cluster from Pantoea sp. strain C1B1YArunkumar K.R.
Structure of a carotenoid gene
cluster from Pantoea sp. strain C1B1Y and characterization of β-carotene hydroxylase (crtZ) gene
by functional complementation in Escherichia coli.
Development of strategies for management of infections with carbapenem resist...Bhoj Raj Singh
There is a lot to understand about antimicrobial drug resistance but the little we know is more confusing and less to handle the problem of emerging drug resistance.
Development of strategies for management of infections with carbapenem resist...Bhoj Raj Singh
There is a lot to understand about antimicrobial drug resistance but the little we know is more confusing and less to handle the problem of emerging drug resistance.
VHIR Seminar led by prof. Jean-Jacques Rouby, from the Réanimation Polyvalente Département d'Anesthésie-Réanimation Faculté de Médecine Pierre et Marie Curie UPMC Hôpital Pitié-Salpêtrière Assistance Publique Hôpitaux de Paris.
Abstract:
1 - What we have learnt from experimental studies: relevant animal models,
optimization of aerosol delivery during mechanical ventilation,
penetration of aerosolized antibiotics within the infected parenchyma,
toxicity and pharmacokinetics
2 - the existing human litterature concerning nebulization of antibiotics
in critically ill patients with Ventilator-Associated Pneumonia
3 - The promising place of nebulized colistin and vancomycin for treating
multi-drug resistant Ventilator-Associated Pneumonia
Dr Gokul Bangalore: Over the years antibiotic resistant infections have emerged as a serious threat world over. The mortality is increasing phenomenally and a serious thought should be given to prevent or at least delay the rapid development of resistance. Alexander Fleming clearly said in his speech when he received the Nobel prize in 1950, for the discovery of Penicillin, that if these antibiotics fall into wrong hands and misused, there will be increasing development of antibiotic resistance in bacteria ultimately pushing the world into pre antibiotic era. How true. The world is facing this now. Antibiotics are a single class of drugs which are maximally misused,abused, indiscriminately used and over used. Antibiotic stewardship programs should have been in place at least 40 years back when a pattern of resistance started emerging. Now every individual who prescribe antibiotics should think globally act locally. However there are a number of reasons for the failure of antibiotic stewardship programs. That is a different issue and addressed seriously.Gokul Bangalore: Dr. B. N. Gokul. MBBS, MD (Bangalore), Cert. HIC & ID (Sweden).
Former: Professor of Microbiology, NIMHANS, Bangalore,
Dr. Sid Thakur - Antimicrobial Resistance: Do We Know Everything?John Blue
Antimicrobial Resistance: Do We Know Everything? - Dr. Sid Thakur, Assistant Professor, North Carolina State University, from the 2013 NIAA Merging Values and Technology conference, April 15-17, 2013, Louisville, KY, USA.
More presentations at http://www.trufflemedia.com/agmedia/conference/2013-niaa-merging-values-and-technology
This master's seminar presentation speaks about the role of bacteriophage in the management of different plant diseases.
It deals with the history and discovery of bacteriophages up to current research studies and usage.
Presented by Dr. Jenkins at the 40th Annual Symposium "Diagnostic and Clinical Challenges of 20th Century Microbes", held on Nov 18, 2010 in Philadelphia.
Presented by Dr. Brecher at the 40th Annual Symposium "Diagnostic and Clinical Challenges of 20th Century Microbes", held on Nov 18, 2010 in Philadelphia.
Presented by Ms. Hindler at the 40th Annual Symposium "Diagnostic and Clinical Challenges of 20th Century Microbes", held on Nov 18, 2010 in Philadelphia.
Presented by Dr. Hall at the 40th Annual Symposium "Diagnostic and Clinical Challenges of 20th Century Microbes", held on Nov 18, 2010 in Philadelphia.
Presented by Dr. Miller at the 40th Annual Symposium "Diagnostic and Clinical Challenges of 20th Century Microbes", held on Nov 18, 2010 in Philadelphia.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Gram negative cephalosporium and carbapenem resistance robert bonomo md
1. New global challenges of Gram
negative cephalosporin and
carbapenem resistance
Robert A. Bonomo, MD
Chief, Medical Service
Director VISN 10 GRECC
Louis Stokes Cleveland VAMC
Vice Chairman, Department of Medicine
University Hospitals Case Medical Center
Professor, Case Western Reserve University School of Medicine
Presented at the 41st Annual Symposium
“Global Movement of Infectious Pathogens and Improved Laboratory Detection”
Eastern PA Branch-American Society for Microbiology
November 17, 2011
Thomas Jefferson University, Philadelphia
2. Disclosures
• Support from VA and NIH
• Steris Foundation
• Pfizer
• Excitement rather than give formulas
3. Objectives
• Overview of the problem of ATBR in
Gram negative bacteria
– A. baumannii, Pseudomonas aeruginosa,
and Klebsiella pneumoniae
• Summarize the rapidly expanding
landscape of resistance determinants
• Use this knowledge to devise effective
treatment strategies
6. The clinical challenge of
A. baumannii
• Multi-Drug Resistant (MDR) A. baumannii are
among the most “problematic pathogens”
encountered by clinicians
7. Why? Ab facts…..
• Most common (and emerging) drug
resistant pathogen in the US and world
• 50-70% of Ab clinical isolates are now
eXtensively Drug Resistant (XDR; i.e.
resistant to all antibiotics except
colistin or tigecycline), reflecting a >15-
fold increase since 2000.
• “Pan Drug” Resistant; strains of Ab,
resistant to tige + coli, increasing
Perez et al AAC 2007, Talbot and others, 2006, CID; Talbot ERAIT, 2009, Boucher CID 2009
8. Does resistance matter? Yes
• BSI by XDR Ab cause >50-60% mortality
• In a recent study 13,796 patients in 1,265
ICUs from 75 countries, Ab was one of
only two of 19 microorganisms strongly
linked (p<0.01) to increased mortality by
multivariate analysis;
• Odds ratio for death-1.53
• Resistance + virulence: factors? LPS,
Fe siderophores, PLD, OMPs, biofilm??
McGowan ICHE 2019, Hoffman et al, ICHE 2010, McGowan AJM 2006 Paterson CID 2006, Perez AAC 2007,
Vincent JAMA 2009, Gordon JAC 2009
9. Survey of “Resistance genes” in A. baumannii
bla AMEs QRDR RND OMPs Tet
Efflux pumps
ADC aacC1 gyrA AdeABC HMP-AB tetA
OXA aacC2 parC AdeM OmpA tetB
IMP aacC3 AdeIJK 33-36 kDa tetM
VIM, GIM aacA4 AdeS 25/29 kDa tetX
SIM, SPM, CraS CarO
NDM AdeDE
PER aphA1 Res Is?? OprD PBPs
(43kDA)
TEM* aphA6 AbaR 1-10 OmpW
SHV aadA1 Col R 44, 47kDa, 22 integrons
pmrAB
CTX-M rmt* OMVs
10. “The Resistance Island”
86 Kb, 88 orfs, 82
orfs from another
source and 45
resistance genes
AbaR1-10!
Fournier et al., PLoS Genet. 2006 Jan;2(1):e7. Epub 2006 Jan 13.
11. Threat 1. Carbapenem R
• OXAs and MBLs
• Naturally occurring and acquired
• OXAs- Types and Groups
– Narrow spectrum
– Carbapenem hydrolyzing (CHDLs)
– ES type
• Carbapenemases (Acinetobacter)
– Are not ES; do not have both properties
– Imipenem> meropenem
Poirel et al AAC 2010
13. Threat 2. ColistinR
• Polymyxins (E and B) are cationic polypeptide atbs
• Colistin SO4 for PO and Colistimethate Na+ (sodium
colistin methanesulphonate, colistin sulfomethate sodium)
for IV
• Colistin displaces Ca+2 and Mg+2 from PO4-3 groups of
membrane lipids; Insertion of polymyxins disrupts the
OM and LPS is released ; anti-endotoxin activity ;
rapidly bactericidal???
• Urban et al. reported a case of polymyxin BR A. baumannii
Falgas, et al, CID 2005; Urban 2001 AAC; Li et al AAC 2006;
Li et al Int Journal of Antimicrobial Agents, 2005
14. ColistinR
• ColR due to modifications of LPS;
pmr (Adams…Bonomo, AAC US) vs.
lpxA,-C, and -D (Li and Nation,
Australia); Parks lab in S. Korea
found the same locus as we did.
• Heteroresistance (subpopulations
of genetically identical subclones
that are more R than the parent ) by
Li et al; implications for rx?
• “Colistin dependence”. 77 yo
diabetic male with FI and
Moffatt AAC 2010,
Li et al AAC 2006 ;
bacteremia; “increasingly luxuriant
Hawley et al AAC
2007,
growth”
Adams et al AAC 2009
16. Part II
MDR P. aerugoinosa
The resistance challenge of the ages
17. Pa facts
• Colonization rates by Pa are high in the
hospital (50%); immunity and burn
• Seriously ill patients in ICUs.
• Aggregate NNISS and EU data
– 20 to 30% of nosocomial pneumonias
– 10 to 20% of urinary tract infections
– 3% to 10% of bloodstream infections,
19. Pa and ATBR
• ß-lactamases-all classes represented
– Cephalosporinases,
– class A ESBLs (PER),
– OXA ESBLs (OXA-10, -14),
– Carbapenemases (KPC and GES), MbLs
• Loss of permeability (porins and efflux)
• Quinolones and aminoglycosides
– Active antimicrobial efflux
– Alterations in DNA gyrase
– Aminoglycoside-modifying enzymes
20. Antimicrobial resistance
• Efflux pumps
– MFS—major facilitator superfamily
– ABC—ATP-binding cassette family
– RND—resistance nodulation division
– SMR—small multidrug resistance
– MATE—multidrug and toxic compound
extrusion
RND and MFS extrude antibiotics and work by proton motive force; In
GNRs, RND works with MFP (periplasmic membrane fusion protein)
and OEP (outer membrane efflux protein) to get thru both membranes
21.
22.
23.
24.
25. The mysteries of the biofilm..
Trends in Microbiology Jan 2001; 9(1): 34-39
27. Why should we be afraid of
Klebsiella pneumoniae KPCs?
28. KPC K. pneumoniae
AMIKACIN R
AMPICILLIN R
CEFAZOLIN R
CEFTAZIDIME R
CIPROFLOXACIN R
TRIMETH/SULFA R
IMI/MERO-PENEM 4 ug/ml → (> 64)
GENTAMICIN S
AMPICILLIN/SUL R
CEFOTETAN R
CEFEPIME R
PIP/TAZO R
29. Clinical impact of KPC
carbapenemases
• “The dependability on “last line”
antibiotics is shattered”
• The emergence of KPC
carbapenemase producing Gram-
negatives is a major threat to the
clinician
– K. pneumoniae, Acinetobacter, E.
coli, Enterobacter, Serratia,
Pseudomonas,… the list grows
Patel and Bonomo, 2011, Current Opinion
30. Clinical issues with KPC
• ATB control ?Cephalosporin and b-
Lactam-b-Lactamase Inhibitor restriction
policies? special populations? Imipenem
restriction ??
• How best to implement IC? Carrot or
stick?
• Detection? ESBL identification?
Inoculum effect?
• Colistin-as empiric Rx ??? combined
with aminoglycosides (gent); rifampin
31. Status of the KPC global
epidemic
• Two phenotypes; MIC< 8 and MIC> 32
• ST258> ST384, ST388, others…
• Plasmids from ST258 and other starins
has been transferred to E. coli in
patients (Kreiswirth lab).
• Colistin resistant ST258
• Novel testing methods (ChromAgar,
Boronates, PCR/ESI-MS, Microarray
methods/Checkpoints
32. Mainly KPC-2 and KPC-3 (KPC-2 to KPC- Thanks Dr. Endimia
11)
Poirel L. et al.
Enterobacteriaceae (K. pneumoniae) Outbreaks
33. Dr. End
“Import/Export” of patients carrying
blaKPC
Naas T et al., AAC 2005 Hammerum AM et al. IJAA 2010
Cuzon G et al.
34. Thanks
Dr. Endimiani
Genetic environment of blaKPC (Tn4401) Structure of Tn4401 and insertion sites
P.aeruginosa Isoform B
Tn4401 is at the origin of acquisition and
dissemination of blaKPC
Possible genesis of Tn4401
Isoform A
• Different isoform suggests that this
region is polymorphic
35. Thanks
Dr. Endimiani
Western Blot
No deletion (isoform B)
68-bp deletion
Relative copy number
100-bp deletion (isoform A) with real-time PCR Molecular characterization of
255-bp deletion (versus rpoB gene)
OmpK35 and OmpK36 genes
c Frameshift
(stop codon after aa 88)
Common in ST258
38. Is there increased mortality??
The mortality in the IRE group was 33%, compared to
9% among controls.
Being an IRE case was significantly associated with
increased mortality (P 0.043)
42. The near future
The exciting future Clonal typing
gyrA, parC
mecA, PVL, TSST,
mupA, nucA
43.
44.
45. Options for treatment?
“The basis for a new
research
agenda in Infectious
Diseases”
Can I approach this based upon a knowledge of genetics?
46. Therapy for MDR Ab et al.
Colistin?
Tigecycline?
Minocycline?
Rifampin?
(Teicoplanin? Vancomycin? Are you crazy!)
Do we have enough patients
studied properly? Animal
models may have
(significant) limitations?
50. Colistin + rif?
Colistin + minocycline?
Not enough data Antagonistic?
Synergy? Sometimes???
Meta-analysis (Falagas IJAA)--no statistical
difference in cure rates when colistimethate sodium
alone was compared with the combinations with
meropenem, piperacillin/tazobactam or
ampicillin/sulbactam
51. The colistin “bottom line”
• “Efficacy rate” of 57-76% in IV form;
“microbiological eradication” of 67-90.9%Renal
tox 0-37%
• Nebulized colistin (CF studies + others)
effective; FDA warning; impact of shift to more
resistant strains ; use with IV!!
• 32 cases “microbiological eradication” in the
CNS with ITh/IVe colistin (safe e 1) (2.5 mg/kg,
10-20 mg ITh)
• Colistin was independently associated with
higher mortality vs. treatment with sulbactam in
patients with A. b infections
52. Colistin dosing
• Administration of a loading dose (300
mg)
• Colistin exposure during the first 12 h
“may be beneficial, providing enough
net killing such that the immune system
may be able to eradicate any remaining
colistin- resistant cells”
53. Major concerns…real ?
1. Rapid resistance
Tigecycline?
can emerge;
2. Cases of Patients % Improvement
breakthrough 25 84
bacteremia
reported; 18 50
3. Adequacy of 17 82.4
blood levels??
29 30
Pachon and Vila Curr Opin 75 70
Investig Drugs. 2009
Feb;10(2):150-6. 34 68
Giamarellou & Poulakou, Drugs. 45 78-90%
2009
bacteremic patients treated with tige failed to
Michalopoulos A, Falagas ME. clear their bacteremia 10-fold more commonly
Expert Opin Pharmacother. than patients treated with comparator drugs
2010 Apr;11(5):779-88. Gordon JAC 2009, Gardiner CID
54. My recommendations
• Susceptible strains
1. A/S, 3 q6; higher doses?
2. Imipenem; meropenem is worrisome;
dori?? Cephalosporins are tricky.
3. Colistin loading dose 5 mg/kg not to
exceed 300 mg then (4.5 mg/kg/day) and
split it tid (1.5 mg/kg q8).
4. Colistin and rifampin, tigecycline, or
minocycline, doripenem?)
58. If NDM-1? Treatment options
►Aztreonam + NXL?
►BAL30072, meropenem
and ??
►Tige?
59. E-722
Activity of the Novel Sulfactam BAL30072,
Alone and in Combination with
Meropenem, Against Diverse Gram-
negative Isolates Carrying NDM-1 β- Dihydropyridone
lactamase Gene. T. R. Walsh et al. siderophore
monocyclic
sulfactam
Organism (N) Ceftazidime Meropenem Aztreonam BAL BAL30072:
30072 Meropenem
A. baumannii (23) >256 256 16 4 1
P. aeruginosa (2) 256 32 16 0.5 <0.125
S. maltophilia (1) 256 64 64 4 1
Escherichia coli (3) 256 32 64 32 1
K. pneumoniae (2) 256 128 64 32 2
C. freundii (3) 128 128 64 8 2
Thanks to Dr. F. Perez
60. KPC Rx
68 blaKPC-possessing K. pneumoniae including
23 tigecycline- and/or colistin-nonsusceptible strains.
By agar dilution, 93% of the overall
KpKPC were susceptible (MIC50/90 of 16/64 g/ml, respectively).
Notably, 5 out of 6 extremely drug-resistant (tigecycline
and colistin nonsusceptible) KpKPC were susceptible
to fosfomycin. Compared to agar dilution, disk diffusion
was more accurate than Etest.
61. Summary
• Extraordinary challenge against cunning
pathogens
• Basic understanding of molecular biology is
needed (the complexities of resistance
genes will only increase)
• Research is needed in therapeutics and
infection control
• CALL TO ARMS: Coordinate scientific and
clinical trials to answer these important
questions
62. Acknowledgments
• NIH, VA Merit Review
• Drs. Alan Evangelista and Linda Miller
• Dr. Barry Kreiswirth
• Chris Bethel, Steve Marshall, Magda Taracila,
Kristine Hujer and Andrea Hujer
• Drs. Krisz Papp-Wallace, Marisa Winkler,
Federico Perez, Curtis Donskey, Dror
Marcham