Infectious Diseases: Antibiotic Resistance & New Drugs PDF

INFD3012 Infectious Diseases: Antibiotic Resistance and the need for new drugs Professor Jamie Triccas School of Medical Sciences Faculty of Medicine and Health [email protected] The University of Sydney Page 1 ...

INFD3012 Infectious Diseases: Antibiotic Resistance and the need for new drugs Professor Jamie Triccas School of Medical Sciences Faculty of Medicine and Health [email protected] The University of Sydney Page 1  Copyright COMMONWEALTH OF AUSTRALIA Copyright Regulation WARNING This material has been reproduced and communicated to you by or on behalf of the University of Sydney pursuant to Part VB of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice The University of Sydney Page 2  Learning Objectives – Discuss the 3 major classes of pathogens considered pathogens of major health risk: methicillin-resistant Staphylococcus aureus Multi-drug resistant & pan-drug resistant Gram negative bacteria MDR and XDR Mycobacterium tuberculosis – Describe the health significance and mechanism of resistance utilised by the major members of the ESKAPE pathogens The University of Sydney Page 3  Antibiotic resistance- the major players Can group into 3 classes of pathogens of major health risk: 1. methicillin-resistant Staphylococcus aureus (MRSA) - ~12,000 deaths per year in the US - $3 billion to $4 billion of additional health care costs - Rising prevalence of MRSA increases the likelihood of vancomycin-resistant S. aureus (VRSA) http://www.cdc.gov/drugresistance/ threat-report-2013/pdf/ar-threats-2013-508.pdf The University of Sydney Page 4  Antibiotic resistance- the major players Can group into 3 classes of pathogens of major health risk: 2. Multi-drug resistant (MDR) & pan-drug resistant (PDR) Gram negative bacteria - e.g. Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa - Can be resistant to all of the antibiotic classes commonly used to treat Gram negatives The University of Sydney Page 5  Antibiotic resistance- the major players Can group into 3 classes of pathogens of major health risk: 3. MDR and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (MDR-TB and XDR-TB) - MDR-TB treatment requires a 2-year course of antibiotics -XDR-TB often fatal Percentage of new TB cases with multidrug- resistant/rifampin- resistant TB World LECTURE IN WEEK 8 Health Organization The University of Sydney Page 6  Cost of Alternative Antibiotics to treat common infections standard TB drugs ~ US$20, MDR-TB drugs up to US$5000 The University of Sydney Page 7  Antibiotic Discovery and Resistance Development Resistance Anti-infective Discovery 1st Mechanisms of Organisms agent (introduction) report resistance ed Penicillin G 1940 (1943) 1940 Penicillinase S. aureus Streptomycin 1944 (1947) 1947 S12 ribosomal mutations M. tuberculosis Tetracycline 1948 (1952) 1952 Eflfux Shigella dysenterie Erythromycin 1952 (1955) 1956 23S rRNA methylation S. aureus Vancomycin 1956 (1972) 1988, 2004 D-Ala-D-Ala replacement E. faecalis, S. aureus Methicillin 1959( 1961) 1961 MecA (PPP2a) S. aureus Gentamicin 1963 (1967) 1969 Modifying enzymes S. aureus Nalidixic ac. 1962 (1964) 1966 Topoisomerase mutations E. coli Cefotaxime 1975 (1981) 1981, 1983 AmpC ß-lactamases, ESBL Enterobacteriaceae Imipenem 1976 (1987) 1986 Adquired carbapenemases P. aeruginosa, S. marcescens Linezolid 1979 (2000) 1999 23S RNA mutations S. aureus, E. faecalis Daptomycin 1980 (2004) 2005 ? S. aureus, E. faecalis The University of Sydney Page 8 The University of Sydney Page 9  Antibiotic Use and Resistance The University of Sydney Page 10  Why don’t we have (more) new antibiotics? Lewis, Cell 181, April 2, 2020 The University of Sydney Page 11  The ESKAPE pathogens Enterococcus faecium Staphylococcus aureus Klebsiella pneumoniae Acinetobacter baumannii Pseudomonas aeruginosa Enterobacter species The University of Sydney Page 12  Enterococcus faecium – Vancomycin-resistant entercocci (VRE) – Entercocci- most prevalent aerobic cocci in bowel – Over 90% infection E. faecium due single clonal type (CC17) – E. faecium resist B-lactams in general, aminoglycosides – CC17 highly resistant to ampicillin and quinolone – Use cephalosporin is associated increased colonisation of VREs The University of Sydney Page 13  Vancomycin-resistant E. faecium in Europe % change VRE between Absolute VRE proportions, 2018 2012/2013 and 2018 The University of Sydney Page 14  Enterococcus faecium – Six different types of vancomycin resistance shown by enterococcus : Van-A, Van-B, Van-C, Van-D, Van-E and Van-F (G and L). – Van-A, Van-B and Van-C most prevelant – Van resistance ‘cassettes’ typically acquired by transposable genetic elements – Induced in presence vancomycin The University of Sydney Page 15 The University of Sydney Page 16  Staphylococcus aureus Penicillin Methicillin 2% Methicillin- 35% Methicillin- Penicillin clinical use discovered resistant resistant 1950 1975 1925 Methicillin 2000 Vancomycin 50% SA Penicillin Resistance resistant Vancomycin- resistance Intermediate Resistance to Vancomycin Staphylococcus aureus Sir Alexander Fleming The University of Sydney Page 17  Staphylococcus aureus – Up to 70% S. aureus resistant all penicillins and cephalosporins (MRSA) – Hospital-acquired MRSA: greater mortality and increased hospital stay compared MSSA – Greater risk for patients with open wounds, devices (e.g. catheters), elderly (immuno-compromised) – Community-acquired MRSA: mainly skin and soft tissue, severe invasive disease described – Susceptible non-B-lactams – Strains more virulent than HA-MRSA The University of Sydney Page 18  HA-MRSA vs CA-MRSA -CA-MRSA strains have smaller region for mecA; fitness cost for HA- MRSA - CA-MRSA higher expression of common virulence factors (esp. toxins) - CA-MRSA strains express Panton-Valentine Leukocidin gene -PVL common in CA-MRSA but can be in MSSA The University of Sydney Page 19  HA-MRSA vs CA-MRSA The University of Sydney Page 20  Staphylococcus aureus The University of Sydney Page 21 The University of Sydney Page 22 The University of Sydney Page 23  Staphylococcus aureus Vancomycin-intermediate S. aureus (VISA) – Cell wall thickening, reduce uptake of vancomycin – Higher rate of colonisation but not increased clinical impact – Vancomycin-resistant S. aureus (VRSA) – Rare; high level resistance (~1000 mg/ml) cases – Acquired VacA gene from a vancomycin-resistant strain of Enteroccocus faecalis The University of Sydney Page 24  B-lactams trimethoprin detergents aminoglycosides The University of Sydney Page 25  Klebsiella pneumoniae – K. pneumoniae an important nosocomial infection (UTIs, pneumonia) – ‘Prototype’ bug that contains extended-spectrum B- lactamases (ESBLs) – ESBLs display resistance to 3rd generation cephalosporins – Strains often resistant to other drug classes (e.g. aminoglycosides, fluoroquinolones) – ESBLs are common B-lactamases that have mutated to obtain broader spectrum – Encoded by plasmids and highly transmissible The University of Sydney Page 26  Extended-spectrum B-lactamases (ESBLs) - B-lactamases that hydrolyze extended-spectrum cephalosporins 3 major classes: 1. TEM B-lactamases most common B-lactamase; ~140 TEM types; common E. coli and K. pneumoniae - Amino acids around active site change to allow activity against 3rd gen cephs The University of Sydney Page 27  Extended-spectrum B-lactamases (ESBLs) 2. SHV beta-lactamases: structure similar TEMs and similar mode of action, common in K. pneumoniae; ~ 60 variants - TEM and SHV susceptible to B-lactamase inhibitors 3. CTX-M beta-lactamase- early 1990s, now most prominent ESBLs -Differ to TEM and SIV, acquired from Kluyvera; ~80 CTX-M enzymes -Preferences for cefotaxime and ceftriaxone but some enzymes active against all cephalosporins The University of Sydney Page 28  The large family of bacterial B-lactamases Each dot represents a unique protein sequence. Connections between proteins represent minimal similarity The University of Sydney Page 29  Klebsiella pneumoniae – Carbapenems drug of choice to treat K. pneumoniae ESBL (stable to ESBLs) – BUT K. pneumoniae has 3 Carbapenemases (CRKP) – Located on plasmids – High rates morbidity and mortality, especially critically ill (12-44% mortality rate) – Limited range of susceptibility (usually polymixin E and aminoglycosides) The University of Sydney Page 30  New Delhi Metallo-beta-lactamase-1 (NDM-1) The University of Sydney N Engl J Med 2010; 363:2377-2379 Page 31  Acinetobacter baumannii Normal environmental colonisers Causative agent of nearly all types of nosocomial infection: BSI (32-52% mortality), UTI, pneumonia, wound, meningitis – Risk factors: intubation, surgery, prior Abx therapy, underlying pulmonary disease – Major increase in resistance since 1980s, now have‘pan-drug’resistance – New generation Abs have some effect (e.g tigecycline) Increase of Carbapenem- Resistant Acinetobacter baumannii Infection in in Taiwan The University of Sydney Page 32  Pseudomonas aeruginosa - opportunistic pathogen, most common hospital acquired infection - Bacteremia: ~50% mortality ICU - Endocartitis: e.g. infection of prosthetic heart valves - Pneumonia: most common cause ventilator-associated pneumonia (VAP) - Mortality rate 80-100% for patient with fulminant bacterimic pneumonia; inappropriate Abx therapy major risk factor - Burn wound sepsis: most common cause - Infection of eyes, ears, CNS and UTIs The University of Sydney Page 33  Pseudomonas aeruginosa - large number of resistance mechanisms (chromosomal not plasmid) 1. Multi-drug and specific efflux pumps 2. Reduced outer membrane permeability 3. Enzymatic inactivation (aminoglycosides, B-lactamases, carpenemases) - OXA-type beta-lactamases confer resistance to ampicillin, high activity against oxacillin, poor inhibition by clavulanic acid - OXA-ESBLs predominately in P. aeruginosa 4. Altered drug targets (pencillins, quinolones) The University of Sydney Page 34