RESISTANCE John A. Bosso, Pharm.D. PHMPR732.resis.bosso.rev7.07 1 Factors in the Selection of Anti-infectives: MICROBIAL RESISTANCE Therapeutics PHMPR-732 John A. Bosso, Pharm.D. In what part of the country is antibiotic resistance among bacterial respiratory pathogens the highest? 1. Northeast 2. Southeast 3. Midwest 4. Southwest 5. West Coast OVERVIEW OF PRESENTATION • Mechanisms of development of resistance • Mechanisms of resistance – Examples • Examples of Problem Bacteria; 2006 and beyond – Mechanisms, prevalence, susceptibility patterns – Respiratory pathogens – Gram-positives – Gram-negatives The history of antimicrobials… 2000 BC: Here, eat this root. 1000 AD: Roots are heathen; say this prayer. 1850: Prayers are superstition; take this potion. 1945: Potions are a crock; take this penicillin. 1955: Oops, forget penicillin. Take tetracycline. 1960-2002: 39 or more “oops.” 2001: The bugs have won. Eat this root.
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RESISTANCEJohn A. Bosso, Pharm.D.
PHMPR732.resis.bosso.rev7.07 1
Factors in the Selection of Anti-infectives:MICROBIAL RESISTANCE
Therapeutics PHMPR-732
John A. Bosso, Pharm.D.
In what part of the country is antibiotic resistanceamong bacterial respiratory pathogens the highest?
1. Northeast2. Southeast3. Midwest4. Southwest5. West Coast
OVERVIEW OF PRESENTATION
• Mechanisms of development of resistance• Mechanisms of resistance
– Examples
• Examples of Problem Bacteria; 2006 and beyond– Mechanisms, prevalence, susceptibility patterns– Respiratory pathogens– Gram-positives– Gram-negatives
The history of antimicrobials…
2000 BC: Here, eat this root.1000 AD: Roots are heathen; say this prayer.1850: Prayers are superstition; take this potion.1945: Potions are a crock; take this penicillin.1955: Oops, forget penicillin. Take tetracycline.1960-2002: 39 or more “oops.”2001: The bugs have won. Eat this root.
RESISTANCEJohn A. Bosso, Pharm.D.
PHMPR732.resis.bosso.rev7.07 2
The Evolution of Bacterial Resistance
Penicillin-susceptible staphylococci
Penicillin-resistant staphylococci 1,2
Methicillin-resistant staphylococci3
Penicillin introduced (1938)
Methicillin introduced (1960)
1. Abraham EP. Chain E. Nature 1940;146:837-9.2. Rammelkamp M. Proc Roy Soc Exper Biol Med 1942;51:386-9.3. Jevons MP. Br Med J 1961;1:124-5.
Impact of Anti-infective Resistance
• Infections with resistant organismsassociated with:– Higher rates of hospitalization– Greater length of hospital stay– Higher rates of illness and death
• Estimated cost of treating associatedinfections in USA is several billion dollars
How do bacteria become resistant?
Intrinsic vs.Acquired Resistance
RESISTANCEJohn A. Bosso, Pharm.D.
PHMPR732.resis.bosso.rev7.07 3
Intrinsic Resistance
• Lack of drug-susceptible target– e.g., resistance of PBPs of enterococci to
cephalosporins• Inherent property of organism preventing abx
from reaching target– e.g., resistance of Gram-negative organisms to
vancomycin due to its inability to penetrate the outermembrane
Acquired Resistance
• Apparent change in genetic informationthrough:– Mutation (chromosomal)– Expression of latent gene– Acquisition of new genetic material
• Conjugation• Transduction• Transformation
Exchange of Genetic InformationThrough Conjugation (± plasmids)
Acqusition of DNA ThroughTransduction (via bacteriophage)
RESISTANCEJohn A. Bosso, Pharm.D.
PHMPR732.resis.bosso.rev7.07 4
Mutation• In general, not a common/frequent mode
of resistance evolution• Hypermutable strains
– Up to 1000X increased spontaneous mutationrate
• Due to defects in genes involved in DNA repair orerror avoidance
• e.g., P. aeruginosa
Horst et al. Trends Microbiol 1999;7:29-36,Miller. Annu Rev Microbiol 1996;50:625-43.
Organisms Known toExchange Resistance Genes in
Nature
Pseudomonads
Enterobacteriaceae
Vibrio cholerae
Campylobacter
Staphylococci
Enterococci
Pneumococci
Streptococci
Tenover. CID 2001:33(suppl):S108
Mechanisms of Bacterial Resistance
• Antibacterial Inactivation
• Alteration of Target Site• Decreased Intracellular concentrations
MECHANISMS OF RESISTANCEVariations on the Theme(s)
• INACTIVATION
• overproduction of inactivating enzymes
• ALTERATION OF TARGET
• overproduction of protein target
• DECREASED PENETRATION
• active efflux pumps
RESISTANCEJohn A. Bosso, Pharm.D.
PHMPR732.resis.bosso.rev7.07 5
Expression of Bacterial Resistance
INDUCTION vs. SELECTIONINDUCTION OF GROUP-1 ß-LACTAMASE PRODUCTION
Extended-Spectrum ß-lactamases (ESBL)[Molecular classes A & D]
• early examples arose from mutation of common ß-lactamases (TEM, SHV)• hydrolyze ceftotaxime, ceftazidime & other broad-spectrum cephalosporins and monobactams• do not hydrolyze carbapenems or cephamycins• inhibited by clavulanate and tazobactam• easily transferrable (conjugative plasmids)• Enterobacteriaceae (K. pneumo, E. coli)
Diagn Microbiol Infect Dis 94;19:203-15 and 20:203-8
RESISTANCEJohn A. Bosso, Pharm.D.
PHMPR732.resis.bosso.rev7.07 9
Overview of Selectedβ-Lactamase–Producing Pathogens
Gram-positivebacteria
Gram-negative bacteria
Plasmid-mediated
Chromosomal Plasmid-mediated
S aureusS epidermidis
E faecalis
Extended-spectrumβ-lactamases
E coliK pneumoniae
Haemophilus spp
Inducible Constitutive
Bush group 1 β-lactamases
SPACE organisms Enterobacter sppC freundii
Jones RN, et al. Diagn Microbiol Infect Dis. 1998;30:215-228.Chambers HF, Neu HC. In: Mandell GL, et al, eds. Mandell, Douglas and Bennett’s Principles andPractice of Infectious Diseases. 4th ed. New York, NY: Churchill Livingstone; 1995:233-246.
• Selective pressures – Conditions enhancing bacterial ability to develop
resistance and proliferate1
– Increased by antibiotic overuse or misuse2
• Proliferation of multiply-resistant clones1
• Inability to detect emerging phenotypes1
• Environmental: antibiotics for non-humanuse1
RESISTANCEJohn A. Bosso, Pharm.D.
PHMPR732.resis.bosso.rev7.07 13
Factors Increasing Resistance inHospitals
• greater severity of illness• immunocompromised patients• newer devices and procedures• ↑ introduction of resistant organisms from
community• poor infection control practices• ↑ antibiotic prophylaxis• ↑ empiric polymicrobial antibiotic therapy• high abx use per geographic area per unit time
McGowan. Bull NY Acad Sci 1987;63:253-68.
Evidence that Antibiotic UseInfluences Resistance
• Resistance more common in organisms causinghospital-acquired infections
• During outbreaks, patients who have receivedantibiotics are more likely to become infected
• Changes in antibiotic use lead to changes inresistance
• Areas with the highest antibiotic use have thehighest rates of resistance
Evidence that Antibiotic UseInfluences Resistance (con’d)
• Increased duration of therapy causesincreased likelihood of superinfection orcolonization
• Increased dosage causes increased likelihoodof superinfection or colonization
Settings for Antibiotic Resistance
• Hospitals– tertiary– community
• Nursing Homes• Day Care Centers• The Community
RESISTANCEJohn A. Bosso, Pharm.D.
PHMPR732.resis.bosso.rev7.07 14
Day Care Foreign
Community(Outpatients)
Other(e.g., feedlots)
CommunityHospitals
TertiaryHospitals
Nursing Homes
GC, Shigella
Environments that influence the evolution andspread of antimicrobial resistance
What are today’s bigresistance problems?
The IDSA Big Six
Increasing incidence in hospital- and community-acquired cases with few therapeutic options
MRSA
Causes a variety of severe infections with increas-ing incidence in ICUs; wide-based resistance
Pseudomonasaeruginosa
Common cause of BSI, IE, CAB, meningitis & IAIwith few therapeutic options
Vancomycin-resistantE. faecium
Common Gm- aerobic pathogens causing life-threatening diseases; increasing resistance
ESBP-producing E.coli & Klebsiella spp
Increasing incidence, high mortality; availabletherapies all have limitations
Aspergillus spp
Problematic, MDR, nosocomial and comm-unity-acquired pathogen of increasing incidence
Acinetobacterbaumannii
Why:Organism
Talbot et al. CID 2006;42:657-68.
Worldwide Resistance toSelected Antimicrobials
1. NNIS System, Am J Infect Control. 2003;31:481-498. 5. Christiansen et al. Antimicrob Agents Chemother. 2004;48:2049-2055.2. Biedenbach et al. Diagn Microbiol Infect Dis. 2004;50:59-69. 6. Low et al. Clin Infect Dis. 2001;32:S133-S145.3. Jones et al. Diagn Microbiol Infect Dis. 2002;43:239-243. 7. Winokur et al. Clin Infect Dis. 2001;32:S94-S103.4. Bouchillon et al. Int J Antimicrob Agents. 2004;23:181-196.
Note: Resistant isolates have ciprofloxacin MICs ≥ 1 µg/ml. Isolates withintermediate resistance have ciprofloxacin MICs of 0.125 - 0.5 µg/ml.Susceptibility to ciprofloxacin was first measured in GISP in 1990.
Gonococcal Isolate Surveillance Project (GISP) — Percent of Neisseriagonorrhoeae isolates with resistance or intermediate resistance to
ciprofloxacin, 1990–2005www.cdc.gov/std/
Resistance in Respiratory Pathogens(common community pathogens)
• Streptococcus pneumoniae– Resistance to β-lactam antibiotics due to altered penicillin-binding
proteins (PBPs)– Multidrug resistance due to various mechanisms– Macrolide resistance due to altered ribosomes and increased efflux– Tetracycline resistance due to presence of tetM gene
• Haemophilus influenzae– Resistance to ampicillin and amoxicillin due to β-lactamase
production– Resistance to β-lactam antibiotics due to alteration of PBPs (rare)
• Moraxella catarrhalis– Resistance to ampicillin and amoxicillin due to β-lactamase
production
TRUST Studies 2004-2006: AntimicrobialResistance of S. pneumoniae in the US
TRUST Studies (1997-2002):Multidrug-Resistant S. pneumoniae
% o
f Res
ista
ntS.
pne
umon
iae
Isol
ates
1997-1998(TRUST 2)
1999-2000(TRUST 4)
2001-2002(TRUST 6)*
1998-1999(TRUST 3)
2000-2001(TRUST 5)
* 92.4% were R to PEN-AZI-SXT
Thornsberry, et al. CID. 2002:34(S1):S4-S16. Kelly, et al. ICAAC. 2001, abstr 2109. Sahm, et al. ICAAC. 2002, abstr 1640.Data on file, Ortho-McNeil Pharmaceutical, Inc.
PRSP*: Reduced Susceptibilities to β-Lactamsand Macrolides: TRUST 10 (2006), N=426
*PRSP = penicillin-resistant S. pneumoniae (MIC ≥ 2.0 µg/mL); ceftriaxone and amox/clav %S
based on CLSI nonmeningitis breakpoints. Data on file, Ortho-McNeil, Inc.
98.1
80.5
42.0
20.0
0.9
Levofloxacin Resistance in Common GramNegatives 2003 - 2004
USAMinnesota – Native American ChildrenNebraska – Native American Children
San Francisco – MSMLos Angeles – MSM; Prison Inmates (>900 cases)
Boston – MSM
MMWR 52:88, 2003
RESISTANCEJohn A. Bosso, Pharm.D.
PHMPR732.resis.bosso.rev7.07 17
CA-MRSA Infections Among CompetitiveSports Participants: 2000-2003
• Outbreaks of SSTI due to CA-MRSA reported fromColorado, Indiana, Pennsylvania, Los Angeles Countybetween 2000 & 2003
• Sports involved included fencing, wrestling, andfootball
MMWR 52:793, 2003
Community-Associated and Health Care-AssociatedMethicillin-Resistant Staphylococcus aureus Cases, by
Infection Type
* If patients had more than 1 type of infection, only 1 was selected for inclusion in this table. The hierarchy for choosing the type of infection forpatients with multiple sources was: bacteremia, bone, pleural fluid, peritoneal fluid, joint, surgical specimen, postoperative wound, eye, ear,sputum, urine, and skin.† Refers to the statistical probability that the type of infection among community-associated cases differed from the percentage among health care-associated cases (α = .05).‡ Among health care-associated isolates, some respiratory tract isolates were obtained from endotracheal tubes, and some urinary tract isolateswere obtained from Foley catheters.§ Included bone, peritoneal fluid, joint, surgical specimen, and postoperative wound.
From: Centers For Disease Control and Prevention. Slide presentation: Campaign to PreventAntimicrobial Resistance,slide 10. Available at:http://www.cdc.gov/drugresistance/healthcare/ha/slideset.ht, Accessed June 22, 2004.
From: Centers For Disease Control and Prevention. Slide presentation: Campaign to PreventAntimicrobial Resistance,slide 10. Available at:http://www.cdc.gov/drugresistance/healthcare/ha/slideset.htm, Accessed June 22, 2004.
In vitro activity does not necessarily correlate with clinical results.Yellow numbers show pathogens with levo > 5% higher susceptibility than cipro.LVX = levofloxacin; CIP = ciprofloxacin; AMP = ampicillin; CRO = ceftriaxone; PTZ = piperacillin/tazobactam;GEN = gentamicin; SXT = trimethoprim/sulfamethoxazole; 30 geographically distributed sites in TRUST 9.a: LVX & CIP do not have clinical indications for S. maltophilia. Data on file, Ortho-McNeil, Inc.Gatifloxacin and moxifloxacin were not reported for Enterobacteriaceae, since there are no CLSI breakpointsfor moxifloxacin and testing of gatifloxacin is recommended for urine isolates only
Antimicrobial % Susceptibility: P. aeruginosa, 2003-2005
TRUST 7 TRUST 8 TRUST 9Antimicrobial 2003 2004 2005Ceftazidime 80.6 75.4 83.2Cefepime 79.5 76.2 81.8Gentamicin 72.3 82.3 82.7Pip/Tazo 87.0 81.9 87.1Imipenem 78.8 80.5 84.5Ciprofloxacin 68.8 64.3 67.2Levofloxacin 65.3 60.9 65.9Isolates (labs) 882 (36) 745 (30) 549 (30)% Suscep is similar for ciprofloxacin and levofloxacinIn vitro activity does not necessarily correlate with clinical results.
Karlowsky, et al. CID 2005:40 (S2): S89-98. Data on file, Ortho-McNeil, Inc.
RESISTANCEJohn A. Bosso, Pharm.D.
PHMPR732.resis.bosso.rev7.07 19
Riccio et al. Antimicrob Agents Chemother. 2000;44:1229-1235.
* Carries the IMP-2 gene cassette† Does not carry the IMP-2 gene cassette, shown for comparison
MIC (µg/mL)Resistance Profile of Selected Bacteria With and Without IMP-2
β-Lactamase–resistantA baumannii
• A metallo-β-lactamase (IMP-2) was identified inA baumannii strain AC-54/97
– Allelic determinant (blaIMP-2) is integron-borne– The gene cassette confers beta-lactam resistance– Variants of this resistance determinant exist in nature and can be
acquired by clinically relevant species
Net
ilmic
in32
20.25
Am
ikac
in>64
11
1. Wang et al. Antimicrob Agents Chemother. 2004;48:1295-1299.2. Wang et al. Antimicrob Agents Chemother. 2003;47:2242-2248.
Plasmid-MediatedFluoroquinolone Resistance
• Fluoroquinolone resistance results from plasmid-carrying qnr gene
• 110 ciprofloxacin-resistant K pneumoniae and E coliwere screened in the United States:– qnr detected in K pneumoniae 8/72 (11.1%)– Not found in any E coli (38 tested)
• Strain relatedness– 4 strains carried original plasmid pMG252– Five carried new plasmids encoded for FOX-5β-lactamase (AmpC-type)
– Two strains produced SHV-7 ESBL• E coli isolates from Shanghai carrying qnr exhibit
fluoroquinolone resistance
1
2
Resistance at MUSC 2005*(% resistant)
295824Ciprofloxacin
122623Tobramycin
25120Imipenem
376415Cefepime
NRNR20Cetriaxone
246718Pip/Tazo
NRNR28Amp/Sul
NRNR100Ampicillin
P. aeruginosaA. baumanniiK. pneumoniaeAntibiotic
*Source: 2005 annual antibiogram data; non-urine only
RESISTANCEJohn A. Bosso, Pharm.D.
PHMPR732.resis.bosso.rev7.07 20
MUSC; 5/07
MUSC; 5/07MUSC; 5/07
RESISTANCEJohn A. Bosso, Pharm.D.
PHMPR732.resis.bosso.rev7.07 21
Geographic Variation in Resistance
• USA– S. pneumoniae– H. influenzae
• Worldwide– M. tuberculosis– S. pneumoniae– ß-lactamase producers
• e.g., ESBLs, Carbapenemases, IRBLs
S. pneumoniae Antimicrobial ResistanceTRUST 10 (2006)
3,014 isolates from 137 labs.In vitro data does not necessarily correlate with clinical results.Resistance rates for Delaware is from TRUST 8 (2003-2004). Data on file, Ortho-McNeil, Inc.
S. pneumoniaePenicillin Resistance
(Resistant, MIC ≥ 2 µg/mL)
National Rates:Azithromycin = 30.8% RErythromycin = 31.3% R
National Rate:Penicillin = 14.1% R
20-49.9% R
12-19.9% R
<12% R
≥ 50% R
S. pneumoniaeAzithromycin Resistance
(Resistant, MIC ≥ 2 µg/mL)
DC DC
Viruses & Fungi
• Resistance may be intrinsic or acquired• Mechanisms typically involve:
– Altered target site– Decreased cell penetration (esp. fungi)– Selection of less susceptible species
• e.g., with non-albicans Candida
Antifungal Resistance
• Basic Mechanisms– Altered target site– Increased drug efflux– Decreased drug influx– Mutation
forming a channel resulting in disruption ofthe protein gradient
– MOR: alteration of lipid composition ofplasma membrane (decreased ergosterolcontent) leading to lower affinity for AmBbinding
Antifungal Resistance
• Azoles– MOA: ergosterol biosynthesis inhibition
• Bind lanosterol demethylase– MOR:
• Increased efflux– Candida drug resistance gene (CDR) overexpression
• Decreased influx– Change in sterol composition of plasma membrane
leading to decreased drug uptake
Antifungal Resistance
• Azoles (continued)– MOR:
• Altered target enzyme– Overexpression of lanosterol demethylase– Mutation of gene encoding lanosterol
demethylase (ERG11)• Alteration of ERG3 genes
– Altered sterol ∆(5,6) desaturase causing anaccumulation of precursor that can supportfungal cell growth in presence of azoles
Fluconazole Susceptibility over 12 years:1992-2003
Susceptibility % S, S-DD, and R by yearSpecies (N) Category* 1992 1995 1997 1999 2001 2003C. albicans S (<8ug/ml) 100 89 99 100 99 97 (4518) S-DD (16-32 ug/ml) 0 2 0 0 0 1 R (>64 ug/ml) 0 9 1 0 1 2C. glabrata S 15 49 46 84 64 57 (1228) S-DD 67 36 46 12 29 32 R 18 15 8 4 7 11C. parapsilosis S 98 93 100 100 99 94 (956) S-DD 0 7 0 0 0 6 R 2 0 0 0 1 0
M. Pfaller, personal communication
RESISTANCEJohn A. Bosso, Pharm.D.
PHMPR732.resis.bosso.rev7.07 23
Antifungal Resistance
• 5-Fluorocytosine– MOA: disrupts protein synthesis– MOR:
• Mutation leading to decreased activity ofcytosine permease or deaminase uptake ortransformation to active formintracellularly
• Loss of activity of uracil phosphoribosyl-transferase leading to decreaed 5-FCconversion to active form
Antifungal Resistance
• Glucan Synthesis Inhibitors– Echinocandins
• MOA: inhibit synthesis of 1,3 ß-D-glucan, acomponent of the fungal cell wall
• MOR: mutation leading to alteration of theß-glucan synthase
Sensitivity (IC50) of Glucan Synthesis EnzymeComplex of Selected Candida Species to Inhibition
by Caspofungin
9.9 - 32 C. guilliermondii
11 - 206 C. krusei
200 - 400 C. parapsilosis
0.5 – 3.1 C. tropicalis
0.3 – 4.0 C. glabrata
0.5 – 1.3 C. albicans
IC50 (ng/ml) Species
RESISTANCEJohn A. Bosso, Pharm.D.
PHMPR732.resis.bosso.rev7.07 24
Effect on Morbidity & Mortality
“...for both nosocomial and community-acquired infections, the mortality, the likelihoodof hospitalization, and the length of hospital staywere usually twice as great for patients infectedwith drug-resistant strains....”
Holmberg et al. Rev Infect Dis 1987;9:1065-78
A local pediatrician calls your pharmacy seeking advise onempiric therapy for a 2 year old with acute otitis media. Shewas successfully treated one month ago for the same conditionwith amoxicillin. The child is in day care and has two siblings athome, both under the age of 6 years.
• What risk factors does the child have for infection with apenicillin/amoxicillin-resistant bacteria?
• Which antibiotic should you recommend?
Good Websites for Resistance Info
• Comprehensive sites– Bugs & Drugs on the Web
http://www.antibioticresistance.org.uk– Alliance for the Prudent Use of Antibiotics
http://www.tufts.edu/med/apua/index.html– Canadian Committee on Antibiotic Resistance
http://www.ccar-ccra.com• Prevention in Institutions