RESISTANCE John A. Bosso, Pharm.D.people.musc.edu/~bossoja/IDModule/resistanceHO.pdf · RESISTANCE...

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.



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



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)



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



Expression of Bacterial Resistance

INDUCTION vs. SELECTIONINDUCTION OF GROUP-1 ß-LACTAMASE PRODUCTION

e.g.,

NORMAL (UNINDUCED STATE)

Regulator Gene

ß-lactamase

INDUCED (TEMPORARY) STATE

Regulator Gene

NO COOH

ß-lactam antibiotic

ß-lactamase



Induction Potential forAmpC ß-lactamases

Highest

Lowest

Carbapenems & cephamycinsAminopenicillinsCarbenicilin, ticaracillinUreidopenicillinsCephalosporinsClavulanic AcidCefepime, cefpiromeSulfone inhibitorsAztreonam

NORMAL (UNINDUCED STATE)

Regulator Gene

ß-lactamase

CONSTITUITIVE (STABLYDEREPRESSED) STATE

(VIA MUTATION)

Regulator Gene

ß-lactamase

Mutation SELECTION OF RESISTANTMUTANTS



Resistant StrainsRare

xx

Resistant Strains Dominant

Antimicrobial Exposure

xxxx

xxxx

xx

Selection for Antimicrobial-ResistantStrains

Antibacterial Inactivation

THE ß-LACTAMASES

Class A, C, and D β-lactamases:Mode of Action

OH NO

NO O

NHO OOH

H2O

NOOH

Binding

Acylation

Hydrolysis

Non-covalent complex

Covalent acyl enzyme

Adapted from Livermore DM. Clin Microbiol Rev. 1995;8:557-584.

Classification of ß-lactamases• Two families have evolved over time: the

serine ß-lactamases (classes A,C, D) andthe metallo-ß-lactamases (class B)

• Molecular class (primary structure)1

– Classes A - D• Substrate spectrum & response to

inhibitors– Bush-Jacoby-Medeiros classification2

1. Ambler. Philos Tans R Soc Lond B Bop; Sci 1980;289:321-312. Bush et al. Antimicrob Agents Chemother 1995;39:1211-33



Examples of ß-lactamases ofGram-negative Bacteria

D+AmpC & carba’sOXA-23

A+++AmpC & carba’sKPC

B0AmpC & carba’sIMPCarbapenemase

C0ESBL & cephamycinsACC-1AmpC

D+old & new BLsOXA-10

A++++old & new BLsCTX-M

A++++old & new BLsPER-1

A++++old & new BLsTEM-12ESBL

D+older BLs & methOXA-1

A+++older BLsTEM-1Broad spectrum

Mol. Cls.CA inhSubstratesExß-lactamase

Adapted from Jacoby et al. N Eng J Med 2005;352:380-91.

Amp C ß-lactamases(Molecular class C)

• Inducible/selectable resistance• Chromosomal and plasmid mediated• Hydrolyze most ß-lactams (except carbapenems and

cefepime)• Must be expressed at high levels to confer resistance to

3rd generation cephalosporins– High level expression of chromosomal Amp C ß-lactamase must

generally be induced while high level expression is common forplasmid-mediated

• Originally P. aeruginosa, Acinetobacter, Serratia,Providencia, etc. but now moved (via plasmids) to morecommon organisms (E. coli and K. pneumoniae)

Bacteria Producing Inducible AmpC ß-lactamases

• Serratia marcescens; Providencia retgeri &stuartii; Acinetobacter spp; Citrobacter freundii;Enterobacter aerogenes, cloacae & sakazakii

• Hafnia alvei; Morganella morganii; Aeromonashydrophilia & sobria; Chromobacteriumviolaceum; Rhodobacter sphaeroides

• Pseudomonas aeruginosa

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



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.

Other Inactivating Enzymes

• Adenylation

• Acetylation

• Phosphorylation

Enzyme Streptomycin Gentamicin Tobramycin Amikacin

6-adenylyltransferase (6-AAD)

3'-phosphotransferase (3'-APH)

6'-acetyltransferase (6'-AAC)

4'-adenylyltransferase (4'-AAD)

2''-phosphotransferase/6'acetyltransferase (2''-APH/6'-AAC)

+

-

-

-

-

-

-

-

-

+

-

-

+

+

+

-

+

+

+

+

Summary of Enterococcal Aminoglycoside-Modifying Enzymes

OH

OH OH

OH

OHOH

O(4')

(3')

O

CH NH22(6')

NH2

NH2

(3)

(1)

O

(2'')

CH OH2

NH2

O

acetylationadenylylation

phosphorylation

acetylation

adenylylationphosphorylation

SITES FOR AMINOGLYCOSIDE MODIFICATION



Decreased Intracellular ConcentrationsDecreased Penetration

• Decreased penetration through outer wall– Defense mechanism of Gram-negative bacteria– Antibiotics affected include:

• ß-lactams• Quinolones• Aminoglycosides

• Biofilms– Exopolymer matrix– Decreased penetration or antibiotic binding

• e.g., aminoglycosides

Decreased Antibiotic Penetration

Active Efflux

• Tetracyclines– As with S. aureus

• Macrolides– As with S. pneumoniae

Antibiotics Affected by Efflux Pumpsin P. aeruginosa

MexA-MexB-OprM MexC-MexD-OprJ MexE-MexF-OprN MexX-MexY-OprM

Aztreonam Cefepime Chloramphenicol AmikacinCarbenicillin Cefuroxime Ciprofloxacin CefepimeCefotaxime Chloramphenicol Clavulanate CefotaximeCeftazidime Ciprofloxacin Imipenem CiprofloxacinChloramphenicol Erythromycin Levofloxacin ErythromycinCiprofloxacin Levofloxacin Norfloxacin GentamicinClavulanate Nafcillin Sulbactam LevofloxacinLevofloxacin Norfloxacin Trimethoprim TetracyclineMeropenem Tetracycline TobramycinNafcillin TrovafloxacinNorfloxacinPiperacillinSulbactamTetracyclineTrimethoprim

Aeschlimann JR. Pharmacotherapy 2003;23:916-24.



Altered Antibiotic Target Site

• ß-lactams• Quinolones• Aminoglycosides• Macrolides• Tetracyclines• Rifampin and TMP/SMX• Glycopeptides

Antibiotic Resistance in S. pneumoniae: a casestudy in altered target sites

DNA polymeraseRifampin

DNA gyraseTopoisomerase IV

Fluoroquinolones

23S ribosomal RNA subunitMacrolides, lincosamides,streptogramins*

Penicillin-binding proteinsß-lactams

Target AlteredAntibiotic/Class

*resistance phenotype MLSB

Multiple resistance mechanisms canbe present in the same organism

Prevalence of Pansusceptibility, Single-drug Resistance(SDR), and Multidrug Resistance (MDR) Phenotypes

Among Clinical Isolates of P. aeruginosa Collected From theUS (2001-2003)

Karlowsky JA, et al. Clin Infect Dis 2005; 40: S89-S98



Mechanisms of Resistance:Disturbing the Normal Flora

• Resistance to colonization byopportunistic organisms: colonizationresistance - provided by normal flora & various

physiologic factors• Anitmicrobial admnistration may alter

this defense system by altering normalflora

Why has resistance become socommon?

1. Tenover. Clin Infect Dis. 2001;33:S108-115.2. Levy. Clin Infect Dis. 2001;33:S124-S129.

Resistance: Factors AffectingEmergence and Spread

• 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



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



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.

EuropeMRSA3 28.5%P aeruginosa/cefepime2 12.4%P aeruginosa/PIP-TAZ2 14.0%VRE3 4.4%ESBL (K pneumoniae)3 17.3%S pneumoniae/penicillin4 36.8%

United States/North AmericaMRSA1 52.7%P aeruginosa/cefepime2 6.8%P aeruginosa/PIP-TAZ2 10.3%VRE3 17.7%ESBL (K pneumoniae)3 4.9%S pneumoniae/penicillin4 40.3%

Asia PacificMRSA5 32-92%P aeruginosa/cefepime2 6.5%P aeruginosa/PIP-TAZ2 10.9%VRE6 1.0%ESBL (K pneumoniae)7 24.6%S pneumoniae/penicillin4 60.5%

Latin AmericaMRSA3 35.3%P aeruginosa/cefepime2 13.9%P aeruginosa/PIP-TAZ2 23.5%VRE3 5.6%ESBL (K pneumoniae)3 35.8%S pneumoniae/penicillin4 40.3%



Community-Acquired Infections

• URI (H. influenzae, M. catarrhalis)• N. gonorrhoeae• E. coli• S. pneumoniae• Enteric pathogens

– Shigella, Salmonella, Campylobacter• M. tuberculosis• CAMRSA

Gonococcal Isolate SurveillanceProject (GISP) — Percent of Neisseriagonorrhoeae isolates with resistance or

intermediate resistance tociprofloxacin, 1990–2005

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

2004=4,309 isolates, 220 labs; 2005=4,840 isolates, 182 labs; 2006=3,014 isolates, 137 labsData on file, Ortho-McNeil Pharmaceutical.*Ceftriaxone nonmeningitis NCCLS breakpoints 1/2/4, M100-S14, Jan 2004. Karlowsky, et al. CID. 2003;36:963-70. Sahm, DF. Clin Cornerstone. 2003; (S3):S4-S11.

0

5

10

15

20

25

30

35

40

04 05 06 04 05 06 04 05 06 04 05 06

Penicillin Azithromycin Ceftriaxone Levofloxacin

18.6

16.4

15.4

19.3

14.1

22.0

25.0

0.8 0.8

28.8

0.5

30.8

1.4

1.8

0.7

2.0

0.9

1.8

1.1

0.2

0.8

0.0

0.6

0.0

Resistant

Intermediate

Perc

ent o

f iso

late

s



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

TSN Data

31.65.962.6134,635P. aeruginosa

18.33.378.469,906P. mirabilis

6.11.392.6109,903K. pneumo

11.30.388.5506,525E. coli

10.62.087.437,332E.cloacae%R%I%STotal#Organism

• TSN® Database - Focus Technologies, Inc., Herndon,VA

Recent (2001-2003) Outbreaks ofCommunity-Acquired MRSA Infections -

USAMinnesota – Native American ChildrenNebraska – Native American Children

San Francisco – MSMLos Angeles – MSM; Prison Inmates (>900 cases)

Boston – MSM

MMWR 52:88, 2003



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.

Naimi TS et al. JAMA 2003;290:2976,

<.001<.001<.001 .07

<.001 .21

343 (37) 11 (1)

205 (22) 83 (9)

185 (20)110 (12)

98 (75) 9 (7) 8 (6) 5 (4) 1 (1)10 (8)

Skin/soft tissueOtitis media/externaRespiratory tract‡BloodstreamUrinary tract‡Other§

P Value†Health-Care Associated

(n=937)Community-Associated

(n=131)Infection Type*

No. (%) of Methicillin-Resistant S aureus Cases

Hospital-Acquired Infections

• Gram-negative organisms– Enterobacteriaceae– P. aeruginosa– Acinetobacter spp.– B. fragilis

3rd generation cephalosporin-resistant Klebsiella pneumoniae

Fluoroquinolone-resistant Pseudomonas aeruginosa

Non-Intensive Care Unit Patients

Intensive Care Unit Patients

Antimicrobial Resistance amongPathogens Causing Hospital-onset Infections

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.



Hospital-Acquired Infections

• Gram-positive Organisms– Methicillin-resistant Staphylococcus

aureus– Methicillin-resistant Staphylococcus

epidermidis– Enterococci

Methicillin (oxacillin)-resistantStaphylococcus aureus

Vancomycin-resistantenterococci

Non-Intensive Care Unit Patients

Intensive Care Unit Patients

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.

Antimicrobial Resistance AmongPathogens Causing Hospital-onset Infections

Gram-Negative Surveillance TRUST 9 (2005) % Susceptible

80.087.694.391.444.889.592.4105C. freundii

79.893.299.699.684.081.487.8263P. mirabilis

87.1

6.7

95.2

80.0

98.2

98.5

PTZ

89.927.0------34.884.389S. maltophiliaa

7.782.712.2---67.265.9549P. aeruginosa

96.897.696.012.791.396.0126S. marcescens

85.091.775.013.389.290.8120E. cloacae

92.096.796.7---93.895.7276K. pneumoniae

80.594.698.658.890.190.31303E. coli

SXTGENCROAMPCIPLVXnOrganism

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.



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

Strain No. Am

pici

llin

Car

beni

cilli

n

Cep

halo

thin

Cef

oxiti

n

Cef

tazi

dim

e

Cef

epim

e

Imip

enem

Mer

open

em

Azt

reon

am

Gen

tam

icin

Tobr

amyc

in

A baumannii AC-54/97 >64 >64 >64 >64 >64 >64 >64 >64 >64 >64 32

E coli DH5a(pBAUX-30)* >64 >64 >64 >64 >64 8 2 1 0.25 2 8E coli DH5a(pBC-SK)† 1 4 4 2 0.12 ≤ 0.06 0.12 ≤ 0.06 0.25 0.5 0.25

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



MUSC; 5/07

MUSC; 5/07MUSC; 5/07



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




• Polyenes (amphotericin B)– MOA: targets plasma membrane ergosterol

forming a channel resulting in disruption ofthe protein gradient

– MOR: alteration of lipid composition ofplasma membrane (decreased ergosterolcontent) leading to lower affinity for AmBbinding


• 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


• 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




• 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


• 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



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

– CDChttp://www.cdc.gov/drugresistance/healthcare/default.htmhttp://www.cdc.gov/ncidod/dhqp/index.html

– Association for Professionals in Infection Control & Epidemiologyhttp://www.apic.org

RESISTANCE John A. Bosso, Pharm.D.people.musc.edu/~bossoja/IDModule/resistanceHO.pdf · RESISTANCE...

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