Antibiotic Resistance and Its Relationship to Antibiotic Use

Antibiotic Resistance and Its Relationship to Antibiotic Use

Antibiotic StewardshipCurriculum

Developed by:Vera P. Luther, M.D.

Christopher A. Ohl, M.D.Wake Forest School of

MedicineWith Support from the Centers

for Disease Control and Prevention

Objectives1. Define antibiotic susceptibility, antibiotic resistance

and breakpoint2. List four methods for determining antibiotic

susceptibility3. Discuss factors that contribute to antibiotic

resistance4. List five bacterial resistance mechanisms and the

antibiotic classes each affects5. Understand the clinical implications of antibiotic

resistance for Staphylococcus aureus, Streptococcus pneumoniae and gram-negative organisms

Outline• Introduction• Key Terms• Susceptibility Testing Methods• Factors Contributing to Antibiotic

Resistance • Mechanisms of Resistance• Clinical Examples• Conclusion

Introduction• Since the first use of antibiotics in the

1930s and 1940s, bacteria quickly adapted and developed mechanisms to escape their effects

• Over the following decades, new antibiotics were developed to overcome resistance

• Since the 1990s, new antibiotic development has fallen sharply while bacterial resistance continues to increase

• Antibiotic resistance is responsible for countless human deaths and billions of dollars in healthcare expenses

• Imidazole-resistant Candida spp. • Multidrug-resistant tuberculosis• Multidrug-resistant malaria• Anti-viral resistant influenza

IntroductionResistance Beyond Typical Bacteria



Key Terms• Antibiotic = A drug that kills or inhibits the growth of microorganisms

• Resistant = Somewhat arbitrary designation that implies that an antimicrobial will not inhibit bacterial growth at clinically achievable concentrations

• Susceptible = Somewhat arbitrary designation that implies that an antimicrobial will inhibit bacterial growth at clinically achievable concentrations

Key Terms

• MIC = Minimal inhibitory concentration. Lowest concentration of antimicrobial that inhibits growth of bacteria. Commonly used in clinical lab• MBC = Minimal bactericidal concentration. Concentration of an antimicrobial that kills bacteria. Used clinically only in special circumstances• Breakpoint = The MIC that is used to designate between susceptible and resistant. Arbitrarily set by a committee



MIC = 6.25 mcg/mL

Minimum Inhibitory Concentration

Well Plate for MIC Testing

Many Labs Use Automated Testing

Automated Methods

Other Methods for Determining Susceptibility

E-test®Kirby-Bauer

Disk Diffusion

Agar dilution

Concept of Breakpoint to Determine Susceptibility

Antibiotic MIC Breakpoint

Susceptibility

Ampicillin >16 8 ResistantGentamicin 2 4 SusceptibleCephalothin >16 N/A ResistantCefepime 8 32 SusceptibleCefotaxime 16 16/32 Intermediat

eCeftazidime 2 32 SusceptibleAztreonam 4 16 SusceptibleCiprofloxacin 2 2 ResistantAmp/Sulbactam

>16 8 Resistant

Meropenem 4 4/8 Intermediate

Pip/tazo 8 32-64/128

Susceptible

EXAMPLE: Susceptibility testing for a single isolate of Pseudomonas aeruginosa

-Breakpoint for intermediate resistance for meropenem is 4 and for piperacillin/tazobactam (pip/tazo) 32-Pip/tazo is the better choice between the two -Ciprofloxacin is a poor choice even though the MIC is lowest of the three



Agriculture

Inpatient

Outpatient

Antibiotic Use Leads to Antibiotic Resistance

Reasons for Antibiotic Overuse : Conclusions from 8 Focus

GroupsPatient Concerns• Want clear

explanation• Green nasal discharge• Need to return to work

Physician Concerns• Patient expects

antibiotic• Diagnostic uncertainty• Time pressure

Barden L.S. Clin Pediatr 1998;37:665

Antibiotic Prescription

Antibiotic Use Leads to Antibiotic Resistance

• Resistant bacteria or their genetic determinates are selected when colonizing or infecting bacteria are exposed to antibiotics

• Resistant bacteria can then be transmitted between patients

• Highest risk patients:– Immunocompromised– Hospitalized– Invasive devices

(central venous catheters)

Outline• Introduction• Key Terms• Susceptibility Testing Methods• Factors Contributing to Antibiotic Resistance • Mechanisms of Resistance

– Overview– Specific Examples

1. Antibiotic Degrading Enzymes2. Decreased Permeability3. Efflux Pumps4. Target Alterations

• Clinical Examples• Conclusion

RCycle of Antibiotic Resistance Acquisition:Bacterial SelectionUnder increasing antibiotic selection pressure:1.Bacteria resistant to a particular drug are selected and replicate2.Different antibiotics select different bacteria but can select resistant phenotypes to other drugs as well3.This results in multidrug-resistant (MDR) organisms and increases their total number

Replication

Replication

Selection by Drug X

Selection by Drug Y

Resistance to: Drug X Drug Y Drug Z

Antibiotic Mechanism of Action

DaptomycinDaptomycinDaptomycinDaptomycinDaptomycinLinezolid

Daptomycin

Linezolid

Mechanisms Of Antibiotic Resistance• Bacteria are capable of

becoming resistant through several mechanisms

• One or many mechanisms may exist in an organism

• Multidrug-resistant bacteria often have multiple mechanisms

• Genes encoding resistance may exist on plasmid or chromosome Alteration in

Target Molecule

Decreased Permeability

Mechanisms of ResistanceAntibiotic Degrading Enzymes

• Sulfonation, phosphorylation, or esterifictation – Especially a problem for aminoglycosides

• β-lactamases– Simple, extended spectrum β-lactamases (ESBL),

cephalosporinases, carbapenemases– Confer resistance to some, many, or all beta-lactam

antibiotics– May be encoded on chromosome or plasmid– More potent in gram-negative bacteria– Examples: S. aureus, H. influenzae, N.

gonorrhoeae, E. coli, Klebsiella sp., Enterobacter sp., Serratia sp., other enteric bacteria, anaerobes

Extended Spectrum -lactamases

-lactamases capable of hydrolysing extended spectrum cephalosporins, penicillins, and aztreonam

• Most often associated with E. coli and Klebsiella pneumoniae but spreading to other bacteria

• Usually plasmid mediated• Aminoglycoside, ciprofloxacin and trimethoprim-

sulfamethoxazole resistance often encoded on same plasmid

• Has become a significant resistance determinate in acute and long-term care facility enteric pathogens

Class A Carbapenemases• Most common in Klebsiella pneumoniae (KPC)• Also seen in E. coli, Enterobacter, Citrobacter,

Salmonella, Serratia, Pseudomonas and Proteus spp.

• Very often with multiple other drug resistance mechanisms, resistance profile similar to ESBL but also carbapenem resistant

• Became problem in New York City first in 2002-2003 and is being increasingly recognized in Mid-Atlantic US.

• Spreading across species to other gram-negatives and enterobacteriaceae

• Emerging in long-term care facilities

Mechanisms of ResistanceDecreased Permeability

• Pseudomonas spp.• Affects many antibiotics including

carbapenems

Efflux Pumps• Pseudomonas spp. (multiple antibiotics)• Tetracyclines• Macrolides

Mechanisms of Resistance

Mechanisms of ResistanceTarget Alteration (cont’d)

• Ribosome • Tetracyclines• Macrolides

•S. pneumoniae, Staphylococcus sp., N. gonorrhoeae, enteric gram-negative rods


Resistance • Mechanisms of Resistance• Clinical Examples

– Staphylococcus aureus– Streptococcus pneumoniae– Escherichia coli

• Conclusion

Illustrative Case 1• A 50 y.o. female with type 2 diabetes mellitus

was admitted for an elective total knee replacement. Postoperative day 4: fever to 39ºC and a gray, purulent wound discharge

• Gram stain of the exudate showed neutrophils and gram positive cocci in clusters

• She was started on IV cefazolin. After two days of therapy she remained febrile and her wound showed little improvement

Case 1GramStain

Illustrative Case 1 (cont’d)• Wound cultures yielded S. aureus resistant to

penicillin, methicillin, all cephalosporins, erythromycin, tetracycline, gentamicin and ciprofloxacin

• The wound was débrided and she was started on IV vancomycin with improvement

• After 4 days of vancomycin she was discharged on oral trimethoprim/sulfamethoxazole for 2 weeks

• 3 months later she experienced a recurrence of symptoms after initial improvement and was diagnosed as having a deep prosthetic joint infection due to MRSA

Increase in MRSA Prevalence in US Comparison to Other Drug-Resistant

Organisms

Wenzel et. al. ICHE 2008;29;1012

Surgical Site InfectionsImpact of Resistance on Clinical Outcomes

UnadjustedMSSA

(N=165)MRSA

(N=121) P Value

Mortality, 90-day 6.7% 20.7% P<.001Length of stay:median days

After surgery 14 (7-25) 23 (12-38) P<.001After infection 10 (4-17) 15 (7-30) P=.001

Adjusted* mortality for MRSA (P=0.003)

*Adjusted for other predictors of mortality: age, physical status, duration of surgery. Engemann JJ, et al. Clin Infect Dis. 2003;36:592-598.

Glycopeptide Resistant S.aureus

• Glycopeptide Intermediate Resistance:– First reported in Japan – Vancomycin MIC 8μg/mL– Still uncommon– All with prolonged vancomycin use due to persistent S.aureus

infections • Glycopeptide High Level Resistance:

– First report in Michigan in June 2002– Vancomycin MIC >128 ug/ml– Diabetic with peripheral vascular disease and chronic renal

failure– Resistance determinant acquired from Vancomycin-resistant

Enterococcus (VRE)– Very uncommon MMWR 2002; 51:565-7

MMWR 2000;48:1165-7Smith TL et al. NEJM 1999;340:493-501

Illustrative Case 2• 67 y.o. man with chronic lymphocytic

leukemia admitted with sudden onset high fever, rigors, pleuritic chest pain and productive cough

• Physical exam and chest x-ray confirmed pneumonia

• Started on IV azithromycin

Illustrative Case 2 (cont)• Gram stain showed numerous

neutrophils and sheets of lancet shaped gram positive diplococci

• After 48 hours the patient was still febrile and developed progressive respiratory tract failure

• Blood culture from admission yielded S. pneumoniae resistant to penicillin, ceftriaxone, erythromycin and clindamycin

Gram stain

2009 S. pneumoniae Susceptibility

CDC ABC surveillance NetworkInvasive Isolates (Meningitis, bacteremia, etc.)

http://www.cdc.gov/abcs/reports-findings/survreports/spneu09.pdf

Macrolide-Resistant S. pneumoniae

Prevalence is Increasing in US

Jenkins S. et al Emerg Infect Dis. 2009;5:1260Hicks L et. Al. Emerg Infect Dis. 2010;16:896

Decreased Susceptibility of S. pneumoniae to Fluoroquinolones (FQRSP) in Canada

Relationship of Resistance to Antibiotic Use

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Illustrative Case 3• 45 y.o. female seen in clinic for urinary urgency,

frequency and dysuria. Her urinalysis is positive for leukocyte esterase and 31-40 white blood cells. A urine gram stain was performed and showed 2+ white blood cells and many gram-negative rods

• Urine culture reveals E. coli, which is resistant to ciprofloxacin and trimethoprim-sulfamethoxazole, but is sensitive to ceftriaxone

Community-Acquired Resistant E. Coli

• Mostly UTIs• Young healthy women in

addition to the elderly• 10-20% now resistant to

fluoroquinolones• 30-50% resistant to

trimethoprim-sulfamethoxazole

• CTX-M β-lactamases becoming more common– Cause cephalosporin

resistance



Conclusion• Inappropriate and excessive use of

antibiotics is a major factor contributing to emerging antibiotic resistance

• Determinants of resistance are selected for by antibiotic use

• Multiple mechanisms exist for bacteria to become resistant to antibiotics

• Antibiotic resistance is a problem in outpatient and inpatient settings and is a factor in a wide variety of infections

• Antibiotic resistance continues to emerge as a serious threat to public health

Documents

Antibiotic Resistance and Its Relationship to Antibiotic Use