This document provides an introduction to antibiotics and discusses principles of appropriate antibiotic use. It begins by outlining the goals of understanding why individual antibiotic use matters and how to use antibiotics more effectively. It then discusses the scope of antibiotic overprescribing in the US and consequences such as antibiotic resistance. The document emphasizes optimizing antibiotic therapy through early and targeted use, consideration of local resistance patterns, and de-escalation when possible. It also addresses factors influencing overprescription and strategies to improve appropriate use.

1. INTRO TO ANTIBIOTICS:
PART 1- BASIC PRINCIPLES
July 2, 2015
Dr. James Cutrell
Infectious Diseases

2. Goals of Lecture
At end of lecture, you can answer two critical questions:
1. Why does your use of antibiotics matter?
2. How can you use antibiotics more effectively?
We need a new perception and culture surrounding
antibiotic use – to RESPECT the dangers of antibiotic
misuse and to have CONFIDENCE in the benefits and
ability to use antibiotics wisely!

3. Why does your use of
antibiotics matter?

4. Scope of Antibiotic Prescribing
• 2nd most commonly prescribed
drug class in U.S.
• 5% of world’s population but
nearly 50% of worldwide antibiotic
use in the U.S.
• Accounts for ≈ 20% of typical
hospital pharmacy budget
Fridkin S, et al. MMWR 2014;63(09):194-200.

5. Antibiotic Misuse
• Up to 50% of antibiotics
prescribed are inappropriate
• A recent study found 30% of all
antibiotic days were unnecessary:
• Excessive duration
• Non-infectious etiology
• Colonizers or contaminants
• Redundant coverage
• Failure to de-escalate abx
Hecker MT, et al. Arch Intern Med . 2003; 163:972-978

6. Would we accept this “failure rate” in other
areas of medicine?

7. Consequences of Antibiotic Misuse
Dellit TH, et al. Clin Infect Dis. 2007;44:159-77.
Adverse Drug
Events and
Toxicity
Superinfection
(C. difficile)
Antibiotic
Resistant
Pathogens
Excess Mortality
and Costs
Inappropriate
Antibiotic Use

8. Adverse Drug Events
http://www.cdc.gov/drugresistance/threat-report-2013/

9. Antibiotics and QTc Prolongation
• Culprit Drugs: Macrolides, Fluoroquinolones, Azoles
• Higher risk if baseline QTc prolonged or other high-risk drugs
• 2 large retrospective studies of azithromycin and levofloxacin
use, primarily in outpt URI or COPD, found increased risk of
CVD and all-cause mortality compared to amoxil/no abx1,2
• Retrospective VA study of azithromycin use in hospitalized
CAP patients showed decreased 90-day mortality and small
excess risk of MI compared to other antibiotics3
1. Ray W, et al. N Engl J Med 2012. 366:1881-189. 2. Rao GA, et al. Ann Fam Med. 2014;12(2):121-7.
3. Mortensen EM, et al. JAMA 2014; 311(21):2199-2208.
Take Home Points:
1. Don’t give your patient an abx if they likely
have a viral URI
2. Consider the baseline QTc if using a high-
risk abx but don’t avoid use if indicated

10. Clostridium difficile Infection (CDI)
• Antibiotic exposure is the single most important risk factor
for the development of CDI
• Patients who receive broad-spectrum antibiotics during
hospitalization are 2.9 times more likely to develop CDI
http://www.cdc.gov/drugresistance/threat-report-2013/
Fridkin S, et al. MMWR 2014;63(09):194-200.

11. Antibiotic Resistant Pathogens
Bartlett J, et al. Clin Infect Dis. 2013; 56(10):1445-50)
• The dominant driver of antibiotic resistance is use (and
overuse) of antibiotics
Pathogen Country Antibiotic Usagea Rate of Resistance
Klebsiellab Greece
The Netherlands
38
11
38%
0.2%
MRSAc Greece
The Netherlands
38
11
51%
1.60%
Rates are for 2010 – 2011, for intensive care units in the Netherlands and Greece
a Daily drug dose per 1000 inhabitants
b Bacteremic Klebsiella: rate with carbapenemase-producing strains
c MRSA relative to all S. aureus isolates

12. Antibiotic Pipeline: Running Dry?
http://www.cdc.gov/drugresistance/threat-report-2013/

13. National Action Plan for CARB
https://www.whitehouse.gov/sites/default/files/docs/national_action_plan_for_combating_antibotic-
resistant_bacteria.pdf

14. Competing Tensions in Antimicrobial Use
Need for timely,
appropriate antimicrobial
initiation in serious
infections
Need to avoid
unnecessary
antimicrobial use to
prevent resistance and
adverse effects
Collateral
Damage
Hit Hard
Up Front

15. Targeted Approach to Abx Therapy
• Optimize antimicrobial effectiveness
• Early, appropriate therapy (Broad-spectrum in severe infections)
• Consider local susceptibility data and host risk for resistant pathogens
• Limit unnecessary antimicrobial use
• Reassess diagnosis and response to Rx at 48-72 hours
• De-escalate based on culture results
• Use shortest duration necessary
• Follow local protocols/guidelines for optimal Rx
• Prospective audit and feedback
• Apply formulary control/restrictions

16. Why do we overuse antibiotics?

17. Psychology of Antibiotic Prescribing
Drivers of Antibiotic Use include:
• Physician uncertainty and anxiety over “missing an infection” >
anxiety over potential risks of antibiotic use
• Stated or perceived patient expectations
• Emphasis on potential benefit to the individual patient over the
societal risk of antimicrobial resistance
Antibiotics are unique as the only drugs that lose their efficacy
over time (for all patients) the more they are used.
--Dr. Brad Spellberg
Flanders SA, et al. JAMA Internal Med 2014; 174 (5): 661-662.

18. How can you use antibiotics
more effectively?

19. Questions to Ask When Starting an Abx
• Is an antibiotic indicated based on clinical findings?
• Have appropriate cultures been sent before starting
antibiotics?
• What is appropriate empiric Rx based on most likely
pathogens?
• Are there important host factors to consider?
• What is the best drug dose and route of administration?
• What is the anticipated duration of therapy?
Reese RE et al. Principles of Antibiotic Use. In: A Practical
Approach to Infectious Diseases 5th ed. 2003

20. 3 Approaches to “Learning” Antibiotics
1. Pharmacologic Drug Class
• Traditional abx lectures in med school; good introduction to abx
• May be difficult to translate into clinical practice
2. Organism-Specific Activity
• Useful for key pathogens (MRSA, Pseudomonas)
3. Empiric Rx for Clinical Syndromes
• Based on site of infection and most common expected pathogens
(e.g. CAP, acute bacterial meningitis)
• More on this in Intro to Antibiotics: Part II
• Write down any questions re: antibiotics on index card

21. Antibiotic Educational Resources
• Antimicrobial Resource
Guidebook
• On UT ASP website
• Online or Smartphone Apps
• Johns Hopkins Abx Guide
• Sanford Guide
• Antibiotic Basics for
Clinicians 2nd edition
by Alan Hauser
Burdette S D et al. Clin Infect Dis. 2012;55:114-125

22. Antibiotic Mechanisms of Action

23. Antibiotic PK/PD Principles
Craig WA. Clin Infect Dis 1998; 26:1-12.
• Pharmacokinetics (PK): effect the body has on a drug
• Pharmacodynamics (PD): effect a drug has on the body
and the bug

24. Pharmacokinetics: Absorption
• Affected by a number of
physiologic parameters
• IV route preferred in serious
infections or if concerns re: GI
absorption
• IV-to-PO switch key for certain
agents when tolerating po
• Avoids IV access complications
• Decreased costs
• Decreased hospital LOS
ABX W/ Excellent PO Bioavailability
Fluoroquinolones
Metronidazole
Clindamycin
TMP-SMX
Linezolid
Rifampin
Fluconazole

25. Pharmacokinetics: Distribution
Patient is admitted with fever, HA and signs of sepsis and
empirically started on Vanc and pip/tazo. LP is performed with
findings c/w acute bacterial meningitis. What is the problem
with this abx regimen?
- Pip/tazo (Zosyn) has suboptimal CNS penetration.
Patient is admitted with fevers, SOB and pleuritic chest pain.
Blood Cx grow MRSA with an MIC of 2. The patient is started
on Daptomycin. CXR shows multifocal dense consolidation in
the right lung. What is the problem with this abx regimen?
- Daptomycin is inactivated by pulmonary surfactant so it is
ineffective against PNA.

26. Pharmacokinetics: Metabolism
• Many antibiotics interact with CYP 450 enzymes, leading to
important drug-drug interactions
• Affects statins, benzos, immunosuppressants, anticonvulsants,
contraceptives, etc.
• Potent inhibitors Increase other drug levels
• Macrolides (clarithromycin)
• Azoles (fluconazole, itraconazole)
• HIV protease inhibitors (ritonavir)
• Ciprofloxacin
• Potent inducers Decrease other drug levels
• Rifampin, Rifabutin
• Anticonvulsants

27. Metabolism: Examples
An HIV patient was diagnosed with TB at an OSH and started on RIPE.
He now presents to his HIV clinic with a new HIV viral load of 23k
despite med adherence. What happened?
- Rifampin induced metabolism of HIV medications leading to
virologic failure. Rifabutin is substituted at adjusted doses in TB
Rx for most HIV regimens.
An HIV patient is admitted to ICU and intubated for respiratory failure.
His HIV medications are continued. Now, he is ready for extubation
so his sedatives (midazolam and fentanyl) are held, but the patient
will not wake up for 3 days. What happened?
- HIV regimen likely includes ritonavir, which inhibits midazolam
metabolism and dramatically increases AUC. Alternate benzos
such as lorazepam should be used in pts on HIV PIs.

28. Antibiotics and Warfarin
• Carefully review drug interactions and monitor INR
closely when starting abx in patients on warfarin!
• Profound increase in effect/INR:
- TMP/SMX - Metronidazole
• Potential significant increase in effect/INR:
- Azole antifungals - Fluoroquinolones - Clarithromycin
• Decrease in effect/INR:
- Rifampin - Rifabutin

29. Pharmacokinetics: Excretion
• Most agents are renally excreted and may require dose
adjustment based on estimated CrCl
• Some notable agents primarily hepatic clearance
• Macrolides, nafcillin, ceftriaxone, clindamycin, linezolid, echinocandins
• May be able to utilize to therapeutic advantage in dosing
• For patients on chronic hemodialysis, cefazolin (2 g/2 g/3 g) or
cefepime (2 g/2 g/2 g) can be dosed during 3x-weekly HD sessions
without additional IV access

30. Pharmacodynamics
PD Parameter Drug Class
% Time > MIC Beta-lactams
Tetracycline
Linezolid
AUC/MIC FQ
Vancomycin
Azithromycin
Cmax/MIC Aminoglycosides
Rybak M. Am J Infect Control 2006; 34(5):S38-45.

31. Extended or Continuous Infusion:
Beta-Lactams
• Optimize % Time > MIC parameter
• Continuous infusion
• Extended infusion
• Smaller doses more frequently
• May help Rx bugs with higher MICs
• Primarily used with following abx:
• PCN G, nafcillin, pip/tazo
• Cefazolin, cefepime
• Meropenem (extended infusion)
• Emerging data of improved clinical
outcomes compared to intermittent
dosing
Abdul-Aziz et al. Annals of Intensive Care 2012, 2:37.

32. Once Daily Aminoglycoside Dosing
• Maximizes clinical efficacy
while minimizing toxicity
for GNR infections
• Initial dose given based
on dosing weight
• Gent/tobra: 5-7 mg/kg
• Amikacin: 15 mg/kg
• Check level 8-12 hours
after first dose to
determine interval based
on nomogram

33. Antibiotic Drug Allergies
• Common cause of broad spectrum or suboptimal abx Rx
• HISTORY IS KEY (Current and prior Rxn)
• PCN Allergy
• 10% of patients “PCN allergic”; 90% of these will tolerate a PCN
• Skin testing available for PCN
• Cross-reactivity to Cephs (10% 1st gen, 1-2% 3rd gen)
• Cross-reactivity to Carbapenems (10% early studies, 1-2% in practice)
• No cross-reactivity with Aztreonam
• Can consider desensitization (proven, severe rxn with no
alternative Rx) or graded challenge (less severe rxn)

34. Antibiotics and Microbiology 101

35. Antibiotic Susceptibility Testing
• Traditional parameters of antibiotic efficacy
• Minimum Inhibitory and Bactericidal Concentrations (MIC and MBC)
• MIC: minimum drug concentration to inhibit growth
• MBC: minimum drug concentration to kill 99.9% of bacteria
• Breakpoint: MIC cut-off to define bacteria as susceptible,
intermediate, or resistant to an antibiotic (defined by FDA and CLSI)
Park S, et al. J Korean Med Sci. 2008 Feb;23(1):49-52
MIC Breakpoints for M. abscessus

36. Susceptibility Testing Methods
Automated Systems
E-testing
Disc Diffusion
Microbroth
Dilution
Method

37. Interpretation of Susceptibility Results
PSEUDOMONAS AERUGINOSA:
SUSC INTP
AMIKACIN....................... <=16 S mcg/ml
CEFEPIME......................... >16 R mcg/mL
CEFTAZIDIME................... >16 R mcg/ml
CIPROFLOXACIN................. >4 R mcg/ml
GENTAMICIN.................... <=4 S mcg/ml
IMIPENEM.......................... >8 R mcg/ml
PIPERACILLIN/TAZ.............. 64 S mcg/mL
TICAR/K CLAV'ATE............ >64 R mcg/mL
TOBRAMYCIN.................... <=4 S mcg/ml
Remember measuring susceptibility in test tube,
not in the patient!
The “90 – 60” Rule

38. VA Antibiogram

39. Bacteriocidal vs. Bacteriostatic Drugs
Bacteriocidal Bacteriostatic
Beta-lactams
Vancomycin
Fluoroquinolones
Aminoglycosides
Daptomycin
Rifampin
Metronidazole
Macrolides
Clindamycin
Linezolid
Tetracyclines
Tigecycline
Chloramphenicol
• Laboratory, not a clinical, term
• Single agent can be -cidal and -static depending on organism
• Unimportant for uncomplicated infxn with intact host immunity
• May be preferred where host defense is incomplete:
• Endocarditis, Meningitis, Febrile Neutropenia, Osteo
Finberg RW. Clin Infect Dis 2004;39:1314-20

40. Antimicrobial Stewardship

41. • An effort to promote best antibiotic practices, by ensuring
the right drug is used for the right bug, at the right dose,
for the right duration. The primary goal is to improve
patient outcomes, while simultaneously decreasing
toxicity, antibiotic resistance, C. difficile infections, and
cost.
Antimicrobial Stewardship: What is it?
Right DRUG for Right BUG,
Right TIME and Right DOSE
for the Right DURATION
Dellit TH, et al. Clin Infect Dis. 2007; 44:159–77.

42. #1 Observe antibiotic “best practices”
What can you do?
http://www.cdc.gov/drugresistance/threat-report-2013/

43. #2 Optimize dose and route of antibiotic
administration
• Therapeutic Drug Monitoring (Vancomycin, AGs)
• Continuous or extended infusions
• IV-to-PO Switch
What can you do?
ABX W/ Excellent PO Bioavailability
Fluoroquinolones
Metronidazole
Clindamycin
TMP-SMX
Linezolid
Rifampin
Fluconazole

44. #3 Avoid double anaerobic coverage
• Avoid adding clindamycin or metronidazole to beta-
lactams with excellent anaerobic coverage such as pip-
tazo and carbapenems
• Exceptions: metronidazole for C. difficile or clindamycin
for toxic shock syndrome or necrotizing fasciitis
• One study from national VAs found that 25% of all
metronidazole days of therapy were NOT indicated
What can you do?
Huttner B, et al. J Antimicrob Chemother. 2012;67(6):1537-9.

45. #4 De-escalate/stop antibiotics or shorten
duration of therapy when appropriate
• Importance of “antibiotic timeout” to reassess clinical status
and culture results at 48-72 hours
• Multiple RCT and meta-analyses demonstrate non-inferior
outcomes with shorter Rx courses
• VAP (Non-PseA)= 8 days
• Cellulitis = 5 days ≈ 10 days
• UTI or pyelonephritis = 7 days
• CAP = 5 days (with high dose FQ)
What can you do?
Bartlett J, et al. Clin Infect Dis. 2013; 56(10):1445-50.

46. #5 Avoid antibiotics for inappropriate
indications
• Upper respiratory tract infections (colds, acute
bronchitis, non-strep pharyngitis)
• Early or mild sinusitis
• Asymptomatic bacteriuria
What can you do?
Little or no potential benefit to Abx and significantly
outweighed by potential harms!

47. • Discuss indications, appropriate
use and risks of abx
• Recommend specific
symptomatic Rx and a back-up
plan
• Constructively correct false
popular beliefs
What can you do?
www.cdc.gov GET SMART Campaign
#6 Educate your patients on when
antibiotics are and are NOT effective

48. #7 Follow and become good “mentors”
of wise antibiotic use
What can you do?

49. VA Intranet Stewardship
Resources

50. Parkland Intranet
Stewardship
Resources

51. UTSW Intranet Stewardship
Resources

52. Conclusions
• Antibiotics are an important shared resource and the
ways that we use them matter now and for the future
• Need to UNDERSTAND and RESPECT the
consequences of antibiotic misuse or overuse
• Need to gain CONFIDENCE in the benefits and ability to
use antibiotics wisely
Your program leadership, faculty, ID fellows, other
residents, pharmDs, and stewardship teams are
committed to helping you achieve these goals!

53. Questions?