Learning Objectives • Understand the definition of bactericidal and static therapies • Identify the advantages and limitations of cidal and static therapies • Assess the significance of evidence related to cidal versus static therapies and determine their applicability in those with complex infections
Which of the following regions are you from? • Atlantic • Quebec • Ontario • BC • Prairies • Other
How do you identify yourself primarily • Adult ID • Paed ID • Medical microbiology / clinical microbiology • Intensivist • Industry?
How long have you been in practice? • 0-10 years • 10-20 years • 20+ years • None of your business
Which team will get further in the NHL playoffs? • Canadiens • Penguins • Bruins • Flyers • Raptors
Case Question • A 58 year old woman presents with fever of 38.6. • She has had a left arm PICC for the last 2 months for chemo Rx • for breast cancer. She is alert and normotensive. She is not • neutropenic and has not had chemo for 5 wks. A blood culture is • collected and grew MRSA. A TEE is normal. • You remove the PICC and prescribe which antibiotic • Single bactericidal agent • Single bacteriostaticagent • ≥ 2 antibiotics • Doesn’t matter
The Case for Bacteriostatic Antibiotics in Complex Infections Edward A. Dominguez, MD FACP FIDSA Methodist Transplant Physicians Dallas, Texas, USA
Disclosures for E A Dominguez • Pfizer: Consultant; Speaker bureau; Advisory boards • Cubist: Speaker bureau • Astellas: Speaker bureau
What’s in Play? • Bacterial infections • Definitions and their limitations • Is an antibiotic cidal, static, or both? • Disadvantages of bactericidal therapy • Advantages of bacteriostatic therapy • A sampling of static vs. cidal studies
What’s NOT in play? • Antifungal therapy • Antiparasitic therapy • Antiviral therapy • Monotherapy vs. combination therapy
What is Cidal? What is Static? • Concept is only 35 years old: • Shah PM, et al. Dtsch Med Wochenschr. 1976;101:325-328. • Two components to the distinction • MBC/MIC • Static: MBC/MIC ≥ 16 • Cidal: MBC/MIC ≤ 4 • Time-Kill curve • Cidal if > 3-log reduction in CFU/ml after 24 hours incubation in liquid media (standard inoculum: 5 x 105 CFU/ml in a volume of 0.01 ml)
The Tool: Time-Kill Curve • Provides full dynamic profile of antibiotic • Determines concentration response relationships • Provides insight into potential for resistance development and for drug synergy • Provides log-linear killing rate and cidal rate constant
Problems with the Time Kill Curve • Growth conditions (e.g. pH, protein binding) • Test duration (18-24 hrs) • Testing done in log-phase growth, but most bacteria causing infections are in stationary phase1,2 • Unclear if there is clinical utility3 • Strictly interpreted, interpretation only applies to the tested organism under tested conditions • Kim KS, et al. Antimicrob Agents Chemother. 1981;19:1075-77. • Eng RH, et al. Antimicrob Agents Chemother. 1991;35:1824-28. • Peterson LR, et al. Antimicrob Agents Chemother. 1978;13:665-68.
Bacteriostatic Macrolides Tetracyclines Glycylcyclines Sulfonamides Clindamycin Linezolid Bactericidal Β-lactams Aminoglycosides Vancomycin Flouroquinolones Daptomycin Metronidazole Which Side is Your Antibiotic On?
However… Some are Both4 • Macrolides may show in vitro bactericidal activity vs. S. pneumoniae and S. pyogenes. • Linezolid shows in vitro bactericidal activity vs. S. pneumoniae and other streptococci. • Quinupristin-dalfopristin shows in vitro bacteriostatic activity vs. E. faecium. 4. Pankey GA, Sabath LD. Clinical Infect Dis. 2004;38:1864-70.
The Problem of Inoculum • MBC testing standard uses concentration of bacteria of 105 in log-phase. • Many localized infections have bacterial concentrations of 108-10 CFU/gm tissue, mostly in stationary phase.5 • These conditions may render cidal antibiotics ineffective • Vancomycin for experimental GPC endocarditis6 • Penicillin for experimental S. pyogenes thigh abscesses7 • Levison ME, et al. Infect Dis Clin North Am. 1989;3:415-421. • Cantoni L, et al. Antimicrob Agents Chemother. 1990;34:2348-53. • Stevens DL, et al. J Infect Dis. 1988;158:23-8.
Disadvantages of Bactericidal Therapy • Rapid lytic action may lead to endotoxin surge • Gram-negative meningitis in infants11 • Infant botulism12 • Enterohemorrhagic E. coli infection13 • Increased cerebral edema • Pneumococcal meningitis14 • Mustafa MM, et al. J Infect Dis. 1989;160:891-95 • Johnson RO, et al. Am J Dis Child. 1979;133:586-93. • Nau R, et al. Clin Microbiol Rev. 2002;15:95-110. • Friedland IR, et al. Lancet. 1992;339:405-08.
Advantages of Bacteriostatic Therapy • THE major advantage may be in some toxin-producing bacterial infections • Clindamycin inhibits TSST-1 by S. aureus regardless of growth phase8 • Clindamycin is more effective than penicillin in models of S. pyogenes and C. perfringens myositis9-10 • Long post-antibiotic effect • Efficacy correlates usually with 24-hr AUC/MIC • Van Langevelde P, e al. Antimicrob Agenst Chemother. 1997;41:1682-85. • Stevens DL, et al. J Infect Dis. 1987;155:220-28. • Stevens DL, et al. J Infect Dis. 1988;158:23-28.
Tygecycline Community Acquired Pneumonia Studies15 15. Tanaseanu, et al. Diagn Microbiol Infect Dis. 2008;61:329-38.
Linezolid Nosocomial Pneumonia Studies16 Intent-to-treat analysis of prospective studies 16. Wunderink RJ, et al. Chest. 2003;124:1789-97.
Speaking of Linezolid • Linezolid is bacteriostatic vs. S. aureus • Rabbit S. aureus endocarditis model17 • Bacteriostatic when using standard intermittent infusion • Bactericidal when using continuous infusion to maintain levels > MIC 17. Jacqueline C, et al. Antimicrob Agents Chemother. 2002;46:3706-11.
Conclusions • In vitro definition may not correlate with in vivo activity • Clinical distinction between bacteriostatic and bactericidal activity is situational • Site of infection • Inoculum of bacterial • PK/PD characteristics of the antibiotic • Host defense mechanisms • For many infections, there is no proven superiority for bactericidal therapy
Cidal vs Static AntibioticsThe Pro-Cidal pointor: The worse the disease, the more cidal agent is preferred Ethan Rubinstein MD, LL.b. University of Manitoba
Conflicts Consultant: Astellas, Aventis-Sanofi, Atox, Bayer, BiondVax, MeMed, Cubist, Fab Pharma, J & J, Pfizer, Merck, Theravance, Wyeth –Canada, Research grants: Daiichi, Bayer, Theravance, AstraZeneca Speakers Bureau: Merck-Canada, Astellas-Canada, Pfizer Int. Pfizer-Canada, Aventis-Sanofi
Why do we care if an anti-microbial agent is bactericidal? • What is a bactericidal agent? • What are the rules for determining whether a drug is static or cidal? • Under what clinical situations is a cidal agent mandated? Preferred? • Under what clinical situations might the use of a cidal agent be bad? Why?
Question 1: Under which clinical situation(s) would a rapidly bactericidal agent be bad? • Endocarditis • Pneumococcal bacteremia • Osteomyelitis • Leptospirosis • Brain abscess
Answer • 4. Leptospirosis/ Tertiary syphilis • Reason: Jarish Herxheimer Reaction in Syphilis, Lyme, leptospirosis-rapid release of toxins causing fever hypotension leucocytosis etc.
Top’s Textbook of Infectious Diseases, 1960 • “ WHILE IT IS TRUE THAT MANY DRUGS ARE BACTERIOSTATIC AT A MUCH LOWER CONCENTRATION THAN THAT AT WHICH THEY ARE BACTERICIDAL, ALMOST ALL AGENTS ARE ULTIMATELY FATAL IF A SUFFICIENT LEVEL IS REACHED . The best definition is generally obtained with the concentration which is usually found in serum. It has been very difficult to establish the importance of killing power as a factor in clinical results because it is only one of several factors
Question 2 How is bactericidal activity defined? • Animal studies • In vitro studies • Clinical trials • Combination of the above
Answer to question 2 2. In vitro studies only
What is a bactericidal agent? Bactericidal: kill of 99.9% of bacteria in vitro within 18-24 h. Bacteriostatic : kill of 90-99% of bacerial inoculum within 18-24 h
Method of Defining Bactericidal Activity Figure. A fixed culture of bacteria is added to each of the 6 test tubes. The first tube serves as the growth control, and no antibiotic is added to this tube. Tubes 2–6 contain antibiotic in serially diluted proportions ranging from 0.5 to 8 mg/mL. After 18–24 h of incubation, the first tube that appears visibly clear represents the MIC. However, to determine the minimum bactericidal concentration (MBC), each tube is subsequently plated onto agar plates and incubated. The first serial plated agar dish demonstrating no growth (or a 99.9% decrease) represents the MBC. In the case above, the MIC is 2 μg/mL, and the MBC is 4 μg/mL Critical issues: Inoculum > 5 x105 cfu/mL Sub-culture volume ; 0.1 mL to predict >99.9% kill Static MBC: MIC ratio > 4 NCCLS Document M26-A, 1999
Problems with the in vitro testing • Static antibiotic concentration- while in the body concentration fluctuates • Fixed number of bacteria (never in the body) • Logarithmic growing bacteria (in the body bacteria are in log + stationary phases) • Lack of serum (protein binding) • Transfer of antibiotic during sub-culturing • Utility of SBT is not clinically proven
Cidal vs Static antimicrobial agents • Drugs that bind to the cell wall like penicillin are likely to be cidal whereas agents that interfere with metabolic pathways like sulfonamide drugs and folate antagonists are likely to be static, exceptions exist • An antimicrobial agent can be cidal for one strain and static for another strain of the same organism
Shortcomings of cidality • The Eagle Musselman paradoxical effect • Tolerance is when MBC is ≥ 32 times the MIC
Question 3: In which clinical condition have bactericidal agents shown to be superior to static agents? • Streptococcal throat • Urinary tract infection • Bacterial meningitis • Septic shock • Typhoid fever
Answer 3. Bacterial meningitis
Based on which data? • Historical Data: Pneumococcal meningitis • Treatment of bacterial endocarditis • Animal models
Question 4: In a patient highly allergic to penicillin that presents with lobar pneumonia and bacteremia caused by S. pneumoniae which agent would you prefer? • Sulfa-agent • Low dose Chloramphenicol • Low dose Quinupristin/Dalfopristin • Low dose Linezolid • High dose Linezolid
Answer to question 3 • 5. High dose Linezolid Bostic et al. Diagnost Microbiol & Infect Dis 1998;30:109-112 Zuenko et al. Antimicrob Agents Chemother 1996; 40:839 Pankey & Sabath Clin Infec Dis 2004;38:864