1. General Principles of Antimicrobial Therapy

2. Concept #1: The guiding principle of antibiotic selection Antibiotic coverage should be kept to the narrowest spectrum, least expensive, least toxic agent(s) that will adequately treat the most likely pathogens.

3. Concept # 2: It is safe to be focused When a causative infectious agent has been identified, antibiotic coverage should be narrowed to treat that organism.

4. Concept #3: Reasons to use two or more antibiotics simultaneously When one antibiotic cannot adequately cover the empiric spectrum When synergy is necessary to obtain cidal levels (e.g., serious enterococcal and pseudomonal infections) To prevent the emergence of resistance (e.g., TB, HIV) To achieve additive effects on resistant infections (e.g., PVE, H. pylori) To treat multiple phases (forms) of the same pathogen (e.g., TB, parasitic diseases) When a single antibiotic would have to be given in toxic doses

5. Using antibiotics to inhibit toxin production Usually this is done for severe toxigenic staph or strep infection (e.g., TSS, necrotizing fasciitis) The theory is that, in infected areas where microbial density is high, the bacteria – are nutrient-limited and in stationary phase – do not synthesize PBPs – are less susceptible to beta-lactam antibiotics, BUT – are alive and actively synthesizing toxins Hence, treatment with protein synthesis inhibitor (to inhibit toxin production) should improve outcome. Although clindamycin is commonly added to beta- lactams in severe Gram-positive infection, there is little clinical data to support this practice (see aminal model results on next slide).

6. Efficacy of clindamycin in an animal model of streptococcal myositis (from Stevens et al. JID 1988; 158: 23) Clindamycin Erythromycin Penicillin G Untreated @ 16h 100 90 80 70 60 50 40 30 20 10 0 2 4 6 8 10 12 14 16 18 Delay in treatment (hrs) % survival after 14 d

7. Reasons NOT to use multiple antibiotics when you don’t have to May result in antagonism between agents (depending on the combination) Increases the likelihood of a toxic or allergic reaction to one of the agents – Additive (I.e., different adverse effects from different agents) – Synergistic (e.g., increased nephrotoxicity with vancomycin and gentamicin) Encourages the development of multi-drug resistance Increases the cost of care

8. Concept # 4 : “ More of a good thing is NOT always better” The dosing of antibiotics should be adjusted to provide effective levels at the site of infection. Unnecessarily high doses of some antibiotics may -- – increase the risk of toxicity – paradoxically result in less killing in vitro (the “Eagle effect”). The significance of this effect in vivo is not known. Killing of enterococci by amoxicillin over 24 hrs at concentrations of 1, 10, and 100 mcg/ml (compared with no antibiotic, i.e., control) (from Antimicrob Ag Chem 1986;30:258)

9. Concept # 5: “Not all fevers are infection.” Drugs Immunologically-based disorders – Temporal arteritis – Still’s disease – Vasculitis – Lupus Inflammatory and granulomatous conditions – Inflammatory bowel disease – Wegener’s granulomatosis – Sarcoidosis – Graft-versus-host disease Neoplasms Endocrine disorder – Thyroid disease – Hypoadrenalism Other – Thrombophlebitis and pulmonary embolism – Liver disease/cirrhosis – CNS disorders Common non-infectious causes of fever:

10. Concept # 6: Antibiotics should be dosed according to their pharmacokinetics and pharmacodynamics Equivalent bacteriologic cure and outcome Effective because – Post-antibiotic effect – Concentration dependant killing Decreased toxicity Avoids overuse of alternative agents Advantages of single daily dosing of aminoglycosides For example...

11. Principles of Antimicrobial Use (summary) Use narrowest spectrum, least expensive, least toxic antibiotic to cover likely organisms Direct therapy based on culture and susceptibility data Avoid overlapping antimicrobials Combination therapy for resistant Gram negative organisms, nosocomial pneumonia and febrile neutropenia

12. Resources 1. Antimicrobial guidelines - Booklet https://ummcpharmweb.med.umich.edu/di/clinical/abxbook/ant imicrobial_guidelines/ 2. Antimicrobial Restriction Program 3. Infectious Diseases Consult Service