Question 5

Highest mark

Discuss the factors that may affect your choice of antimicrobial agent in a critically ill septic patient, giving examples where relevant.

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College answer

Not available.

Discussion

The tabulated answer below was largely derived from an article by Surbhi et al (2011) from the Mayo Clinic Proceedings. Neither this short version nor the long version that follows are suitable for a 10-minute answer, but should be viewed as vague guides.

Factors which influence antibiotic choice
Disease factors	Host factors	Organism factors	Drug factors
Travel history Occupation Recreational exposure IVDU Severity of illness, urgency of therapy Reliability of cultures	Age Clearance organ function Allergies Immune status, HIV Pregnancy and lactation	Source control Susceptibility Empiric vs specific Intra vs. extracellular Duration of therapy Assessment of response	Cost Toxicity Bioavaiability Source site penetration Drug synergy Bacteriostatic vs bactericidal

MORE Factors which Influence the Choice of Antibiotic Therapy
Factors		Discussion and examples
Disease specifics	Travel history	Geography of endemic regions (eg. leptospirosis) Known ongoing outbreaks (eg. Ebola, H1N1, MERS)
	Occupational exposure	Abbatoir workers (Coxiella burnetii) Fisherman (Vibrio vulnificus) Cattle farmers (Brucella sp.)
	Recreational exposure	IV drug use (endocarditis) Pets or animal exposure (eg. psittacosis or toxoplasma) Bushwalking (eg. tick-borne disease) Alcoholism (prognostic importance in community-acquired pneumonia)
	Recent antimicrobial use	Was it the right antibiotic? i.e. was the course of antibiotics ineffective because of poor agent choice? Did it select for a specific group of organisms? Prophylaxis vs. endemic pathogens (eg, malaria)
	Empiric vs. definitive	Are we convinced of the diagnosis? Is there a need to cover broadly?
	Urgency and timing	Septic patient (every hour delay is associated with a 1% mortality increase)
	Reliability of cultures	Are we sure we cultured the correct pathogen? Is a polymicrobial infection possible (eg. diabetic foot)?
Host factors	Clearance	Decreased renal clearance (by renal failure) Increased renal clearance (by dialysis, or in pregnancy) Decreased hepatic clearance (eg. cirrhosis) Exotically altered clearance (eg. plasma exchange, haemoperfusion, adsorption on to ECMO circuit surfaces, and so forth).
	Age	Paediatric dosing needs to be adjusted to weitght Geriatric dosing needs to account for change in volume of distribution and clearance
	Genetic variation	Genetic differences in side effects from antibiotics Congenital idiosyncracies preventing the use of certain antibiotics (eg. G6PD deficiency resulting in haemolysis when exposed to dapsone or nitrofurantoin) Hepatic enzyme defects
	Pregnancy and lactation	Early pregnancy teratogenesis (eg. nitrofurantoin, chloramphenicol, sulfonamides) Late pregnancy teratogensis (eg. tetracyclines)
	Immunocomptence	Steroid use Post-splenectomy, unvaccinated (susceptible to encapsulated organisms) Chemotherapy Solid organ or bone marrow transplantation

	Allergies	Fatal hypersensitivity reaction vs. some sort of mild scaly rash with a little itching.
Organism factors	Susceptibility	ESCAPPM, MRO, etc Community prevalence of drug resistance Tendency to develop resistance during treatment
	Biology	Intracellular pathogen vs. extracellular Unusual life cycle (eg. helminthes, malaria) - need to kill the eggs or dormant cocoons or whatnot
	Source control	Success of therapy overall is largely determined by this
	Duration of therapy	Short course, eg. in urosepsis Long course, eg. osteomyelitis
	Assessment of response	To repeat the cultures, or not? Is there a point in monitoring serology?
Drug factors	Cost	Fluconazole: $57.99 AUD for 28 capsules (200mg) Anidulafungin: ~$ 300 AUD per single 200mg dose. Cost of monitoring the drug levels How much is a life worth? you amoral monsters, etc.
	Toxicity	Risk vs benefit Some drugs (eg. chloramphenicl) are uniformly "too toxic for use", as there are less toxic alternatives in almost every situation.
	Bioavailability	Convenience of oral dosing Certainty of IV dosing Altered absorption via GI tract in context of critical illness, shock states, low flow, what have you.
	Site penetration	Basic chemistry of the drug influences this aspect. Eg: Penetration to the CSF (lipophilicity) Exclusive distribution into the circulating volume, (hydrophilicity, or high serum protein binding) Weird organ preference (eg. the strange affinity of fluoroquinolones for the prostate) Exclusion of a drug from a specific organ (eg. the inactivation of daptomycin by lung surfactant)
	Bactericidal vs bacteriostatic	Some agents are bacteriostatic against one pathogen and bactericidial against another There may not be any in-vivo difference
	Synergistic combination	Need for multiple agent therapy (eg. in Pseudomonas) Unquestioned need for synergy (eg. cocktail for TB) Advantage from synergy (eg. ampicillin with gentamicin for enterococci) Need for broad-spectrum coverage (in which case you use multiple agents to start with, and then narrow the spectrum of cover) Need for polymicrobial coverage (eg. surgical triple therapy, or in context of bone marrow transplant) Need to prevent emergence of resistance (eg. the argument offered to defend the use of selective digestive tract decontamination; also, a genuine argument for the use of rifampicin and fusidic acid together)

References

Oh's Intensive Care Manual: Chapter 72 (pp. 738) Principles of antibiotic use by Jeffrey Lipman

Roberts, Jason A., and Jeffrey Lipman. "Pharmacokinetic issues for antibiotics in the critically ill patient." Critical care medicine 37.3 (2009): 840-851.

Craig, William A. "Basic pharmacodynamics of antibacterials with clinical applications to the use of β-lactams, glycopeptides, and linezolid." Infectious disease clinics of North America 17.3 (2003): 479-501.

Craig, William A. "Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men." Clinical infectious diseases (1998): 1-10.

Craig, William A. "Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins." Diagnostic microbiology and infectious disease 22.1 (1995): 89-96.

Weinstein, Melvin P., et al. "Multicenter collaborative evaluation of a standardized serum bactericidal test as a predictor of therapeutic efficacy in acute and chronic osteomyelitis." The American journal of medicine 83.2 (1987): 218-222.

Leggett, J. E., et al. "Comparative antibiotic dose-effect relations at several dosing intervals in murine pneumonitis and thigh-infection models." Journal of infectious diseases 159.2 (1989): 281-292.

Moore, Richard D., Paul S. Lietman, and Craig R. Smith. "Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration." Journal of Infectious Diseases 155.1 (1987): 93-99.

Daikos, GEORGE L., VALENTINA T. Lolans, and G. G. Jackson. "First-exposure adaptive resistance to aminoglycoside antibiotics in vivo with meaning for optimal clinical use." Antimicrobial agents and chemotherapy 35.1 (1991): 117-123.

MacKenzie, F. M., and I. M. Gould. "The post-antibiotic effect." Journal of Antimicrobial Chemotherapy 32.4 (1993): 519-537.

Athamna, A., et al. "In vitro post-antibiotic effect of fluoroquinolones, macrolides, β-lactams, tetracyclines, vancomycin, clindamycin, linezolid, chloramphenicol, quinupristin/dalfopristin and rifampicin on Bacillus anthracis."Journal of Antimicrobial Chemotherapy 53.4 (2004): 609-615.

Stubbings, William J., et al. "Assessment of a microplate method for determining the post-antibiotic effect in Staphylococcus aureus and Escherichia coli." Journal of Antimicrobial Chemotherapy 54.1 (2004): 139-143.

Woodnutt, Gary. "Pharmacodynamics to combat resistance." Journal of antimicrobial chemotherapy 46.suppl 3 (2000): 25-31.

LONGACRE, AB. "Factors influencing the choice of antibiotics in therapy." The New Orleans medical and surgical journal 103.4 (1950): 160-167.

Leekha, Surbhi, Christine L. Terrell, and Randall S. Edson. "General principles of antimicrobial therapy." Mayo Clinic Proceedings. Vol. 86. No. 2. Elsevier, 2011.

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