A contemporary approach to rational antimicrobial prescribing: Part 2
Antimicrobial guidelines are a great resource to help you prescribe rationally, but understanding what goes into these guidelines can provide you with the information to guide antimicrobial choice when faced with an unfamiliar infection.
What to Prescribe
Based on Microbiology or Epidemiology
Where possible, culture and sensitivity should guide antimicrobial therapy. However, we don't always have time to wait and sometimes need to start treatment empirically. In these cases, published evidence on the suspected disease and the likely causative organisms should guide empirical choices.
For example, infections of the skin are commonly Gram-positive cocci or yeasts, while urinary tract infections are most commonly caused by bacteria from the Enterobacterales family. Many countries now have national guidelines that take these factors into account, which can be helpful references.
One more caveat
It is important to understand that a positive culture is not always evidence of infection or that the causative organism has been isolated. A positive culture in the absence of clinical signs, or culture of an organism not usually associated with infection at the sampled site, may signify colonization or contamination of the sample and may not warrant treatment.
In cultures with multiple isolates, careful consideration should be given to whether one or more are the likely pathogens to treat based on the site and expected organisms. Blanket treatment of all cultured species may be unnecessary.
In an ideal world, only clinically relevant isolates should be reported to the clinician, but it does appear to be the case that cultures are often reported without interpretation, leaving that up to the case clinician.
Consider the site of infection
Effective treatment relies upon an appropriate concentration being reached at the site of infection. Drug distribution can vary greatly for different tissues and sites, with certain tissues having barriers to drug diffusion, so it is essential to choose a drug that will concentrate in the affected site. Again, this will be incorporated into antimicrobial stewardship guidelines.
Tissue barriers
Sites with barriers to drug diffusion include:
Central nervous system (CNS)
Eye
Prostate
Bronchial epithelium of the respiratory tract
Generally, lipophilic molecules will distribute to these tissues better and may influence antimicrobial choice. These include:
Potentiated sulfonamides
Fluoroquinolones
Metronidazole
Amphenicols
Lincosamides (e.g. clindamycin)
Macrolides
Inflammation and breakdown of these barriers can allow drugs to penetrate that would not normally be able to, such as penicillins and other beta-lactams. This is often utilized for managing CNS or respiratory infections, where beta-lactams are commonly used due to their broad spectrum of activity. Although tetracyclines are lipid-soluble, they reportedly do not reach therapeutic concentrations in cerebrospinal fluid.
Urinary tract
Many antibiotics are excreted in high concentrations in the urinary tract. Consequently, microbiological breakpoints for urinary tract infections are often higher than those for soft tissue infections. Therefore, doses for urinary tract infections may be lower than that for infections elsewhere.
Serum, extracellular and intracellular infections
Some pathogens invade host cells and live intracellularly, while other infections may largely reside in the blood. In addition to an antibiotic's lipophilicity, plasma protein binding will affect their distribution within the body. Thankfully, antibiotics which concentrate well within the cell are largely the same as those that can overcome tissue barriers such as potentiated sulfonamides, sulfonamides, fluoroquinolones, lincosamides, tetracyclines and macrolides.
Certain antibiotics are very highly-protein bound and largely stay within the vasculature such as daptomycin, although these are not often used in veterinary medicine. Beta-lactams and aminoglycosides are moderately protein bound and were thought to distribute largely to the extracellular fluid compartment but more recent evidence has questioned this assumption for aminoglycosides. Glycopeptides have variable protein binding and distribution, making it hard to predict serum concentrations, but again, these are not often used in animals.
Low-priority and Narrow Spectrum
In an effort to protect our new and broad-spectrum antimicrobials for more resistant infections, we should prioritise low-priority and narrow spectrum drugs where possible. The World Health Organisation (WHO) has established AWaRe categories (Access, Watch, Reserve) to guide which antimicrobials use in human medicine. For animals, the WHO maintains a list of medically important antimicrobials (formerly known as critically important antimicrobials), which prioritises antimicrobials in terms of their important to human healthcare. The European Medical Association - Antibiotic Expert Ad Hoc Group has it's own categorisation (ABCD; Avoid, Restrict, Caution, Prudence) for antimicrobials used for veterinary medicine, which is also based off of the list of medically important antimicrobials. There is some suggestion of developing a vet-AWaRe categorisation but this will take time to come to fruition, if the project gets going.
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Spellberg B. 17 - Principles of Anti-infective Therapy. John E. Bennett, Raphael Dolin, Martin J. Blaser. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (Ninth Edition). W.B. Saunders. 2019.
Brian Markey, Finola Leonard, Marie Archambault, Ann Cullinane and Dores Maguire. Clinical Veterinary Microbiology (Second Edition). Mosby Elsevier. 2019
Guidelines:
The International Society for Companion Animal Infectious Disease has several guidelines of it's own (although some are getting quite out of date) and also lists relevant guidelines from other organisations on it's website
WHO AWaRe classification of antibiotics for evaluation and monitoring of use
Considering the site of infection:
Dowling P. 23 - Antimicrobial Therapy of Selected Organ Systems. Steeve Giguère, John F. Prescott, Patricia M. Dowling. Antimicrobial Therapy in Veterinary Medicine (Fifth Edition). Wiley Blackwell. 2013.
Papich, M G. 140 - Antibacterial Drug Therapy. Etienne Côté, Stephen J. Ettinger, Edward C. Feldman. Ettinger's Textbook of Veterinary Internal Medicine (Ninth Edition). Elsevier. 2024.
Maurin M, Raoult D. Use of aminoglycosides in treatment of infections due to intracellular bacteria. Antimicrob Agents Chemother. 2001;45(11):2977-2986. doi:10.1128/AAC.45.11.2977-2986.2001
Levison ME, Levison JH. Pharmacokinetics and pharmacodynamics of antibacterial agents. Infect Dis Clin North Am. 2009 Dec;23(4):791-815, vii. doi: 10.1016/j.idc.2009.06.008
Bongers S, Hellebrekers P, Leenen LPH, Koenderman L, Hietbrink F. Intracellular Penetration and Effects of Antibiotics on Staphylococcus aureus Inside Human Neutrophils: A Comprehensive Review. Antibiotics (Basel). 2019 May 4;8(2):54. doi: 10.3390/antibiotics8020054