Adverse Consequences of Antibiotic Use

Although antibiotics are undoubtedly one of the most beneficial discoveries of science, their use does carry risks. They can adversely affect patients by eliciting allergic reactions, causing direct toxicity, or altering the normal bacterial flora, leading to superinfections with other organisms. Antibiotic use is the primary driving force in the development of antibiotic resistance, which can affect not only the treated patients but other patients by trans-mission of resistant organisms. It is important to keep in mind all of these potential adverse consequences when using antibiotics.

Antibiotic Allergy

Through formation of complexes with human proteins, antibiotics can trigger immunologic reactions.  These reactions may manifest immediately (such as anaphylaxis or hives) or be delayed (rashes, serum sickness, drug fever). Because of their highly reactive chemical structure and frequent use, betalactam drugs are the most notorious group of drugs for causing allergic reactions. It is difficult to determine how likely it is that a patient with an allergy to a particular antibiotic agent will have a similar reaction to an-other agent within that class. While some (highly debated) estimates of the degree of cross-reactivity are available for beta-lactam drugs, estimates for cross-reactivity within other classes (for example, be-tween fluoroquinolones) are essentially nonexistent.  Because labeling a patient with an allergy to a particular antibiotic can limit future treatment options severely and possibly lead to the selection of inferior drugs, every effort should be made to clarify the exact nature of a reported allergy.

Antibiotic Toxicities

Despite being designed to affect the physiology of microorganisms rather than humans, antibiotics can have direct toxic effects on patients. In some cases this is an extension of their mechanism of ac-tion when selectivity for microorganisms is not perfect. For example, the hematologic adverse effects of trimethoprim stem from its inhibition of folate metabolism in humans, which is also its mechanism of antibiotic effect. In other cases, antibiotics display toxicity through unintended physiologic interactions, such as when vancomycin stimulates histamine release, leading to its characteristic red man syndrome. Some of these toxicities may be dose related and can be attenuated by dose reduc-tion; this often occurs when doses are not adjusted properly for renal dysfunction and thus accumulate to a toxic level.

Superinfection

The human body is colonized by a variety of bacteria and fungi. These or-ganisms are generally considered commensals, in that they benefit from living on or in the body but do not cause harm (within their ecologic niches). Colonization with commensal organisms can be beneficial, given that they compete with and crowd out more pathogenic organisms. When administration of antibiotics kills off the commensal flora, pathogenic drug-resistant organisms can flourish because of the absence of competition. This is considered a superinfection (i.e., an infection on top of another infection). For example, administration of antibiotics can lead to the overgrowth of the gastro-intestinal (GI) pathogen  Clostridium difficile,  which is often resistant to most antibiotics. C. difficile can cause diarrhea and life-threatening bowel inflammation. Similarly, administration of broad-spectrum antibacterial drugs can select for the over-growth of fungi, most commonly yeasts of the genus Candida. Disseminated Candida infections carry a high risk of mortality. To reduce the risk of superinfection, antibiotics should be administered only to patients with proven or probable infections, using the most narrow-spectrum agents appropriate to the infection for the shortest effective duration.

Antibiotic Resistance

Thousands of studies have documented the relationship between antibiotic use and resistance,  both at a patient level (if you receive an antibiotic, you are more likely to become infected with a drug-resistant organism) and a society level (the more antibiotics a hospital, region, or country uses, the greater the antibiotic resistance). The development of antibiotic resistance leads to a vicious spiral where resistance necessitates the development of broader-spectrum antibiotics, leading to evolution of bacteria resistant to those new antibiotics, requiring ever broader-spectrum drugs, and so on. This is particularly problematic because antibiotic development has slowed down greatly. Although we can see clearly the broad relationship between antibiotic use and resistance, many of the details of this relationship are not clear. Why do some bacteria develop resistance rapidly and others never develop resistance? What is the proper duration of treatment to maximize the chance of cure and minimize the risk of resistance?

Guidelines

Until we develop a more sophisticated understanding of the relationship between antibiotic use and resistance on a micro level, we are left with some general guidelines for minimizing the potential for development of resistance:

Avoid Using Antibiotics to Treat Colonization or Contamination

A substantial percentage of all antibiotic use is directed toward patients who are not truly infected,  but in whom organisms are recovered from culture. Isolation of Staphylococcus epidermidis from a single blood culture or Candida species from a urinary culture in a catheterized patient are common situations in which patients should be scrutinized to determine whether an infection is truly present. A proper diagnosis is key.

Use the Most Narrow-Spectrum Agent Appropriate for the Patient’s Infection

Broader-spectrum agents multiply the number of bacteria affected by the drug, increasing the chances both for development of resistance and superinfection. “Broader” and “newer” are not synonymous with “better”: for example, good old penicillin kills susceptible organisms more rapidly than almost any drug on the market. The treating clinician’s goal always should be definitive, narrow-spectrum therapy.

Use the Proper Dose

Bacteria that are exposed to low concentrations of antibiotics are more likely to become resistant than those exposed to effective doses. After all, dead bugs don’t mutate! Further research in pharmaco-dynamics should make it easier to determine the proper dose for each patient and thus to reduce the likelihood that resistance will develop.

Use the Shortest Effective Duration of Therapy

Unfortunately, duration of therapy is one of the least-studied areas of infectious diseases. Examination of standard treatment durations says much more about how humans think than about how antibiotics and bacteria truly interact—durations are typically 5, 7, 10, or 14 days, more in line with our decimal system and the days in a week than with anything studied precisely. New studies are showing that shorter durations of therapy are often just as effective as prolonged courses and possibly less likely to select for resistance. As studies progress and determine additional factors that indicate when infections are sufficiently treated, it should be possible to define more accurately the length of therapy on a patient-by-patient basis. Many clinicians find that “old habits die hard,” however, and should remember that learning new evidence about duration of therapy is important as it emerges.

References

Gallagher ,J.C. and MacDougall ,c. (2012). Antibiotics Simplified. Second Edition. Jones & Bartlett Learning, LLC.