Abstract & Commentary
Synopsis: Antipyretics may interfere with the PMN transport of some antibiotics and their release at the site of infection.
Source: Mandell GL, Coleman EJ. Effect of antipyretic agents on uptake, transport, and release of antimicrobial agents by human polymorphonuclear leukocytes. J Infect Dis. 2002;185:1314-1319.
Some antibiotics are concentrated in polymorphonuclear leukocytes (PMN) and may be dependent on them for their efficacy. This appears particularly true with azithromycin, which may barely reach MIC levels for respiratory pathogens in the serum yet is clinically effective. This is likely due to the uptake of the drug into PMNs, which may concentrate it 100-fold or more compared to the serum. With chemotaxis, the antibiotic is then transported to the site of infection, where it is released to help destroy the bacteria. It turns out this mechanism of action may be relevant to some other antimicrobials as well, including moxifloxacin, which is concentrated in PMN as well, although only 10-fold.
Mandell and Coleman developed a complex yet elegant and reproducible assay method to test the ability of PMNs to transport the antibiotic using an agar plate with a chemoattractant. It was also possible to use the same plate for bioassay of the antibiotic by seeding it with a susceptible organism. The effect of acetaminophen, acetylsalicylic acid (ASA), and ibuprofen were measured by adding them to the PMNs collected and incubating these with the antibiotic of choice.
The antipyretics were first tested and found not to influence chemotaxis. The antibiotics have been previously tested and found to have no effect. When the 2 were combined, however, ASA was found to inhibit the uptake of azithromycin but not moxifloxacin. Acetaminophen and ibuprofen had no effect on uptake. When transport and release were tested, however, all of the antipyretics were found to inhibit the effect at therapeutic levels. The effect was generally concentration-dependent and most prominent with acetaminophen.
Comment by Alan D. Tice, MD, FACP
Routine orders for antipyretics for "fever" are generally discouraged by infectious diseases specialists but they are often overruled or worn down by the incessant requests of conscientious nurses for orders in case a fever should occur or when the patient is suffering from a temperature of 100° or higher. A body temperature of over 98.7° is still seen as disease in itself despite the best efforts of Mackowiak and associates.1 Perhaps it is also a matter of having a medicine that can produce a demonstrable effect within minutes that makes an antipyretic so appealing. On the other hand, it may well be that we are compromising the host and even inhibiting the ability of antimicrobials to do their work.
This work adds another piece of information to bolster the argument against the routine use of antipyretics for "fever" and to limit the use of unnecessary medicines in the treatment of infections. It also brings up a number of questions that deserve further investigation. What are the effect of steroids in this system? Why is ASA different from ibuprofen in its effect on PMN uptake of azithromycin? Should one be preferred if temperature control really is needed? What is the effect of temperature itself on the assay? The interest in antipyretics also brings up the possible value of fever in host response, especially in light of the apparent value of warming during surgery in reducing postoperative infections.2
As our understanding of infectious diseases and antimicrobials increases, the pathogenesis and effect of interventions should become clearer and help us in our efforts to control disease and understand the role of immune modulators and cytokines.
Dr. Tice, Infections Limited, PS, Tacoma, WA; Infectious Disease Consultant, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, is Associate Editor of Infectious Disease Alert.
References
1. Mackowiak PA, et al. Fever—Basic mechanisms and management. 2nd ed. Philadelphia, Penn: Lippincott-Raven; 1997.
2. Tice A. Warming Up to Prevent Infection. Infectious Disease Alert. 2001;20(24):185-186.
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