FAQs on Antibiotic Myths: The Author Responds

Brad Spellberg, MD

Disclosures

November 17, 2016

Editor's Note: A recent Medscape article, Antibiotics: 5 Myths Debunked , has attracted a large number of Medscape readers who have so far posted more than 100 comments. While most of these have been favorable, a few specific, repeated themes have challenged some of the busted myths. We asked the article's author to respond to these frequently asked questions (FAQs).

Brad Spellberg, MD

FAQ #1: If patients do not complete their course of antibiotics, won't they just take the leftovers in the future the next time they get sick?

This is a risk, yes. But the fundamental point of busting the myth about taking antibiotics for long periods of time is that, based on many dozens of randomized clinical trials across many types of infections, giving shorter courses of therapy is effective.[1,2,3,4,5,6,7,8,9,10,11,12] It will be rare that patients feel sufficiently better to stop their antibiotics before completing a short, 5-day course of antibiotics for cellulitis or community-acquired pneumonia, or 5-7 days for pyelonephritis, for example. Thus, giving evidenced-based, short-course therapies will reduce the risk of patients feeling better before completing their therapy and will minimize the number of pills they have left.

In contrast, if providers continue to prescribe 10- to 14-day courses of therapy, patients who feel better and stop taking the pills before completing the full course are more likely to end up with leftover pills.

At the time the provider gives the prescription to the patient, instructions should reiterate that the patient should not stop the medications without first consulting the provider. On the rare occasion when a patient does feel better before completing a short-course regimen, a dialogue should occur between the patient and the provider, and if the patient truly feels better, the provider can counsel the patient to stop therapy and to either bring the remaining pills back or dispose of them. Realistically, neither of these may occur, but even if the patient retains leftover pills, at least the number of pills left over will be fewer than if the patient had been given a 2-week course of therapy.

Let's not let the perfect be the enemy of the good—shorter is indeed better.

FAQ #2: How can patients be trusted to stop their own therapies?

I did not suggest that patients should stop their own therapies. I indicated that patients should be encouraged to reach out to their providers and discuss the possibility of stopping if they felt better before completing the prescribed course of therapy.

Medicine in the 21st century is a team sport. I would hope that all providers would encourage partnership with their patients as a means to optimize care outcomes. I would also hope that medicine has moved past the mid-20th century paternalism when doctors were promoted as being all-knowing and patients were expected to obey without questioning.

The failure of the medical community to appropriately utilize antibiotics in the 20th century, resulting in the crisis of antibiotic resistance that confronts us, is a testament to the fact that providers are far from all-knowing. We have badly abused and misused these drugs as a matter of routine; we have no moral high ground to insist that patients do exactly what we say with these drugs. A dialogue between patient and provider can help us move towards more prudent use of antibiotics, particularly if we are educating both patients and providers about the dangers of overuse.

FAQ #3: Don't data show that short-course therapies are ineffective for group A streptococcal pharyngitis? Which infections call for short-course therapies?

I did not address streptococcal pharyngitis nor recommend short-course therapy for this infection in the original article. I specifically addressed only cellulitis, acute bacterial sinusitis, community-acquired pneumonia, nosocomial pneumonia/ventilator-associated pneumonia, complicated urinary tract infections, and complicated intra-abdominal infections. As mentioned in the article, the evidence for short-course therapies for these infections is quite substantial, based on numerous randomized controlled trials (and meta-analyses of said randomized controlled trials).[1,2,3,4,5,6,7,8,9,10,11,12]

I did not address streptococcal pharyngitis because the data surrounding its treatment are more complex; indeed they are substantially more complex than many of the comments left in response to the original article would imply. What is fairly clear is that shorter courses of penicillin therapy can result in increased clinical failure and relapse of streptococcal pharyngitis.[13,14,15] However, multiple trials have also found that short courses of other agents (eg, cephalosporins), which have superior pharmacology to that of penicillin, result in similar clinical cure and relapse rates compared with standard penicillin courses for streptococcal pharyngitis.[13,14,15]

Furthermore, meta-analyses have not found a difference in rates of rheumatic fever with these newer, short-course regimens compared with standard penicillin; however, rates of rheumatic fever were so low that even the meta-analyses were underpowered to definitively establish similar efficacy using this endpoint.[13,14,15]

The risk for rheumatic fever makes group A streptococcal infection unique; we are not so much using antibiotics to treat the infection as to reduce the risk for an autoimmune complication of the infection resulting from molecular mimicry. These complexities are why I did not address group A streptococcal pharyngitis in the original article.

I do not agree with commenters who indicated that we know that all short-course therapies are inferior for streptococcal pharyngitis. Meta-analyses of multiple randomized trials have found that short-course cephalosporin regimens seem to be clinically similar to standard penicillin regimens.[13,14,15] However, because these studies have not been able to definitively establish the relative risk for rheumatic fever, patients should indeed be advised to complete the prescribed course of therapy and not to stop early for this disease until such time as additional studies are completed, or when national guidelines change to take a stand in favor of short-course, non-penicillin-based therapies.

FAQ #4: What about the effect of antibiotic use in animals?

The article was written for providers for human patients; therefore, I did not address agricultural uses of antibiotics. Clearly, agricultural use contributes to the potential for environmental reservoirs of antibiotic resistance and contributes to spread of antibiotic resistance to humans. For a summary of this topic, see a position paper, Antibiotic Resistance in Humans and Animals, written for the National Academy of Medicine. In short, we certainly need to greatly curtail our antibiotic use in agriculture.

FAQ #5: Does exposure to antibiotics drive resistance, based on the length of time exposed, number of doses exposed, or something else?

This question cannot be precisely answered for all drugs and all conditions on the basis of specific datasets. Unmetabolized antibiotic and metabolic breakdown products that retain antimicrobial activity will be excreted into the environment and continue selecting for resistance in the environment long after the patient completes the course of therapy. Just because we prescribe an antibiotic for 7 days does not mean that bacteria are only exposed to it for 7 days; our normal flora and bacteria in the environment will continue to be exposed to the antibiotic or its breakdown products for some time after completion of therapy.

What is probably true is that the more antibiotic we put into the environment, the more resistance will be selected among more bacteria. So, generally speaking, our goal should be to use fewer tons of antibiotics across all classes. We put more than 17,000 tons of antibiotics into the environment every year in the United States alone (80% for agriculture, 20% for human use).[16] Surely we can do better.

FAQ #6: What was meant by the assertion that appropriate antibiotic use leads to resistance?

Several readers objected to the assertion that all antibiotic use leads to resistance, not just inappropriate use. My point was to underscore that if we completely eliminated inappropriate use, antibiotic resistance would still emerge because all antibiotic use can select for resistance, including "appropriate" use.

All antibiotic use causes selective pressure in our normal flora and/or after excretion in the environment, which drives the emergence of resistance. It is factually incorrect to claim that "appropriate" use will not lead to emergence of resistance.

Furthermore, no consensus definition of what constitutes "appropriate" versus "inappropriate" therapy has yet been established. Different people mean different things by "inappropriate" therapy. Is fluoroquinolone use as a first-line option to treat community-acquired pneumonia appropriate? It is FDA approved. Its use is based on randomized controlled trials. It is guideline compliant. And, in the expert opinion of myself and others, it is completely inappropriate.[17] To use orally bioavailable agents active against pseudomonas to kill Streptococcus pneumoniae and atypical organisms is not appropriate when we have so many other, narrower-spectrum agents available, and we have no alternatives to the quinolones for oral agents with broad-spectrum gram-negative activity.

Whether dosing differences lead to differences in clinical emergence of resistance is also debatable. The fallacy of this argument is that it presumes that resistance emerges at the site of infection. Although modeling suggests that many antibiotics have mutation-prevention concentrations that are active in vitro or at the site of infection, during clearance, the concentration of the antibiotic inevitably declines as the drug or its metabolites are exposed to the body's normal flora and then excreted in the environment. The normal flora in the body are still going to be exposed to subtherapeutic levels, and therefore, resistance selection is still going to occur.

FAQ #7: Was the article evidence-based?

I refer the reader to the numerous references in the article, as well as the references in the JAMA Internal Medicine editorial summarizing the data on short-course antibiotic therapy.[1,2,3,4,5,6,7,8,9,10,11,12]

FAQ #8: Are the data supporting static versus cidal comparisons relevant?

Concerns were raised about the choices of antibiotics used in the randomized controlled trials that I cited comparing static to cidal therapy. Please note that I did not design those trials! I cited them as evidence that cidal agents have not resulted in superior cure rates compared with static agents, and this is clearly true.

Nevertheless, several readers commented that vancomycin is cidal but only "weakly," and that linezolid has better pharmacology, so trials comparing these drugs are not fair comparisons of a cidal versus static agent. However, the fact that linezolid's pharmacology allows it to be superior to its cidal comparator underscores the point made in the article. The key is not static versus cidal but how well we can deliver an active agent to the site of infection. Furthermore, despite daptomycin being the most rapidly cidal gram-positive antibiotic currently available, it was no more effective than vancomycin for treatment of methicillin-resistant Staphylococcus aureus infections in a pivotal trial of its effectiveness in bacteremia and right-sided endocarditis.[18]

With respect to whether the infections studied in static versus cidal comparisons are relevant, bacterial meningitis, typhoid fever, nosocomial pneumonia, etc, are all severe, life-threatening infections for which cidal therapy has been found not to be superior in efficacy to static therapy.

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