Antibiotic dogma, dictums and myths: Do we still hold these ‘truths’ to be self-evident?
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The way it has always been
In the current era of medicine, the creation of practice guidelines and the care we provide to our patients are based on a combination of data gathered from 1) well-conducted, prospective, randomized clinical trials; 2) large cohorts of retrospective observational studies; and when these are lacking, 3) reliance on our knowledge and understanding of firm, basic scientific principles, as well as our individual and collective accumulated experiences. Nevertheless, notwithstanding our best intentions to “stick to evidence-based medicine,” and irrespective of medical or surgical specialty, a significant portion of our daily clinical practices remain rooted in dogma, dictum and tradition. In other words, “that is how we always did it.” The field of infectious diseases is no exception, particularly surrounding the general overall concept of anti-infective therapies and specifically in relationship to how, when and why we prescribe antibiotics and for how long they are administered. Traditional infectious diseases practices that were once strictly adhered to — such as treating asymptomatic bacteriuria before total joint arthroplasty surgery, prolonged pre-emptive empiric administration of broad-spectrum antibiotics for type III open orthopedic fractures, and double or dual coverage for infections caused by Pseudomonas aeruginosa — have since either convincingly been disproven as being beneficial or have come under closer scrutiny and are now carried out only in certain specific circumstances.
As another example, the recommendation to routinely screen and treat asymptomatic bacteriuria in pregnancy has been called into question following the publication of a large European randomized prospective cohort study of over 4,000 pregnant women that examined the maternal and neonatal consequences of treated and untreated asymptomatic bacteriuria. Although the proportion of preterm births did not differ between women with or without asymptomatic bacteriuria, including those who received treatment or placebo, the possibility of developing pyelonephritis associated with no treatment was still determined to be statistically significant; however, the absolute risk remained low. The current consensus on the management of asymptomatic bacteriuria in pregnant women remains unaltered, but the door has been opened to future studies aimed at comparing its benefits with potential harm.
To this day, traditional approaches to antimicrobial therapy can still be overheard by medical students and residents alike during hospital ward rounds as if they are “antibiotic gospel.” A few classic illustrations of durable, “dyed in the wool” dictums include the often untrue or unproven perceptions that bactericidal agents are superior to bacteriostatic antibiotics; lengthier durations of therapy result in better outcomes and fewer relapses; and that for a set of specific infections, the antibiotic cannot be given orally but rather must be administered intravenously. It turns out that when thoroughly scrutinized, these customary beliefs are found to have been often forged by misguided concepts and a paucity of evidence. In many instances, the actual basis for how we have historically treated or attempted to prevent infections is confusing at best, often the result of inadequate and outdated scientific knowledge, poor trial design and dependence on use of older, inferior antimicrobial agents.
The way it should be
Simply stated and conceptually speaking, the role of antimicrobials in the prevention or treatment of active infections is to eradicate the causative organisms as quickly and efficiently as possible before they enter tissue, or from the site of an already established active infection. In other words, eliminate the invading bacteria before they have the chance to harm or destroy tissues as a result of pathogen toxin production — or more generically, as a result of local or systemic collateral damage secondary to the immune system’s innate and adaptive inflammatory response. In clinical trials, success is defined in both clinical (eg, end-organ damage, morbidity and mortality, etc.) and microbiologic terms (ie, bacterial eradication). With that goal in mind, it is easy to understand the notion that drugs that are defined as bactericidal are inherently superior to those categorized as bacteriostatic, even though the definitions of their killing power are derived from somewhat arbitrary in vitro laboratory parameters.
Specifically, bactericidal is defined as a minimal bactericidal concentration (MBC) no greater than four times the minimal inhibitory concentration (MIC), and a 1,000-fold (99.9%) reduction in bacterial concentration after 24 hours of growth in the presence of the antimicrobial agent under ideal laboratory growth conditions. However, many antibiotics labeled as bacteriostatic actually satisfy the laboratory bactericidal criteria for certain pathogens, such as clindamycin for Staphylococcus aureus, linezolid for streptococci, and macrolides and chloramphenicol against pneumococci. Furthermore, depending on the actual antibiotic concentration at the infected tissue level, some agents labeled as bacteriostatic according to the MBC/MIC in vitro parameters actually achieve a high enough concentration at the site of infection to rapidly diminish bacterial concentrations, satisfying the prerequisites to earn the designation of “bactericidal.”
In contrast, antimicrobials such as beta-lactams, which enjoy bactericidal status, on occasion may not attain an MBC of greater than four times the MIC at the site of infection and therefore will fail to behave in a bactericidal manner. This specifically occurs when the MIC of the offending pathogen is high even though, according to the values assigned by the Clinical and Laboratory Standards Institute, it falls within the so-called range of susceptibility for that “bug-drug” combination. One such example is when physicians use piperacillin-tazobactam to treat infections caused by gram-negative bacilli with MIC values of 16 to 32 mg/mL, which effectively prohibits this time-dependent beta-lactam drug’s key pharmacokinetic/pharmacodynamic (PK/PD) parameter from being realized — maintaining a concentration of the drug above the MIC of the organism at the site of infection for 40% to 50% of the dosing interval (time > MIC). This scenario is particularly true when the antibiotic is administered as a prolonged infusion, resulting in steady, plateaued drug levels that may not reach drug concentrations at the infection site of at least, ideally, four to five times the MIC, which is essential for time-dependent antimicrobial agents to assert their maximal killing effect.
Besides drug concentrations, other factors that may affect whether or not an antibiotic performs in a cidal or static fashion — most of which are not easily accounted for when treating a specific infection — include the inoculum and growth phase of the bacterial organisms, the physiologic environment at the site of infection (eg, pH, anaerobic vs. aerobic, etc.), as well as the ability of the pathogen to form biofilms. The fact of the matter is that there is no clinical proof of superiority of bactericidal over bacteriostatic antimicrobial agents. A review of dozens of randomized controlled trials has failed to exhibit a significant clinical benefit or greater efficacy of one agent over the other. With that being said, most clinicians would still select a bactericidal antibiotic known to have rapid bacterial killing capability when treating infections in privileged sites that are somewhat protected from immune defenses (ie, meningitis, endocarditis), in immunocompromised hosts (ie, neutropenic fever) or in those instances in which a delay of adequate antimicrobial therapy is unequivocally associated with increased rates of mortality (ie, septic shock).
Duration of treatment
The lack of data from randomized clinical trials, coupled with an underlying fear of potentially increased morbidity, mortality and clinical relapse, are some of the likely factors playing a role in what historically has been a preference for longer durations of antimicrobial therapy. Traditionally, the number of days that make up antimicrobial courses seems to be determined based on multiples of 7, for reasons that Brad Spellberg, MD, interestingly attributes to the Roman Emperor Constantine the Great, who apparently decided almost 17 centuries ago that the week should consist of 7 days. A 7- to 10-day course is also popular for no good reason. The concept of longer treatments would seem to suggest that it is imperative to eliminate each and every last bacterial organism, even though a confirmation of total microbiologic eradication from the site of infection is neither achievable nor frankly necessary — except for easily obtained cultures (eg, blood and urine). As with several customary habits in the day-to-day practice of infectious diseases, unproven anti-infective treatments persist, albeit without established clinical benefit, unless the intervention is shown to be harmful. Consequently, longer courses only serve to provide the practitioner and patient alike with a false sense of security. In other words, “just in case.”
Several studies have compared shortened antibiotic courses to longer traditional treatments. Although generally designed to look at clinical outcome, duration-of-treatment trials studying skin and soft tissue, urinary tract, intra-abdominal, respiratory tract (community and hospital associated) infections and gram-negative bacillary bacteremia (in noncritically ill patients predominantly involving Enterobacteriaceae), for the most part, have demonstrated that courses shortened to 7 or fewer days have proven to be as efficacious as standard, longer treatment durations.
As anticipated, fewer days of treatment translate into decreased overall treatment costs, shorter hospital stays and earlier removal of intravascular lines, thus reducing the risk for secondary infections and adverse events. It is still too early to objectively measure the effect of shorter courses on antimicrobial resistance, though intuitively one would predict a slowing of resistance development because the overprescribing of antibiotics is believed to be one of the major drivers of this phenomenon. Shortened antibiotic courses have also been adopted in infection prevention strategies, with infective endocarditis and surgical prophylaxis (in most cases) now limited to one dose only. Even so, lengths for treatment recommended in the guidelines for endocarditis and meningitis, though never studied in randomized clinical trials involving humans, remain unchallenged to this day.
Unfortunately, the noninferiority of shorter treatment courses to longer courses has mostly been evaluated in cohorts of hospitalized patients, from whom objective data can more easily be collected and measured. The transition to shorter courses of antibiotic treatments in the outpatient setting where most antimicrobials are prescribed would conceivably be an arduous task, much like the ongoing efforts to educate medical practitioners about the perils of treating asymptomatic colonized bacterial sites and acting on laboratory tests that may have no clinical relevance. Nevertheless, this undertaking is in desperate need of action. Because there are no official antimicrobial stewardship programs in the outpatient setting, the onus of spreading the word that “less is more” will in large part be placed in the hands of the infectious diseases practitioner.
The IV vs. oral quandary
Because the bulk of proven or suspected infections is treated in the outpatient setting, most antibiotics are prescribed as oral medications. On the other hand, most hospitalized patients generally receive their antibiotics intravenously, presumably for legitimate medical reasons such as critical illness, nil per os (nothing by mouth) status, compromised gut function, undependable or unpredictable drug bioavailability and the need for specific drugs having no oral formulation. Yet, a large proportion of antibiotics dispensed in the hospital setting intravenously are done so with no clear indication and strictly on the basis of the patient having been admitted to the hospital. However, we can all agree that as long as PK/PD principles are understood and adhered to, which would allow the drug to be delivered in sufficient concentrations at the site of infection to exert its antimicrobial activity, then the degree of bacterial elimination at that site should be no less effective whether or not the antibiotic is given orally or parenterally. In simplistic terms, “the bug does not know how the drug got there.” As a matter of fact, one of the most successful and easily implemented interventions in most hospital antimicrobial stewardship programs has been an automatic switch from IV to oral antibiotics. This commonsense intervention has proven to decrease both IV catheter and hospital admission days.
There is a paucity of available human trial evidence for the treatment of osteomyelitis and endocarditis, but there is unbridled acceptance that such deep-seated infections should be treated only with prolonged IV antibiotic therapy.
Results of the recently published European Oral versus Intravenous Antibiotics for Bone and Joint Infection (OVIVA) trial and the Partial Oral Treatment of Endocarditis (POET) trial have started a discussion about the use of oral antibiotic therapy, at least on a case-by-case basis, for these infections. Conceptually, the use of oral antimicrobial agents with inherently favorable PK properties and potent antimicrobial activity could be expected to perform as well as those delivered intravenously with the caveat that doses should be taken at appropriate intervals. Trimethoprim-sulfamethoxazole given by mouth compared with a parenteral anti-staphylococcal penicillin resulted in equivalent clinical outcomes in a trial involving S. aureus osteomyelitis, and dating back to the mid-1980s, oral ciprofloxacin was found to be highly effective in the treatment of gram-negative bacillary osteomyelitis. Delafloxacin, a relatively new member of the fluoroquinolone class of antimicrobial agents, has excellent in vitro activity against MRSA, as well as more than adequate PK properties to warrant consideration as a potential optional oral therapy for the treatment of MRSA bone infections. Likewise, the new semisynthetic tetracycline (aminomethylcycline) derivative, omadacycline, recently approved for the treatment of community-acquired pneumonia and acute bacterial skin and skin-structure infections, has a broad spectrum of antibacterial activity, including potent anti-MRSA activity, and perhaps could also become an orally administered treatment option.
Understandably, suggesting that endocarditis can be effectively treated with antibiotics by mouth will surely be a “harder pill to swallow” because the consequences of treatment failure would be more severe than in those with bone infections. However, putting aside concerns for the potential adverse effects (eg, tendon rupture, dysglycemia, cardiac Q-T prolongation, confusion, etc.), it is difficult to imagine that oral antibiotic regimens such as high-dose levofloxacin once or twice a day would not be as efficacious as IV ceftriaxone for the treatment of uncomplicated endocarditis involving pathogens such as sensitive viridans streptococci or members of the HACEK group of bacteria. It is hoped that the POET study will open the door to future well-designed clinical trials that further examine the treatment of endocarditis with oral antibiotics. The potential benefits are numerous. The final, albeit likely most difficult hurdle to overcome is antimicrobial therapy for bacterial meningitis and perhaps herpes simplex encephalitis. Could oral agents one day be considered sufficiently effective in specific cases (eg, moxifloxacin for Streptococcus pneumoniae and Neisseria meningitidis)?
Moving forward
On March 28, 1994, the cover of Newsweek magazine warned us of “The end” of antibiotics. On May 31, 2019, the same news periodical took it a step further when it boldly declared on its cover, “The death of antibiotics,” going as far as to outline the causes of death in what can cogently be described as an obituary for antibiotics and in which the authors poignantly alert us to what this means going forward in terms of health care.
Without question, perhaps second only to vaccinations and sanitation, antibiotics have had the greatest significant effect on infectious disease-related morbidity and mortality and life expectancy. Concerns regarding the potential for bacteria to develop resistance to these compounds can be traced as far back as 1945, when the Nobel Prize-winning discoverer of penicillin, Dr. Alexander Fleming, warned of the predictable perils of misuse and abuse of this miracle drug. Optimistically speaking, and if properly incentivized, the pharmaceutical industry, together with academia, will continue to work toward developing new antimicrobial agents with novel mechanisms of action and anti-resistance features, as well as continue to investigate what may be the future of antimicrobial therapy: peptide and phage therapies. Until that time, we must take our current armamentarium of antibiotics off life support by focusing on prescriber education and restricting their indiscriminate and inappropriate use where possible. Uncovering the veil of antibiotic dictums and dogma may be a challenge but a vital and long-overdue necessity. If not done by those of us in the infectious diseases community, then by whom; if not now, then when?
- References:
- Begley S. Newsweek. The end of antibiotics. https://www.newsweek.com/end-antibiotics-185984. Accessed November 8, 2019.
- Freedman DH. Newsweek. The death of antibiotics: We’re running out of effective drugs to fight off an army of superbugs. https://www.newsweek.com/2019/05/31/death-antibiotics-running-out-effective-drugs-fight-superbug-army-1423712.html. Accessed November 8, 2019.
- Iverson K, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1808312.
- Karlowsky JA, et al. Clin Infect Dis. 2019;doi:10.1093/cid/ciz395.
- Kazemier BM, et al. Lancet Inf Dis. 2015;doi:10.1016/S1473-3099(15)00070-5.
- Li HK, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1710926.
- Pankey GA, Sabath LD. Clin Infect Dis. 2004;doi:10.1086/381972.
- Saravolatz LD, Stein GE. Clin Infect Dis. 2019;doi:10.1093/cid/ciy600.
- Wald-Dickler N, et al. Clin Infect Dis. 2018;doi:10.1093/cid/cix1127.
- Wald-Dickler N, et al. Clin Infect Dis. 2019;doi:10.1093/cid/ciy1134.
- Yahav D, et al. Clin Infect Dis. 2019;doi:10.1093/cid/ciy1054.
- For more information:
- Larry M. Bush, MD, FACP, is an affiliate professor of medicine at the Charles E. Schmidt College of Medicine, Florida Atlantic University, and affiliated associate professor of medicine at the University of Miami Miller School of Medicine, JFK Medical Center, Palm Beach County, Florida.
- Donald Kaye, MD, MACP, is a professor of medicine at Drexel University College of Medicine, associate editor of the International Society for Infectious Diseases’ ProMED-mail, section editor of news for Clinical Infectious Diseases and an Infectious Disease News Editorial Board Member.
Disclosures: Bush and Kaye report no relevant financial disclosures.