Do tetracyclines have the potential to reduce the risk of Clostridium difficile infection?

KEYWORDS:

• Clostridium difficile infection
• antibiotics
• tetracyclines
• doxycycline
• microbiome
• microbiota
• dysbiosis
• infectious diseases

Despite advances in antibiotic stewardship, hand hygiene, isolation practices, and dedicated cleaning protocols in hospitals; Clostridium difficile remains the leading health-care-associated pathogen in the United States, accounting for over 450,000 cases a year [1]. Interestingly and unfortunately, Clostridium difficile infection (CDI) is no longer just a nosocomial pathogen and does not affect just the elderly who are hospitalized, but affects younger people without comorbidities, prior hospitalization or even antibiotics, and is now being seen even in the pediatric population. These infections not only lead to significant morbidity, low quality of life and loss of work days but are also associated with high mortality with an estimated 29,300 deaths annually in the United States [1]. Similar trends have been seen in Europe and the rest of the world. The hypervirulent C. difficile strain – ribotype 027 has been associated with outbreaks in England, Netherlands, and many other hospitals throughout Europe [2,3]. Data from Germany demonstrates that the incidence of CDI in hospitals are 2–4 times more than nosocomial infections caused by methicillin resistant S. aureus [4]. It has been shown that 48% of all gastrointestinal infections in European hospitals are related to C. difficile and up to 7.7% of all health-care-associated infections are secondary to CDI [5]. The European Centre for Disease Prevalence and Control (ECDC) recognizes CDI as a priority among healthcare associated infections in Europe.

Well-established and common risk factors for CDI include older age, comorbidities, inflammatory bowel disease, health-care exposure, hospitalization, antibiotic exposure, and proton-pump inhibitors [6,7]. Antibiotics are the commonest risk factor for development of CDI with about 5–10% patients with antibiotic exposure developing CDI. This risk stays for at least 12 weeks, and further increases with high anti-anaerobic spectrum, number of antibiotics, duration along with number of courses, interval between courses and overall spectrum of activity [8,9]. A healthy colonic microbiome is highly susceptible to the effects of systemic antibiotics, and both broad and narrow spectrum systemic antibiotics decrease colonization resistance by disrupt the host microbiota. Certain antibiotics such as fluoroquinolones, clindamycin, broad-spectrum cephalosporins and penicillins are associated with a higher risk of CDI compared to tetracyclines, aminoglycosides, metronidazole or vancomycin [8,10]. The other major risk factor for CDI is increasing age and presence of systemic comorbid conditions. These patients generally are predisposed to other infections, such as urinary tract infections or upper respiratory infections [8].

A common clinical question that treating physicians are posed in their daily practice is the choice of antibiotics for systemic infections in patients who are at a higher risk for CDI or for those with a recent or remote history of CDI to minimize risk of future CDI, protect against CDI, while still be effective to treat the underlying infection. There are no large well-done studies that answer this question but studies have suggested that tetracyclines as a class of antibiotics may confer a lower risk of CDI when compared to other antibiotics. A small observational case-control study demonstrated a 27% decreased CDI risk in the doxycycline plus ceftriaxone arm compared to ceftriaxone alone [11]. In contrast, another study showed no protective effect of tetracyclines on the risk of CDI [12].

Tetracyclines with doxycycline being the commonest, have activity against both gram-positive and gram-negative bacteria. Interestingly, tetracyclines also have anti-inflammatory properties that may contribute to their therapeutic benefits [13]. Tetracyclines have excellent bioavailability and tissue penetration, and bind to the bacterial 30s ribosomal subunit and inhibit protein synthesis [14]. Details on US FDA approved indications for tetracyclines and doxycycline are outlined in Table 1 [15].

Table 1. Approved indications for tetracycline and doxycycline.^a

Tetracyclines are indicated in the treatment of infections caused by susceptible strains of the designated organisms in the conditions listed below:

Upper respiratory tract infections caused by Streptococcus pyogenes, Streptococcus pneumoniae, and Hemophilus influenzae Lower respiratory tract infections caused by Streptococcus pyogenes, Streptococcus pneumoniae, Mycoplasma pneumoniae, and Klebsiella sp. Skin and soft tissue infections caused by Streptococcus pyogenes Infections caused by rickettsia including Rocky Mountain spotted fever, typhus group infections, Q fever, rickettsial pox Psittacosis caused by Chlamydophila psittaci Infections caused by Chlamydia trachomatis such as uncomplicated urethral, endocervical or rectal infections, inclusion conjunctivitis, trachoma, and lymphogranuloma venereum Granuloma inquinale caused by Klebsiella granulomatis Relapsing fever caused by Borrelia sp. Bartonellosis caused by Bartonella bacilliformis Chancroid caused by Hemophilus ducreyi Tularemia caused by Francisella tularensis Plague caused by Yersinia pestis Cholera caused by Vibrio cholerae Brucellosis caused by Brucella species (tetracycline may be used in conjunction with an aminoglycoside) Infections due to Campylobacter fetus As adjunctive therapy in intestinal amebiasis caused by Entamoeba histolytica. Urinary tract infections caused by susceptible strains of Escherichia coli, Klebsiella, etc. Other infections caused by susceptible gram-negative organisms such as E. coli, Enterobacter aerogenes, Shigella sp., Acinetobacter sp., Klebsiella sp., and Bacteroides sp. In severe acne, adjunctive therapy with tetracycline may be useful.

When penicillin is contraindicated, tetracyclines are alternative drugs in the treatment of the following infections:

Syphilis and yaws caused by Treponema pallidum and pertenue, respectively Vincent’s infection caused by Fusobacterium fusiforme Infections caused by Neisseria gonorrhoeae Anthrax caused by Bacillus anthracis Infections due to Listeria monocytogenes Actinomycosis caused by Actinomyces species Infections due to certain Clostridium species

Doxycycline is a tetracycline-class antimicrobial indicated for:

Rickettsial infections Sexually transmitted infections Respiratory tract infections Ophthalmic infections Anthrax, including inhalational anthrax (post-exposure) Alternative treatment for selected infections when penicillin is contraindicated Adjunctive therapy in acute intestinal amebiasis Severe acne Prophylaxis of malaria

^aTable reused from the FDA tetracycline and doxycycline drug label

The C. difficile bacterium appears to be susceptible to tetracyclines and this decreased risk of CDI may be due to this in vitro activity of tetracyclines against C. difficile [16]. In a study, the majority (84%) of C. difficile isolates had a low minimum inhibitory concentration of ≤0.25 mg/L to tetracyclines [16]. The overall resistance rates of C. difficile isolates to tetracyclines are low (9.2%) [17]. Tetracyclines appear to be microbiota sparing compared to other antibiotics. A recent assessment of soil microbiota response to antibiotics concluded that tetracyclines had a shorter effect on disruption of the soil microbiome compared to other antibiotics [18]. A mouse study demonstrated that tetracyclines have a shorter dysbiosis duration than other antibiotics [19]. Tigecycline, a tetracycline has been used to treat refractory CDI [20]. The exact mechanism by which tetracyclines confer this decreased risk remains unclear.

With a hypothesis that tetracyclines may be associated with a decreased risk of CDI compared to other antibiotics, a systematic review and meta-analysis was conducted [21]. A comprehensive search of several databases including but not limited to Ovid, Cochrane, Medline, Web of Science and Scopus revealed case-control studies and cohort studies but no randomized controlled trials that compared the risk of CDI with tetracyclines compared to other antibiotics or no antibiotics [21]. Among case-control studies, cases were defined as patients with CDI and controls were defined as patients with no CDI and that evaluated the occurrence of CDI with tetracyclines compared to other antibiotics (no tetracyclines) or no antibiotics.

A systematic-review and meta-analysis of six studies of which four were case-control and two were cohort was performed which demonstrated that tetracyclines were associated with a statistically significant 38% decreased risk of CDI compared with other antibiotics. There was significant heterogeneity among the studies (due to different patient populations, study settings and comparison groups) with an I² of 53% [21]. Interestingly, when analyses were performed based on study design, there was a decreased risk of CDI among the cohort studies but not in case-control studies. A smaller sample size could explain this lack of protection seen in case-control studies. There was a significant decrease in the risk of CDI with tetracyclines in the studies using a clinical definition rather than administrative diagnostic codes [21]. Although administrative codes are sensitivity to diagnose CDI, cases diagnosed clinically with laboratory confirmation are more reliable. Tetracyclines were associated with a lower risk of CDI in studies with inpatients only but not in studies that combined inpatients and outpatients [21]. The protective effect of tetracyclines may be higher in the high-risk inpatients compared to the low-risk outpatient population.

In addition, subgroup analyses separating specific tetracyclines revealed that doxycycline was led to a 45% decreased risk of CDI when compared with non-tetracycline antibiotics [21]. The most commonly used tetracycline is doxycycline which has advantages including better absorption and tissue distribution, longer half-life (necessitating less frequent dosing), and less photosensitivity. Doxycycline has atypical coverage against Borrelia, Chlamydia, Entamoeba, Leptospira, Mycoplasma, Rickettsia, and Vibrio (Table 1). Additionally, it is recommended that for outpatient treatment of community-acquired pneumonia, tetracyclines can be used instead of macrolides as monotherapy in previously healthy patients and can also be used as part of combination therapy (e.g. with beta-lactam antibiotics) in patients with comorbidities [22,23].

There remain several unanswered questions. The available studies are observational and vary in several ways, including study design, patient population, North American pulsed-field gel electrophoresis type 1 status of the infection, method of CDI diagnosis, time period of prior antibiotic exposure, and dose and duration of tetracycline and antibiotic use and adjusting for confounders. Since the mechanism is not completely elucidated, microbial resistance patterns are ever evolving and there is a significant fecal concentration of tetracyclines seen even when low doses are used, these findings should be taken with caution.

Therefore, tetracyclines (particularly doxycycline) are likely associated with a decreased risk of CDI compared to other antibiotics. There is a need for a large comparative study comparing tetracyclines to other antibiotics to assess mitigation of the risk of primary as well as recurrent CDI. At this time, when indicated tetracyclines may be considered as antibiotics of choice for patients at risk of developing or with a history of CDI.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

The manuscript was not funded.