• ANTIBIOTICS
• ANTIMICROBIAL RESISTANCE
• AZITHROMYCIN
• BACTERIAL INFECTION

Where did it all go wrong? Azithromycin, a second generation macrolide antimicrobial, has been demonstrated to be highly efficacious both in vitro (low minimum inhibitory concentration (MIC)) and in vivo against the common bacterial STIs Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Mycoplasma genitalium (MG) and has good treponemicidal activity in animal studies.1 ,2 ^{w1 w2} What's more its long half-life particularly intracellularly enabled it to be administered as single-dose directly observed therapy, the preferred dosing schedule for STIs where poor compliance, and thus potential reduced efficacy, was considered a major concern with multidose regimens.3 Indeed its efficacy against chlamydia was considered to be so good, a test of cure was not considered necessary.

I argue that the evidence indicates that azithromycin 1 g is no longer at least 95% effective in achieving microbiological cure for bacterial STIs as recommended by WHO for first-line treatment and therefore should not be used for treatment.4 In addition, as monotherapy, it is likely to be doing harm by inducing macrolide antimicrobial resistance. First, it is necessary to consider the mode of action and pharmacokinetics of azithromycin given as a 1 g stat regimen (figure 1) and its mechanism of action; second, the mechanism of macrolide antimicrobial development and third, reappraise the evidence of efficacy in vivo against the common bacterial STIs, NG, syphilis, CT, MG and non-gonococcal urethritis (NGU).

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Figure 1

Anticipated serum and tissue concentrations after administration of azithromycin 1 g (adapted from Foulds and Johnson)1 and hypothetical change in serum concentration 5–10 days postadministration. Courtesy of Mr Peter Greenhouse FRCOG. CT, Chlamydia trachomatis; MG, Mycoplasma genitalium; MIC, minimum inhibitory concentration.

Azithromycin is a bacteriostatic antibiotic and duration of exposure to levels >MIC 90 are likely to be important in determining microbiological cure, particularly if the micro-organism is slow growing.5 ,6 Although there is limited evidence on the pharmacokinetics of azithromycin in genitourinary tract secretions, it is not unreasonable to consider serum concentrations as a proxy for these. Thus 1 g is present intracellularly for at least 10 days at an MIC >90% for chlamydia but probably only 6 days extracellularly for MG which replicates, slowly, both intracellularly and extracellularly (figure 1).1 ,2 ,7 Due to the slow clearance of azithromycin surviving bacteria could potentially be exposed to sub-MIC levels for prolonged periods of time which may promote emergence of antimicrobial resistance.7

A single mutation in the 23S rRNA gene confers antimicrobial resistance to azithromycin.5 ,7 Spontaneous genomic mutations are constantly occurring in bacteria, such that it is likely single nucleotide changes that confer high-level antimicrobial resistance would also be likely to be randomly present in bacterial populations prior to treatment—heteroresistance.5 ,8 Bacteria hunt in packs and if you have one STI you are more likely to have another, which may not be apparent either because the infection is incubating and undetectable (syphilis), or is not detected because it has not been tested for. Thus treatment of one bacterial STI increases the risk of other bacterial STIs being exposed to azithromycin.

NG, using all known mechanisms of antimicrobial resistance, has developed antimicrobial resistance to all drugs previously and currently recommended for empirical monotherapy of gonorrhoea.9 Azithromycin as monotherapy is not recommended and dual antimicrobial therapy is now the standard of care.9 ^W1 Indeed recently there was an outbreak of azithromycin resistance NG in the North of England.^W3

Azithromycin antimicrobial resistance is now endemic in syphilis and azithromycin monotherapy as first-line therapy is not recommended.^{w1 w2} Macrolide antimicrobial resistance can easily develop following exposure.^{W1 W2} A recent report from Shanghai, where 95% of isolates had macrolide antimicrobial resistance, suggested that the development of high levels of macrolide antimicrobial resistance may have at least partially been a consequence of exposure to azithromycin or erythromycin prescribed for other bacterial infections.10

Although azithromycin 1 g treatment of chlamydia in a recent meta-analysis was demonstrated to be 94% effective, this dropped to ∼90% in men with chlamydia urethritis and <90% in rectal infection.11 Recent evidence strongly suggests the majority of women with genitourinary infection are coinfected in the rectum.12–14 Whether treatment failure from rectal infection with subsequent auto-inoculation of the genitourinary tract contributes to high reinfection rates in women at 3 months when treated with azithromycin 1 g is unknown but theoretically possible.15

MG is an emerging STI with a significant morbidity, causing NGU, cervicitis (notably postcoital bleeding), probably pelvic inflammatory disease (PID) and facilitates HIV transmission.2 ,16 As no diagnostic tests are widely available commercially, management is often syndromic using azithromycin 1 g.^{W1 W4} Evidence is accumulating that azithromycin 1 g is only 87% efficacious in wild type infection and >10% of wild type infections develop macrolide antimicrobial resistance following treatment.5 ,17 ,18 In 2013, 1.4 million CT infections were treated in the USA (http://www.cdc.gov/std/stats13/chlamydia.htm.pdf) of which probably at least 3% were coinfected with MG, if 90% were treated with azithromycin and one assumes 12% developed antimicrobial resistance this would equate to production of 4500 separate macrolide-resistant isolates, annually, which in turn would be transmissible.16 ,17 Taken together this could explain the observations by Lau et al that from 2009 the efficacy of azithromycin 1 g has dropped from 87% to 67% and why MG macrolide antimicrobial resistance appears to be increasing over time and is now prevalent worldwide ranging from 20% to 100%.5 ,16 ,18

In conclusion, azithromycin as first-line monotherapy is no longer recommended for NG and syphilis. Although recommended for chlamydia and NGU, its efficacy in women may be <95% and its widespread use for treating chlamydia, NGU and their contacts is probably driving the increasing prevalence of MG antimicrobial resistance. Currently only two widely available antimicrobials can effectively treat MG, second-generation macrolides and moxifloxacin.5 Resistance to moxifloxacin is also emerging and it is therefore no surprise that dual macrolide and quinolone antimicrobial resistance isolates have been identified which are in effect untreatable with currently available antibiotics.5

In my opinion, this is an excellent example of how mankind is managing to squander yet another precious resource. Azithromycin, a good antibiotic, can no longer be used for treating syphilis and this is likely to be the case for MG in the not too distant future. Commercial tests for MG will become more widely available from 2016 in Europe and 2017 in USA (personal communication Hologic). Continuing to use azithromycin 1 g for the treatment of NGU and chlamydia with its advantages as single-dose directly observed therapy and being cheap is storing up problems which will become all too evident when testing for MG becomes clinically widely available.