Pumping Azithromycin

abstract & commentary

Synopsis: Nearly half of Neisseria gonorrhea strains isolated from patients in Uruguay expressed the mtr phenotype, with increased antibiotic efflux, with reduced susceptibility to azithromycin.

Source: Zarantonelli L, et al. Decreased azithromycin susceptibility of Neisseria gonorrhoeae due to mtrR mutations. Antimicrob Agents Chemother 1999;43:2468-2472.

Azithromycin is becoming an increasingly popular and cost-effective agent for use in sexually transmitted diseases (STDs), especially in developing countries with Neisseria gonorrhea with increasing rates of resistance to other agents. Zarantonelli and colleagues in Uruguay examined the antimicrobial susceptibility of 51 consecutive isolates obtained from males with uncomplicated acute gonococcal urethritis. As anticipated, many of the isolates were multidrug resistant. Two-thirds demonstrated chromosomally mediated resistance to tetracycline; seven (13.7%) additional isolates had high-level plasmid-mediated resistance to tetracycline.

In addition, clinical isolates with decreased susceptibility in vitro to azithromycin were readily detected. While the MICs for azithromycin remained well within the "susceptible" range (0.32-0.5 mcg/mL) and none were greater than 0.5 mcg/mL, further analysis revealed that the mtr phenotype was expressed by 23 (45%) of the strains. Nearly half the strains with broadly decreased susceptibility to erythromycin, azithromycin, and tetracycline exhibited the mtr phenotype. The mtr phenotypic isolates were generally only ~1/10 as susceptible to azithromycin as the non-Mtr strains.

Comment by Carol A. Kemper, MD

Based on its exceptionally long half-life and excellent tissue penetration, azithromycin has become an increasingly useful agent in the treatment of STDs, especially in developing countries with a high prevalence of penicillin- and tetracycline-resistant N. gonorrhea. Unfortunately, azithromycin resistance is emerging in many of these countries, possibly due to the increasing presence of the mtr resistance phenotype. While some sources describe the mtr resistance phenotype as conferring "reduced permeability" of the cell envelope, the mtr gene actually appears to encode a transcription repressor that modulates expression of an mtr operon. Mutations in the mtr gene that decrease the level of expression of mtrR allow overexpression of an efflux pump. This energy-dependent efflux pump is responsible for the export of all kinds of hydrophobic substances, including dyes, detergents, and antibiotics such as tetracycline, erythromycin, and azithromycin.

In general, the Mtr phenotype of N. gonorrhea raises the MIC two to-fourfold, which is still within the "susceptible" range, but there is concern that additional mutations outside of the mtr gene could further reduce its susceptibility and render azithromycin useless. Clinical failure has been documented in patients with gonorrhea receiving 1.0 gram of azithromycin despite azithromycin MICs of 0.125-0.25. Tapsall has suggested that MIC data may not apply gonococci and should not be relied upon to predict success.1

The mtr phenotype has been widely detected and now accounts for ~50% of isolates in places like Kenya and Uganda, as well as countries in South America. Studies also suggest that the mtr phenotype is more prevalent in homosexually active men compared with heterosexual men or women, possibly due to increased exposure to hydrophobic substances or antibiotics. There is also concern that the singularly long half-life of azithromycin, which provides a significant advantage in the treatment of such obligate intracellular organisms as chlamydia, may have the unfortunate result of increased selective pressure for resistance in gonococci.2

References

1. Tapsall JW, et al. Failure of azithromycin therapy in gonorrhea and discorrelation with laboratory test parameters. Sex Transm Dis 1998;25:505-508.

2. Young H, et al. Azithromycin and erythromycin resistant Neisseria gonorrhoeae following treatment with azithromycin. Int J STD AIDS 1997;8:299-302.

Which of the following statements is false? The mtr phenotype seen in strains of Neisseria gonorrhea:

a. results in overexpression of a hydrophobic efflux pump.

b. reduces the susceptibility of the organism to tetracyclines, macrolides, and azalides.

c. increases the susceptibility of the organism to quinolones.

d. can be detected in up to 50% of isolates in developing countries.