Continuous surveillance of antibiotic resistant Neisseria gonorrhoeae : A tool to forewarn emerging trends in resistance

A DE CREASE IN THE IN CI DENCE OF GON OR RHOEA cases has been re ported in the past 20 years by sev eral west ern coun tries (1-4). Sta tis tics in Can ada show this de cline start ing in the early 1980s, from a peak of 56,336 cases re ported in 1981 to an es ti mated 4500 cases in 1994, a 92% de crease in the to tal number of cases over a 13year pe riod. Al though the in ci dence of gon or rhoea cases is drop ping, there is a con stant in crease in the number of re sis tant iso lates that par al lels the in tro duc tion of new an ti bi ot ics. The abil ity of the gono coc cus to de velop re sis tance to an ti bi ot ics has been shown re peat edly over the years. As early as 1976, chro mo somally me di ated re sis tance to peni cil lin and later mul ti ple re sis tance to other an ti bi ot ics were re ported along with plas mid me di ated re sis tance to peni cil lin (1,5-7). As a re sult, tet ra cy cline was cho sen as the al ter na tive treat ment for penicillinaseproducing Neis se ria gon or rhoeae (PPNG) un til tet ra cy cline re sis tant strains were char ac ter ized in the United States in 1985 and later re ported world wide (8-11). Cur rently, thirdgeneration cephalosporins and qui nolones are the most ef fec tive anti microbials against gon or rhoea (12,13). The de tec tion of these sus cep ti bil ity changes and the ac cu rate pre dic tion of up com ing re sis tance trends are pos si ble only if a con tinu ous sur veil lance pro gram is in ef fect.


THE NA TIONAL SUR VEIL LANCE PRO GRAM FOR AN TI BI OTIC RE SIS TANCE OF N GON OR RHOEAE
The Na tional Labo ra tory for Sexu ally Trans mit ted Diseases (NLSTD), Labo ra tory Cen tre for Dis ease Con trol in Ottawa has con ducted sur veil lance of an ti bi otic re sis tant N gon or rhoeae since 1976.In the early stages of the pro gram, strains pre vi ously iso lated and iden ti fied by pro vin cial labo rato ries were char ac ter ized by an ti bio gram, auxo type, b-la ctamase pro duc tion and plas mid fin ger print ing.With the de vel op ment of new typ ing tech niques the ar ray of pa rameters for char ac teri za tion in creased to in clude se ro typ ing with mono clonal an ti bod ies; con fir ma tion of plas mid me di ated resis tance to tet ra cy cline with DNA probes; ri bo typ ing; pulsedfield gel elec tro pho re sis; and mul ti lo cus en zyme elec tro phore sis (14)(15)(16)(17).These tech niques gen er ate a meas ure of variabil ity that, when com bined with epi de mi ol ogi cal data, al lows for the de ter mi na tion of out breaks.In ad di tion, the NLSTD program pro vides an ex ten sive and com plete da ta base that allows for on going analy sis of gono coc cal re sis tance trends in Can ada.
In 1994 there were 4500 re ported cases of gon or rhoea, rep re sent ing a 47.8% de cline in the number of cases compared with those in 1992 (9421 cases) and a 78.3% drop since 1988 (20,736 cases).How ever, the per cent age of an tibi otic re sis tant iso lates (plas mid and chro mo somally me diated) is in creas ing.The per cent age of re sis tant iso lates al most dou bled to 30.8% in 1994 from 16.5% in 1993, a sixfold in crease since 1988 (Ta ble 1).
Dur ing this pe riod a shift in plas mid me di ated re sis tance, re flect ing the se lec tive pres sure of the an ti bi ot ics used for treat ment, was ob served.Un til 1992, the ma jor ity of iso lates tested were PPNG: 77.7% in 1990, 43.9% in 1991 and 40.9% in 1992.Sub se quently, most iso lates have ex hib ited plas mid me di ated tet ra cy cline re sis tance (TRNG) alone or in com bi nation with peni cil lin re sis tance (PP/TRNG): 43.3% TRNG in 1993, 71.4% in 1993 and 77.9% in 1994 (Ta ble 2).All but six of the 17,225 iso lates tested since 1976 were sus cep ti ble to spectino my cin (mini mum in hibi tory con cen tra tion [MIC] less than 128 mg/L).This steady level of sus cep ti bil ity to spec tino my cin ex hib ited by the gono coc cus may re sult from this an ti bi otic be ing rec om mended as al ter nate and not as first-line treatment.
These data, col lected by the NLSTD Sur veil lance Pro gram, were used to sup port re vi sions to the Ca na dian treat ment guide lines for sexu ally trans mit ted dis eases in 1992 (12).In the re vised treat ment guide lines, the rec om mended ther apy for gono coc cal in fec tions is cef tri ax one, ce fixime or ciprofloxa cin (spec tino my cin al ter na tively), with tet ra cy cline for pos si ble con cur rent chla my dial in fec tion.
Since the im ple men ta tion of the new treat ment guide lines, N gon or rhoeae has been closely moni tored for any changes in sus cep ti bil ity pat terns to both cef tri ax one and cipro floxa cin.To date all iso lates tested are sus cep ti ble to cef tri ax one (MIC 0.25 mg/L or less).Among these iso lates, there are mi nor differ ences in sus cep ti bil ity lev els de pend ing on the strain charac ter is tics.Thus, iso lates char ac ter ized aschro mo somally me di ated re sis tant (CMRNG) to an ti bi ot ics have higher MIC 50 and MIC 90 to cef tri ax one (0.008 and 0.032 mg/L, re spec tively) com pared with iso lates char ac ter ized as PPNG, TRNG or suscep ti ble to other an ti bi ot ics (MIC 50 of 0.002 mg/L and MIC 90 of 0.004 mg/L).
Cur rently, there are con cerns with the trend to wards quinolone re sis tance; spe cifi cally, re sis tance to cipro floxa cin.Since 1989, 143 N gon or rhoeae iso lates with re duced suscep ti bil ity to cipro floxa cin (MIC 0.125 mg/L or greater) have been char ac ter ized in Can ada.Of these, 13 iso lates had a cipro floxa cin MIC of 1.0 mg/L or greater.To date, these strains can only be char ac ter ized as sus cep ti ble or hav ing re duced sus cep ti bil ity to cipro floxa cin be cause the defi ni tions for moder ate sus cep ti bil ity or re sis tance to cipro floxa cin have not been es tab lished (18).Eighty-one per cent of these iso lates (116 of 143) were also re sis tant to other an ti bi ot ics: 55.2% were CMRNG and 25.9% were PPNG and/or TRNG.The re maining 27 iso lates (18.9%) were sus cep ti ble to all other an ti bi otics tested.Simi larly, iso lates of N gon or rhoeae with even higher re duced sus cep ti bil ity to cipro floxa cin (up to 32 mg/L) have re cently been re ported world wide (19-22, un pub lished data).
The emer gence of N gon or rhoeae ex hib it ing re duced suscep ti bil ity to cipro floxa cin, a qui nolone rec om mended as primary ther apy for treat ment, dem on strates again the ef fects of se lec tive pres sure of an ti bi ot ics on the gono coc cus.There have al ready been re ports of treat ment fail ure with the rec ommended doses of cipro floxa cin.Bir ley et al (21) re ported treatment fail ure in a case of gon or rhoea caused by a strain with a cipro floxa cin MIC of 16 mg/L.This trend of re duced sus cep tibil ity to qui nolones will likely evolve to to tal re sis tance.
Cur rently, cef tri ax one, ce fixime and cipro floxa cin (spectino my cin al ter na tively) re main the most ef fec tive pri mary treat ments for un com pli cated gon or rhoea.The emerg ing decrease in sus cep ti bil ity to cipro floxa cin con firms the need for ef fec tive sur veil lance pro grams.Con tin ued moni tor ing of an timi cro bial sus cep ti bili ties is es sen tial for the early de tec tion of emerg ing re sis tance, for the for mu la tion of ef fec tive treat ment guide lines and, fi nally, to aid in the evalua tion of newer an ti biot ics as pos si ble al ter nate thera pies.
AC KNOW LEDGE MENTS: I thank the pro vin cial pub lic health labo rato ries, other labo ra tory cen tres and pro vin cial epi de mi olo gists through out Can ada for send ing strains and for sup ply ing clini cal and epi de mi ol ogi cal data.I also thank Maria Car ballo, Mari elle Pauzé and Stepha nie Hickey for their tech ni cal sup port and help in the prepa ration of this manu script.

TA BLE 1 To tal bur den of re sis tance ex hib ited by Neis se ria gon or - rhoeae iso lates in Can ada
Mimi num in hibi tory con cen tra tion 2.0 mg/L or less to one or more an ti bi ot ics *

TA BLE 2 Plasmid-mediated re sis tant Neis se ria gon or rhoeae in Can ada
PPNG Penicillinase-producing N gon or rhoeae; TRNG Plas mid me di ated tet racy cline re sis tance; PP/TRNG Tet ra cy cline re sis tance com bined with peni cil lin re sis tance