S63 Increases in Rates of Resistance to Trimethoprim Pentti Huovinen From the Antimicrobial Research Laboratory, National Public Health Institute, Turku, Finland Trimethoprim alone or in combination with a sulfonamide is an effective and relatively inexpensive antibacterial medication. However, a dramatic increase in the rate of resistance to trimethoprim along with high-level resistance to sulfonamides has been seen during the past two decades. The mechanisms of resistance show a remarkable evolutionary adaptation. Downloaded from https://academic.oup.com/cid/article/24/Supplement_1/S63/283547 by guest on 30 September 2021 Trimethoprim and sulfonamides are both synthetic antibacte- those in industrialized countries. The international WHONET rial agents. Sulfonamides were used for the first time in 1932, surveillance program has shown that only 38%-59% of E. coli and trimethoprim was first used in 1962 [1] . Since 1968, tri- isolates and 47%-77% of Klebsiella pneumoniae isolates in methoprim and sulfonamides have been used in combination Latin America and Asia are susceptible, whereas the corre- because of supposed synergistic action [2]. However, combina- sponding rates in the United States and Sweden are 87%-93% tions of trimethoprim and sulfonamides do not have a clear and 77%-91%, respectively [7]. In addition, the rate of fecal clinical synergism [3-5]. Trimethoprim alone has also been carriage of trimethoprim-resistant enterobacteria has been used as prophylaxis for and treatment of urinary tract infec- shown to be high in developing countries [13]. tions [6]. The rate of trimethoprim resistance among S. saprophyticus Trimethoprim and sulfonamides each cover a wide spectrum isolates has been reported to be only 2% [14]. In my previous of bacteria, including urinary tract pathogens (Escherichia coli, study [7], 1% of 186 isolates were resistant to trimethoprim- other Enterobacteriaceae organisms, and Staphylococcus sap- sulfamethoxazole, and 9% of the isolates were resistant to tri- rophyticus) and respiratory tract pathogens (Streptococcus methoprim. More studies are needed to establish the rates of pneumoniae and Haemophilus influenzae); in combination, resistance to trimethoprim and sulfonamides among S. sapro- they have activity against Moraxella catarrhalis, skin patho- phyticus isolates. gens (Staphylococcus aureus), and enteric pathogens (E. coli Enteric pathogens. The increased rate of trimethoprim re- and Shigella species). sistance among Shigella species is one of the most illustrative Figures on the distribution of trimethoprim and sulfonamides examples of the spread of trimethoprim resistance (figure 1). throughout the world are difficult, if not impossible, to obtain This increased resistance has had a clinical impact since rates except from a few countries that publish annual sales [7]. of sulfonamide resistance among Shigella species have been continuously high at 42%-100%. In the 1970s and early 1980s, trimethoprim resistance oc- Spread of Trimethoprim-Sulfonamide Resistance curred in only a few Shigella isolates [7]. In 1983-1984, about Resistant gram-negative bacilli are easily transferred through 4%-17% of these isolates were resistant to trimethoprim or person-to-person contact [8, 9], and colonization occurs readily trimethoprim-sulfamethoxazole; in 1985, 7%-21% were resis- when the normal flora is suppressed by antibacterial agents [10]. tant, and rates of trimethoprim resistance later were as high as Resistant isolates are also easily transferred by travelers even 52% depending on the Shigella species. Most of the isolates when they are not exposed to antimicrobial agents [11, 12]. were resistant to multiple agents, including ampicillin, tetracy- Urinary tract pathogens. In the 1970s, rarely were >10% cline, chloramphenicol, and streptomycin. In addition to the of E. coli isolates from outpatient urine samples resistant to increased resistance in Shigella species, increased rates of tri- trimethoprim. However, reports from the 1980s showed an methoprim resistance among enterotoxigenic E. coli have been increasing frequency; the resistance rates often reached shown [18, 21]. 15%-20%. The rate of trimethoprim or sulfonamide resistance among Resistance rates among gram-negative pathogens in devel- Salmonella species has not increased as fast as that among oping countries have been reported to be clearly higher than Shigella species, although high-level resistance has also been reported [7]. In addition, other enteric bacterial pathogens, like Yersinia species and Aeromonas hydrophila, have been re- ported to be susceptible to trimethoprim/sulfonamide. Grant support: This work was supported by the Sigrid Juselius Foundation, Helsinki. Respiratory tract pathogens. Although trimethoprim-sulfa- Reprints or correspondence: Dr. P. Huovinen, Antimicrobial Research Labo- methoxazole has been widely used as treatment of respiratory ratory, National Public Health Institute, P.O. Box 57, FIN-20521 Turku, Fin- tract infections, the major respiratory tract pathogens (. in- land. fluenzae, S. pneumoniae, and M catarrhalis) have remained Clnl Inft 1997; (Sppl 1S3- © 1997 by The University of Chicago. All rights reserved. rather susceptible. The rate of resistance to trimethoprim or 1058-4838/97/2401-0037$02.00 sulfonamides among H. influenzae isolates has varied from a S uoie CID 1997; (Su 1 5— — r 1 Iusaie eese- aio o e eeome o i- meoim o imeoim-su- Downloaded from https://academic.oup.com/cid/article/24/Supplement_1/S63/283547 by guest on 30 September 2021 oamie esisace i Shigella secies i iee as o e — wo ees A— eoe aa aae om [15-] esec- iey 1— 0 tll 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 Yr ew ece o 1 i Sai [-] e ae o esisace gees ae ee caaceie i gam-egaie aceia a o imeoim-suameoaoe amog muiesisa oe as ee caaceie i S. aureus. Mos o ese gees S. pneumoniae isoaes as age om 1 o [5] ae asee y eicie iego mecaisms cae cas- owee eicii-susceie S. pneumoniae as eaie is sees (ae 1 susceiiiy o is comiaio [] e ae o imeoim Aoug e ume o eie aseae gees o i- o suoamie esisace amog M catarrhalis as ee e- meoim esisace is ig a suie asmi-oe esis- oe o e ee owe a ose amog S. pneumoniae a ace o suoamies ca e accoue o y su// a su/// H. influenzae [ 7] [7] I sie o e imiise use o suoamies e geeic Staphylococci. Meicii-esisa Staphylococcus aureus eemias o suoamie esisace ae si ey commo a coaguase-egaie sayococci ae oe esisa o i- is esisece ca e eaie y ey eicie eices meoim a suoamies wi esisace equecies o -9 [ 9] bl 1 aseae geeic eemias o imeoim esis- ace Gn Endn rthpr nd Slfnd oyeie asmi a/o tn amiy ye Cassee eg asoso imeoim esisace is meiae y aee iyooae 1 I, dhfrl Yes 157 7 M15 1 V, dhfrV Yes 157 MO eucase i aceia iyooae eucase is a esseia 1 VI, dhfrVl, Yes 157 UK7 eyme i a iig ces imeoim is sucuay aao- 1 VII, dhfrVII Yes 157 Tn5086 gous o iyooae eucase a is comeiie iiio 1 I dhfrlb Yes 157 Tn4132 iyooae eucase i umas is esisa o imeoim 2 IIa dhfrlla Yes 7 7 wic is e asis o is aceia seeciiy 2 II dhfrllb Yes 7 3 2 IIc, dhfrllc Yes 7 Tn5090 Suoamie esisace is meiae y aee iyoeo- III dhfrIII o 1 A1 ae syase; is eyme caayes e omaio o iyo- I ND ND UK113 eoic aci i aceia a some eukayoic ces ike Pneu- VIII, dhfrVIII o 19 Tn5091 mocystis carinii a Plasmodium falciparum [3 31] IX, dhfrlX o 177 C1 Suoamies ae comeiie iiios o e ockig o i- X, dhfrX o 1 GO1 XII, dhfrXII Yes 15 E1 yoeoae syase ia oae iosyesis i e aceia III ND ce [] IIIe ND ND Plasmid-encoded trimethoprim and sulfonamide resistance. Si (Staphylococcus aureus) ND 159 Tn4003 e ume o gees o asmi-ecoe imeoim-esis- a iyooae eucase is aeay 17 Siee o ese OE aa aae om [7] = o eemie CI 1997; (Su 1 Icease aes o imeoim esisace S5 o ase; agai e iegos usuay cay e gees o 1 Muay E esime E uo Emegece o ig-ee imeo- suoamie esisace im esisace i eca Escherichia coli, uig oa amiisaio o Chromosomaltrimethoprimandsulfonamideresistance. imeoim o imeoim-suameoaoe Eg Me 19; Ac- 313-5 quie comosoma imeoim esisace is o ey im- 13 ese SC e ia M Wag Scae I iag Oie e oa ciicay is ye o imeoim esisace is mei- caiage o Escherichia coli esisa o aimicoia ages y eay ae y muaios i e gee o iyooae eucase cie i oso i Caacas eeuea a i Qi u Cia Comosoma imeoim esisace is ou i . influenzae Eg Me 199; 335-9 [3] E. coli [33] a S. pneumoniae [3] I aiio eoge- 1 Sceie iey Susceiiiy o uie isoaes o Sayococcus saoyicus o aimicoia ages aoogy 1991;3135- Downloaded from https://academic.oup.com/cid/article/24/Supplement_1/S63/283547 by guest on 30 September 2021 ous esisace o imeoim occus i may iee ace- 15 Goss ea E Wa owe ug esisace i Shigella ia secies suc as Lactobacillus, Pediococcus cerevisiae, dysenteriae, Shigella flexneri a Shigella boydii i Ega a Waes Bacteroides fragilis, a Clostridium secies [35] Como- iceasig iciece o esisace o imeoim Me [Ci es] soma suoamie esisace is kow o occu i Neisseria 19;7- meningitidis [3] a S. pneumoniae [37] 1 aoea M o issemiaio o imeoim-esisa coes o Shigella sonnei i ugaia Iec is 199;159-53 17 eikki E Siioe A akoa M ig M SusOm uoie Icease o imeoim esisace amog Shigella secies 1975 - Conclusions 19 aaysis o esisace mecaisms Iec is 199; 11 1- uig e as ew yeas a amaic icease i e ae 1 Cakaeomoako A Eceeia ayo Seiwaaa eksomoo o imeoim esisace aog wi ig-ee suoamie U imeoim-esisa Shigella a eeooigeic Escherichia coli esisace as ee see e geeic ikage o gees o sais i cie i aia eia Iec is 197; 735-9 imeoim a suoamie esisace agey iaiaes e 19 eis M Saam MA ossai MA e a Aimicoia esisace o agume o usig e comiaio o imeoim a a Shigella isoaes i agaes 193-199 iceasig equecy o sais muiy esisa o amicii imeoim-suameoaoe suoamie o ee e eeome o esisace I ai- a aiiic aci Ci Iec is 199;1155- io ee ae o sigs a eimiaio o e seecio eec 20.