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 Cl n l Inf t 1997; (S ppl 1 S 3- © 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 uo i e CID 1997; (Su 1
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ime o im esis a ce is me ia e y a e e i y o o a e 1 I, dhfrl Yes 157 7 M 15
1 V, dhfrV Yes 157 MO e uc ase i ac e ia i y o o a e e uc ase is a esse ia 1 VI, dhfrVl, Yes 157 UK 7 e yme i a i i g ce s ime o im is s uc u a y a a o- 1 VII, dhfrVII Yes 157 Tn5086 gous o i y o o a e e uc ase a i s com e i i e i i i o 1 I dhfrlb Yes 157 Tn4132
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IIc, dhfrllc Yes 7 Tn5090 Su o ami e esis a ce is me ia e y a e e i y o e o- III dhfrIII o 1 A 1 a e sy ase; is e yme ca a y es e o ma io o i y o - I UK11 3 e oic aci i ac e ia a some euka yo ic ce s ike Pneu- VIII, dhfrVIII o 1 9 Tn5091 mocystis carinii a Plasmodium falciparum [3 31] IX, dhfrlX o 177 C 1
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XII, dhfrXII Yes 1 5 E 1 y o e oa e sy ase ia o a e iosy esis i e ac e ia III ce [ ] IIIe Plasmid-encoded trimethoprim and sulfonamide resistance. Si (Staphylococcus aureus) 159 Tn4003 e um e o ge es o asmi -e co e ime o im- esis- a i y o o a e e uc ase is a ea y 17 Si ee o ese O E a a a a e om [7] = o e e mi e CI 1997; (Su 1 I c ease a es o ime o im esis a ce S 5
o a s e ; agai e i eg o s usua y ca y e ge es o 1 Mu ay E e sime E u o Eme ge ce o ig - e e ime o- su o ami e esis a ce im esis a ce i eca Escherichia coli, u i g o a a mi is a io o Chromosomaltrimethoprimandsulfonamideresistance. ime o im o ime o im-su ame o a o e E g Me 19 ; Ac- 3 13 -5 qui e c omosoma ime o im esis a ce is o e y im- 13 es e SC e i a M Wa g Sc ae I ia g O ie e o a c i ica y is y e o ime o im esis a ce is me i- ca iage o Escherichia coli esis a o a imic o ia age s y ea y a e y mu a io s i e ge e o i y o o a e e uc ase c i e i os o i Ca acas e e ue a a i Qi u C i a C omosoma ime o im esis a ce is ou i . influenzae E g Me 199 ; 3 3 5-9 [3 ] E. coli [33] a S. pneumoniae [3 ] I a i io e oge- 1 Sc ei e i ey Susce i i i y o u i e iso a es o S a y ococcus
sa o y icus o a imic o ia age s a o ogy 1991; 3 135- Downloaded from https://academic.oup.com/cid/article/24/Supplement_1/S63/283547 by guest on 30 September 2021 ous esis a ce o ime o im occu s i ma y i e e ac e- 15 G oss e a E Wa owe ug esis a ce i Shigella ia s ecies suc as Lactobacillus, Pediococcus cerevisiae, dysenteriae, Shigella flexneri a Shigella boydii i E g a a Wa es Bacteroides fragilis, a Clostridium s ecies [35] C omo- i c easi g i ci e ce o esis a ce o ime o im Me [C i es] soma su o ami e esis a ce is k ow o occu i Neisseria 19 ; 7 - meningitidis [3 ] a S. pneumoniae [37] 1 a oe a M o issemi a io o ime o im- esis a c o es o Shigella sonnei i u ga ia I ec is 19 9;159 -53 17 eikki E Sii o e A a ko a M i g M Su s Om uo i e I c ease o ime o im esis a ce amo g Shigella s ecies 1975 - Conclusions 19 a a ysis o esis a ce mec a isms I ec is 199 ; 1 1 1 - u i g e as ew yea s a ama ic i c ease i e a e 1 C a kaeomo ako A Ec e e ia ay o Se iwa a a eksom oo o ime o im esis a ce a o g wi ig - e e su o ami e U ime o im- esis a Shigella a e e o o ige ic Escherichia coli esis a ce as ee see e ge e ic i kage o ge es o s ai s i c i e i ai a e ia I ec is 19 7; 735-9 ime o im a su o ami e esis a ce a ge y i a i a es e 19 e is M Sa am MA ossai MA e a A imic o ia esis a ce o a gume o usi g e com i a io o ime o im a a Shigella iso a es i a g a es 19 3-199 i c easi g eque cy o s ai s mu i y esis a o am ici i ime o im-su ame o a o e su o ami e o e e e e e o me o esis a ce I a i- a a i i ic aci C i I ec is 199 ;1 1 55- io e e a e o sig s a e imi a io o e se ec io e ec oog CE Sc o CS a eeuwe a K i ge e Mo i o i g o o ime o im o su o ami es wi a e a imme ia e im ac a i io ic esis a ce i Shigellae iso a e i e e e a s 19 -19 9 o e e e o esis a ce Eu C i Mic o io I ec is 199 ;11 1 -7 1 a es C Ma ewso E icsso C u o ime o im/ su ame o a o e emai s ac i e agai s e e o o ige ic Esc e ic ia co i a S ige a s ecies i Gua a a a a Me ico Am Me Sci 199 ; f r n 3 3 9-91 1 uo i e ime o im esis a ce Mi i e iew A imic o Age s Co ig o e M Mac es S Gi e G oo ey M e C emo e 19 7; 31 1 51 - Aus a ia G ou o A imic o ia esis a ce (AGA A a io a us y S M i c i gs G ime o im a su o ami e o e ia o co a o a i e s u y o esis a ce o a imic o ia age s i Haemo- a m C emo e 19 ; 33 7 -9 philus influenzae i Aus a ia os i a s A imic o C emo e 3 Aca Go s ei C a e YA Sy e gis ic ac i i y o ime o im- 199 ; 3 153- 3 su ame o a o e o g am- ega i e aci i o se a io s i i o a i 3 Geo ge M Ki c e e so W Gi iga I i o ac i i y o i o I ec is 1973; 1 (su S 7 -7 o a y a mi is e e a imic o ia age s agai s Haemophilus influen- um i W ami o -Mi e M Co- imo a o e o ime o im a o e? zae eco e e om c i e mo i o e o gi u i a y i a g ou ay- A iew oi o ei e a i e ace i e a y ugs 19 ; 53- ca e ce e A imic o Age s C emo e 1991; 35 19 - 5 O ie Aca A ma G e a Sessio II a o a o y su ei a ce Kayse Mo e o i G Sa a am e seco Eu o ea co a o a i e o sy e gy e wee a esis a ce o ime o im a su o ami es s u y o e eque cy o a imic o ia esis a ce i Haemophilus in- e I ec is 19 ; 351-7 fluenzae. Eu C i Mic o io I ec is 199 ; 9 1 -7 Kasa e A Su quis ime o im a o e i e ea me o u i a y 5 Mu io Co ey a ie s M e a I e co i e a s ea o a mu i e- ac i ec io s eig yea s o e e ie ce i i a e I ec is sis a c o e o se o y e 3 Streptococcus pneumoniae. I ec is 19 ; 35 - 5 1991;1 3 - 7 uo i e Su s Om Swe e g G SkO ime o im a su - o ge se oe G Ma e A owe AW e i g S A imic o- o ami e esis a ce Mi i e iew A imic o Age s C emo e 1995; ia esis a ce amo g es i a o y iso a es o Haemophilus influenzae, 39 79- 9 Moraxella catarrhalis, a Streptococcus pneumoniae i e U i e eyes o g M icke i g K a e A A a e M Mu ay E S a es A imic o Age s C emo e 199 ;3 75- isk ac o s o eca co o i a io wi ime o im- esis a a mu i- 7 Wa ace as S ei g u e A A i io ic susce i i i ies a ug esis a Escherichia coli amo g c i e i ay-ca e ce e s i ous- esis a ce i Moraxella (Branhamella) catarrhalis. Am Me Sci 199 ; o e as A imic o Age s C emo e 199 ; 3 1 9-3 (su 5A -5 9 Wi ga E S aes Mo ime EA S aes M Co o i a io a c oss- Ko i ai e ikoske ai e uo i e A i io ic susce i i i y o co o i a io o u si g ome a ie s wi ime o im- esis a g am- coagu ase- ega i e s a y ococca oo iso a es wi s ecia e e e ce ega i e aci i C i I ec is 1993; 1 75- 1 o a e e s ime- o uci g S a y ococcus e i e mi is s ai s Sca 1 o aa E C ase e A Co o i a io esis a ce A imic o Age s I ec is 1991; 3 3 5-3 C emo e 199 ; 3 9 -1 9 e Ko I u eska A eque cy a a s e a i i y o i- 11 Mu ay E Ma ewso u o E icsso C eyes Eme ge ce me o im a su o ami e esis a ce i me ici i - esis a o esis a eca Escherichia coli i a e e s o aki g o y a ic a imi- S a y ococcus au eus a S a y ococcus e i e mi is C emo- c o ia age s A imic o Age s C emo e 199 ;3 515- e 199 ; 7-71 S66 Huovinen CID 1997;24 (Suppl 1)
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