Trimethoprim resistance was first recognised in gram-negative bacteria 20 years ago. Workers in several research centres have studied the epidemiology and molecular aspects of trimethoprim resistance over the intervening years, initially in gram-negative bacteria and more recently in gram-positive bacteria. The introduction of this completely novel synthetic antimicrobial provided a unique opportunity to study the full evolution of bacterial resistance to an antimicrobial drug, without the pre-existing influence of resistance genes selected by other related compounds. Consequently, the model provided by trimethoprim resistance has considerable relevance to our understanding of the evolution of bacterial resistance to antimicrobial agents in general. Recent years have seen exciting and major advances in the use of modern DNA technology to study the epidemiology of trimethoprim resistance. Considerable progress has been made in evaluating the importance of the different resistance mechanisms, especially those carried by resistance plasmids. Nevertheless, in most countries resistance to trimethoprim has only recently reached clinically significant proportions and it remains a widely used and valuable component of the antimicrobial armamentarium. The papers presented in this review are based on a Symposium held at the 4th European Congress of Clinical Microbiology in April 1989. The Symposium provided a forum for the various aspects of trimethoprim resistance to be brought together and resulted in the collation of research material which forms this review.
HuovinenP,
RenkonenO-V,
PulkkinenL et al. Trimetho-prim resistance of Escherichia coli in outpatients in Finland after ten years’ use of plain trimethoprim. J Antimicrob Chemother1985; 16:435–441
RevesRR,
MurrayBE,
PickeringLK,
PradoD,
MaddockM,
BartlettAV.
Children with trimethoprim- and ampicillin-resistant fecal Escherichia coli in day care centers. J Infect Dis1987; 156:758–762
MurrayBE,
AlvaradoT,
KimK-H et al. Increasing resistance to trimethoprim-sulfamethoxazole among isolates of Escherichia coli in developing countries. J Infect Dis1985; 152:1107–1113
GutmannL,
WilliamsonR,
MoreauN et al. Cross-resistance to nalidixic acid, trimethoprim and chloramphenicol associated with alterations in outer membrane proteins of Klebsiella, Enterobacter and Serratia.. J Infect Dis1985; 151:501–507
AmyesSGB.
The success of plasmid-encoded drug resistance genes in clinical bacteria: an examination of plasmid-mediated ampicillin and trimethoprim resistance genes and their resistance mechanisms. J Med Microbiol1989; 28:73–83
GoldsteinFW,
PapadopoulouB,
AcarJF.
The changing pattern of trimethoprim resistance in Paris, with a review of worldwide experience. Rev Infect Dis1986; 8:725–737
BarthPT,
DattaN,
HedgesRW,
GrinterNJ.
Transposition of a deoxyribonucleic acid sequence encoding trimethoprim and streptomycin resistance from R483 to other replicons. J Bacteriol1976; 125:800–810
ShapiroJA,
SpornP.
Tn402: a new transposable element determining trimethoprim resistance that inserts in bacteriophage lambda. J Bacteriol1977; 129:1632–1635
HuovinenP,
Pulkkine.L,
HelinH-L,
MakilaM,
ToivanenP.
Emergence of trimethoprim resistance in relation to drug consumption in a Finnish hospital from 1971 through 1984. Antimicrob Agents Chemother1986; 29:73–76
MayerKH,
FlingME,
HopkinsJD,
O’BrienTF.
Trimeth-oprim resistance in multiple genera of Enterobacteri-aceae at a U.S. hospital: spread of the type II dihydrofolate reductase gene by a single plasmid. Infect Dis1985; 151:783–789
AmyesSGB,
McMillanCJ,
DrysdaleJL.
Transferable trimethoprim resistance amongst hospital isolates. GrassiGG,
SabathLD.
New Trends in Antibiotics: Research and Therapy. Amsterdam, Elsevier/North Holland Biomedical Press; 1981325–327
RichardsonJF.
Frequency of resistance of trimethoprim among isolates of Staphylococcus epidermidis and Staphylococcus saprophytics. J Antimicrob Chemother1983; 11:163–167
TennentJM,
YoungH-K,
LyonBR,
AmyesSGB,
SkurrayRA.
Trimethoprim resistance determinants encoding a dihydrofolate reductase in clinical isolates of Staphylococcus aureus and coagulase-negative staphylococci. Med Microbiol1988; 26:67–73
CoughterJP,
JohnstonJL,
ArcherGL.
Characterisation of a staphylococcal trimethoprim resistance gene and its product. Antimicrob Agents Chemother1987; 31:1027–1032
BroadDF,
SmithJT.
Classification of trimethoprim-resistant dihydrofolate reductases mediated by R plasmids using isoelectric focussing. Eur J Biochem1982; 125:617–622
GillespieMT,
LyonBR,
LooLS,
MatthewsPR,
StewartPR,
SkurrayRA.
Homologous direct repeat sequences associated with mercury, methicillin, tetracycline and trimethoprim resistance determinats. FEMS Microbiol Lett mi 43:165–171
RouchDA,
MesserottiLJ,
LooLSL,
JacksonCA,
SkurrayRA.
Trimethoprim resistance transposon Tn4003 from Staphylococcus aureus encodes genes for a dihydrofolate reductase and thymidylate synthetase flanked by three copies of IS257. MolMicrobiol1989; 3:161–175
FreisheimJH,
BitarKG,
ReddyAV,
BlankenshipDT.
Dihydrofolate reductase from amethopterin-resistant Lactobacillus casei : sequences of the cyanogen bromide peptides and complete sequence of the enzyme. J Biol Chem1978; 253:6437–6444
GleisnerJM,
PetersonDL,
BlakleyRL.
Amino-acid sequence of dihydrofolate reductase from a methotrex-ate-resistant mutant of Streptococcus faecium and identification of methionine residues at the inhibitor binding site. Proc Natl Acad Sci USA1974; 71:3001–3005
IwakuraM,
KawataM,
TsudaK,
TanakaT. Nucleotide sequence of the thymidylate synthase B and dihydrofolate reductase genes contained in one Bacillus subtilis operon. Gene1988; 64:9–20
SkoldO,
WidhA.
A new dihydrofolate reductase with low trimethoprim sensitivity induced by an R factor mediating high resistance to trimethoprim. J Biol Chem1974; 249:4324–4325
AmyesSGB,
SmithJT.
The purification and properties of the trimethoprim-resistant dihydrofolate reductase mediated by the R-factor R388. Eur J Biochem1976; 61:597–603
PattishallKH,
AcarJ,
BurchallJJ,
GoldsteinFW,
HarveyRJ.
Two distinct types of trimethoprim-resistant dihydrofolate reductases specified by R plasmids of different compatibility groups. J Biol Chem1977; 252:2319–2323
FlingME,
RichardsC.
The nucleotide sequence of the trimethoprim resistant dihydrofolate reductase gene harbored by Tn7. Nucleic Acids Res1983; 11:5147–5158
StoneD,
SmithSL.
The amino acid sequence of the trimethoprim resistant dihydrofolate reductase specified in Escherichia coli by R-plasmid R67. Biol Chem1979; 254:10857–10861
FlensburgJ.,
SteenR. Nucleotide sequence analysis of the trimethoprim resistant dihydrofolate reductase encoded by R plasmid R751. Nucleic Acids Res1986; 14:5933
FlingME,
WaltonL,
ElwellLP.
Monitoring of plasmid-encoded, trimethoprim-resistant dihydrofolate reductase genes: detection of a new resistant enzyme. Antimicrob Agents Chemother1982; 22:882–888
JoynerSS,
FlingME,
StoneD,
BaccanariDP.
Characteris-ation of an R-plasmid dihydrofolate reductase with a monomeric structure. J Biol Chem1984; 259:5851–5856
YoungH-K,
AmyesSGB.
A new mechanism of plasmid trimethoprim resistance. Characterization of an inducible dihydrofolate reductase. J Biol Chem1986; 261:2503–2505
SundstromL. Radstrom P,
SwedbergG,
SkoldO.
Site-specific recombination promotes linkage between trimethoprim and sulfonamide resistance genes. Sequence characterizations of dhfr V and SGI and a recombination active locus of Tn21. MGG1988; 213:191–201
AmyesSGB,
TownerKJ,
CarterGI,
ThomsonCJ,
YoungH-K.
The type VII dihydrofolate reductase: a novel plasmid-encoded trimethoprim-resistant enzyme from Gram-negative bacteria isolated in Britian. J Antimicrob Chemother1989 in press
CarterGI,
TownerKJ,
SlackRCB.
Rapid detection of a specific trimethoprim resistance gene using a biotinylated DNA probe. J Antimicrob Chemother1987; 20:335–341
ZolgJW,
HanggiUJ,
ZachauHG.
Isolation of a small DNA fragment carrying the gene for a dihydrofolate reductase from a trimethoprim resistance factor. MGG1978; 164:15–29
TownerKJ,
YoungH-K,
AmyesSGB.
Biotinylated DNA probes for trimethoprim-resistant dihydrofolate reductases types IV and V. J Antimicrob Chemother1988; 22:285–291
CameronFH,
GrootObblink DJ,
AckermanVP,
HallRM.
Nucleotide sequence of the AAD(2") aminoglycoside adenyltransferase determinant aadB. Evolutionary relationship of this region with those surrounding aadA in R538-1 and dhfrll in R388. Nucleic Acids Res1986; 14:8625–8635
ZolgJW,
HanggiUJ.
Characterisation of an R-plasmid-associated, trimethoprim-resistant dihydrofolate reductase and determination of the nucleotide sequence of the reductase gene. Nucleic Acids Res1981; 9:697–710
Mayon-WhiteRT,
DucelG,
KereselidzeT,
TikomirovE.
An international survey of the prevalence of hospital-acquired infections. J Hosp Infect1988; 11 Suppl A:43–48
FrenchGL,
LingJ,
LingT,
HuiYW.
Susceptibility of Hong Kong isolates of methicillin-resistant Staphylococcus aureus to antimicrobial agents. J Antimicrob Chemother1988; 21:581–588
National Committee for Clinical Laboratory StandardsMethods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically Villanova PA: NCCLS; 1985