Journal of Antimicrobial Chemotherapy (2008) 62, 35– 40 doi:10.1093/jac/dkn147 Advance Access publication 12 April 2008

Trimethoprim and enterococci in urinary tract infections: new perspectives on an old issue Karin Tegmark Wisell1*, Gunnar Kahlmeter2 and Christian G. Giske3 1

Department of Antibiotic Resistance and Hospital Hygiene, Swedish Institute for Infectious Disease Control, 17182 Solna, Sweden; 2Clinical Microbiology, Central Hospital, Va¨xjo¨, Sweden; 3Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden The lack of oral treatment alternatives for enterococcal urinary tract infections (UTIs) has led to a renewed interest in trimethoprim. Enterococci can incorporate exogenously produced folates and thereby reverse the effect of trimethoprim. Although a large proportion of enterococci appear susceptible to trimethoprim in vitro using standard media devoid of folates, a 360-fold increase in the MIC can be seen when susceptibility testing is performed in media containing fresh urine. Even if trimethoprim has a favourable pharmacokinetic profile, with high serum and very high urine concentrations, pharmacodynamic (PD) estimates show that a large proportion of the apparent wild-type isolates (as categorized by standard susceptibility testing) have unfavourable PD indices. The clinical efficacy of trimethoprim in enterococcal UTI is debated. We could identify not more than 38 evaluable cases of enterococcal UTI in the literature. The eradication rate was 82%. Case reports where patients on co-trimoxazole for UTI have developed bacteraemia with enterococci susceptible to trimethoprim seem to support experimental findings that standard antimicrobial susceptibility testing poorly predicts the clinical outcome of trimethoprim therapy. The European Committee on Antimicrobial Susceptibility Testing and the national breakpoint committees in Europe have recently debated the role of trimethoprim in the treatment of enterococcal UTI and agreed to categorize wild-type enterococci as intermediate to trimethoprim and trimethoprim/sulfamethoxazole. This allows the distinction between enterococci with and without acquired resistance mechanisms to trimethoprim. This review discusses the microbiological, experimental, clinical and PD aspects of the usage of trimethoprim for enterococcal UTI. Keywords: MIC, PK/PD, drug susceptibility testing, antimicrobial activity

Oral treatment options are even fewer. Although basically all Enterococcus faecalis isolates are susceptible to amoxicillin and most to nitrofurantoin, resistance to other oral alternatives is frequently observed. Most E. faecium are resistant to all oral therapeutic alternatives (with the exception of linezolid), leaving few or no treatment options, depending on whether nitrofurantoin is perceived to be an efficacious agent in these cases, for relatively simple infections such as UTIs. The lack of oral treatment alternatives for enterococcal infections has lead to a renewed interest in trimethoprim. In vitro, in test systems devoid of folates, a large proportion of enterococci typically exhibit low MICs for trimethoprim.8,9 However, the use of trimethoprim for the treatment of enterococcal urinary infections is controversial due the ability of enterococci to incorporate exogenous folates.10 – 12 As part of the process for harmonizing European breakpoints (through the European Committee on Antimicrobial Susceptibility Testing), breakpoint committees in Europe have been debating the role of

Introduction Enterococci cause a wide variety of diseases with wound and urinary tract infections (UTIs) being the most common and bloodstream infections and endocarditis the most severe and therapeutically challenging. Resistance to most commonly used antimicrobial agents is a typical characteristic of enterococci and an important explanation for their success as nosocomial pathogens.1,2 Enterococci usually feature intrinsic low-level resistance to b-lactams and aminoglycosides and acquired resistance to most other classes of antibiotics.3,4 Systemic treatment options for serious enterococcal infections are ampicillin (although most Enterococcus faecium are resistant), glycopeptides, daptomycin, linezolid, dalfopristin/quinupristin (only E. faecium) and tigecycline.3,5 – 7 The newer compounds have limited approved clinical indications, some of them may require concentration monitoring and they are, in general, expensive and or difficult to administer and not suitable for oral therapy.

.....................................................................................................................................................................................................................................................................................................................................................................................................................................

*Corresponding author. Tel: þ46-8-457-2410; Fax: þ46-8-301797; E-mail: [email protected] .....................................................................................................................................................................................................................................................................................................................................................................................................................................

35 # The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]

Review trimethoprim in the treatment of UTI caused by enterococcal infections. As trimethoprim is widely used for the empirical treatment of UTIs, and due to its favourable pharmacokinetic (PK) properties, the possible use of trimethoprim for enterococcal UTIs will be reviewed.

daily). From this study, an approximate free AUC in serum of 31 mg.h/L could be calculated (Figure 2 and Table 1). The tissue concentration of trimethoprim is usually higher than the corresponding concentration in serum (shown for bile, saliva and sputum). In particular, high concentrations can be found in lung and kidney tissues.16 In prostatic fluid, the levels are found to be two to three times the serum concentration.17 However, lower levels may be present in patients with chronic prostatitis.18 Urine concentrations of trimethoprim are considerably higher than the corresponding plasma concentrations. Continuous dosing of 100 mg once daily gives urine concentrations ranging from 30 to 160 mg/L and a dose of 200 mg once daily produced levels twice as high. The urine concentration seems to be approximately 10 times as high as the corresponding serum concentration.19 – 21

Pharmacokinetics of trimethoprim Trimethoprim is a bacteriostatic compound that inhibits microbial dihydrofolate reductase and thereby renders the bacteria deficient in di- and tetrahydrofolic acid, essential derivatives in nucleotide and amino acid biosynthesis (Figure 1). The PK properties of trimethoprim are summarized in Table 1. Peak plasma concentrations at steady state have been examined in a few studies and showed that an intravenous dose of 160 mg three-times daily gave peak plasma concentrations of 8 mg/L, and if given orally, maximal levels of 5 mg/L were observed.13,14 Bruun et al.15 measured the human plasma concentration of trimethoprim in five healthy individuals throughout a 12 h period after an oral dose of 160 mg (twice

Figure 1. Conversion of dihydrofolate reductase.

folate

into

tetrahydrofolate

catalysed

Enterococci incorporate exogenously produced folates The activity of trimethoprim can be reversed if the bacteria can circumvent the blocked production of tetrahydrofolic acid by incorporating exogenously produced tetrahydrofolic acid or downstream components in the nucleic and amino acid synthesis pathway (Figure 1). In one study, it was shown that enterococci were more susceptible to the reversal of trimethoprim’s antibacterial activity by folates and related compounds than other species.22 Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus agalactiae, E. faecium, E. faecalis and Escherichia coli could all incorporate the exogenous pyrimidine derivative thymidine at high levels. E. coli and the two tested enterococcal species could incorporate the pyrimidine derivative thymine. The ability to incorporate thymidine and thymine probably does not contribute to the resistance of enterococci and other species to trimethoprim, as

by

Table 1. Trimethoprim PK characteristics Pharmacokinetic variable Absorption after oral administration t1/2

Plasma protein binding Excretion Metabolism V

fAUCa plasma AUCb urine

Reference(s) rapid, 90 –100% adults: 8–10 h children: 3 –5.5 h newborn: 19 h 44% mainly renal (40– 60% is excreted in its original form within 24 h) faecal (4%) 10 –20% metabolized, primarily hepatic adults: 1.3–1.8 L/kg children (1–10 years): 1 L/kg newborn: 2.7 L/kg 31 mg.h/L 552 mg.h/L

a

Kasanen et al.27 Drugdex44

Drugdex44, Schwartz and Ziegler45 Drugdex44 Drugdex44 Drugdex44

Kasanen et al.27 Jodal and Fellner,19 Stachowska and Senczuk,20 Kasanen et al.,27 Drugdex44

Calculated from Bruun et al.15 Free(f )AUCplasma ¼ 2.3 mg/L (mean trough concentration)24 h0.56 ( protein binding 44%). Trimethoprim dose 320 mg twice daily. b Calculated from Bruun et al.15 and the approximation that the urine concentration, in general, is at least 10 times as high as the plasma concentration.19 AUCurine ¼ 23 mg/L (approximated mean trough urine concentration)24 h. Trimethoprim dose 320 mg twice daily.

36

Review MIC of trimethoprim. An increased pH partially reversed the resistance of E. faecalis to trimethoprim.

Clinical studies No large randomized prospective clinical studies have been performed in which the effect of trimethoprim or trimethoprim/ sulfamethoxazole on UTIs caused by Enterococcus spp. has been studied. However, a few clinical studies have evaluated the effect of trimethoprim alone or in combination with various sulphonamides on UTI.17,25 – 29 Sulphonamides have no in vitro activity against enterococci, and only sulfamethoxazole has been demonstrated to have an additive effect if combined with trimethoprim (ratio 1:19) and only on E. faecalis.30 Thus, only the contributions of the trimethoprim component will be reviewed below. As there are no control groups in these studies, the results are difficult to interpret. Only in three of the studies could the therapeutic efficacy of trimethoprim be evaluated in relation to the infecting organism, leaving a total of 38 evaluable enterococcal UTIs.17,25 – 29 Sitzen and Rugendorff28 looked at the effect of trimethoprim/ sulfadiazine and trimethoprim/sulfamethoxazole in the treatment of UTIs. The trimethoprim/sulfadiazine group received 180 mg of trimethoprim (and 820 mg of sulfadiazine) (once daily) (enterococci; n ¼ 13), and the trimethoprim/sulfamethoxazole group received 320 mg of trimethoprim (and 800 mg of sulfamethoxazole) (twice daily) (enterococci; n ¼ 12). At follow-up, 3 – 4 weeks after therapy was initiated, and 10 of 12 (83%) and 11 of 13 (85%) patients on the respective dosage were cured microbiologically. This can be compared with UTIs due to E. coli and S. aureus, in which 90% and 100%, respectively, were eradicated. Nielsen et al.17 studied the effect of trimethoprim in combination with sulfamethoxazole. Six patients received 320 mg of trimethoprim daily (and 800 mg of sulfamethoxazole twice daily). The patients were with (n ¼ 5) or without (n ¼ 1) factors predisposing to UTI. Three of five patients (and the only patient without predisposing factors) were cured microbiologically at follow-up on day 14. Stratford and Dixson29 studied trimethoprim and sulfamethoxazole in combination, and patients were given ‘two tablets Bactrim every six or every eight hours’. Most likely, this corresponds to a dose of 80 mg of trimethoprim (and 400 mg of sulfamethoxazole) per tablet and daily doses of 240–320 mg of trimethoprim. Eight patients were identified as having enterococcal UTIs. Of these, seven (87.5%) were cleared at follow-up. The authors also looked at re-infection after Gram-negative UTI and pointed out that a large proportion of re-infections were due to enterococci. Of the total of 38 enterococcal UTIs in the three studies together, 31 were eradicated at follow-up, which gives an overall eradication rate of 82%. A study by Reid and Howard31 looked at the use of trimethoprim as prophylaxis (40 mg twice daily) for UTIs in patients with spinal cord injuries (n ¼ 30). Although the prophylactic therapy significantly reduced the incidence of symptomatic UTIs, the regimen resulted in a 2-fold increase in enterococcal UTIs.

Figure 2. Trimethoprim AUC in steady state. Adapted from Bruun et al.15 with kind permission from the authors and the American Society for Microbiology. TMP conc, trimethoprim concentration.

an animal model showed that these substances were rapidly degraded and consequently did not affect the antimicrobial activity of trimethoprim in vivo.23 E. faecalis and E. faecium were the only species tested that could incorporate dihydrofolate, tetrahydrofolate and formyl-tetrahydrofolate (folinic acid). By adding these folates to the media, the MIC of trimethoprim was increased in the order of 10-fold.22 These results are consistent with those of Zervos and Schaberg24 who compared the MICs of trimethoprim in urine and in Mueller –Hinton broth (MHB) for 21 E. faecalis isolates. The study showed that when the MIC of trimethoprim was determined in urine, a more than 60-fold and 360-fold increase in MIC was seen in the two urine samples tested, respectively (Table 2). The addition of formyl-tetrahydrofolate to MHB increased the MIC of trimethoprim 25-fold. The study also demonstrated a sigmoid relationship between the concentration of formyl-tetrahydrofolate in the medium and the trimethoprim MIC of the enterococci. A linear increase in MIC in relation to formyl-tetrahydrofolate concentration was seen between 0.001 and 0.1 mg/L formyl-tetrahydrofolate, but not at higher concentrations (1 –10 mg/L). These concentrations can be compared with the normal concentration of formyl-tetrahydrofolate in serum which is 6– 20 mg/L and in urine 2– 7 mg/L, i.e. in the range where a significant effect on the MIC of trimethoprim can be expected. Osmolality and pH were also shown to affect the Table 2. Susceptibility of clinical isolates of E. faecalis (n ¼ 21) to co-trimoxazole when tested in MHB, MHB supplemented with tetrahydrofolate and in two different, arbitrarily selected urines

Medium MHB MHBþ tetrahydrofolate (1 mg/L) Urine 1 Urine 2

Trimethoprim/ sulfamethoxazole MIC (mg/L) expressed as the TMP MIC (mean, range)

Increase in MIC

0.13 (0.002–0.625) 3.3 (0.1–12.5)

1 25

8.1 (1.6–50) 46.4 (25–100)

62 357

Case reports of clinical failures TMP, trimethoprim. Adapted from Zervos and Schaberg24 with kind permission from the authors and the American Society for Microbiology.

Two separate reports have been published in which infections with enterococcal isolates with apparent trimethoprim in vitro 37

Review susceptibility failed on trimethoprim/sulfamethoxazole treatment.32,33 Goodhart33 described two patients with uncomplicated UTIs caused by apparently susceptible enterococci, both treated with trimethoprim/sulfamethoxazole. Both patients developed bacteraemia during trimethoprim/sulfamethoxazole treatment, and the in vitro susceptible enterococci could be isolated from the respective blood cultures. The patients recovered after trimethoprim/sulfamethoxazole was discontinued and exchanged for vancomycin plus streptomycin in the first case and penicillin in combination with streptomycin in the second case. Elsner et al.32 presented a case of enterococcal bacteraemia that developed during trimethoprim/sulfamethoxazole prophylaxis.

Table 3. Trimethoprim (TMP)—calculated AUC/MIC and %T/MIC for urine and plasma of six hypothetical MIC valuesa

Animal models

b

MIC fAUC /MIC (mg/L) (plasma)

AUCc/ MIC (urine)

%T (free concentration)/MIC (plasma)d

%T/MIC (urine)e

0.5 10 25 45 50 100

62 3.1 1.2 0.7 0.6 0.31

1104 55 22 12 11 5.5

100 0 0 0 0 0

100 100 100 40 17 0

a

Calculations are based on a trimethoprim dose of 160 mg every 12 h.15 fAUCplasma ¼ 31 mg.h/L (Table 1). c AUCurine ¼ 552 mg.h/L (Table 1). d Approximated from Bruun et al.15 e Approximated from Bruun et al.15 and Jodal and Fellner.19 b

Two animal models investigating trimethoprim/sulfamethoxazole in the treatment of enterococci have been published.34,35 In a rat enterococcal endocarditis model, the efficacy of trimethoprim sulfamethoxazole and ampicillin was compared (n ¼ 31).35 Trimethoprim/sulfamethoxazole had no effect on enterococcal endocarditis in this study. In the trimethoprim/sulfamethoxazole group, the cure rate was 0% (same as placebo) when compared with the ampicillin group for which the cure rate was 38%. Chenoweth et al.34 compared trimethoprim sulfamethoxazole and ampicillin in a mouse peritonitis lethal model (n ¼ 20). With sulfamethoxazole treatment, the mortality was 95% (similar to 100% in the placebo group) when compared with 40% for ampicillin.

dose of 160 mg every 12 h, these criteria can be met with strains having MIC values up to 10 and 45 mg/L, respectively, depending on whether AUC/MIC or %T/MIC is used as the pharmacodynamic (PD) target. Using these theoretical PD MIC breakpoints and the MIC values obtained when testing clinical isolates in fresh urine, a large proportion of the apparent wildtype isolates [as categorized by standard antimicrobial susceptibility testing (AST)] would be categorized as resistant.

Acquired resistance

Conclusions

Although a large proportion of enterococci are susceptible to trimethoprim in vitro, high-level resistance has been reported from many parts of the world.8,9,36,37 Resistance rates of 25 –50% are common. The resistance mechanisms have not been fully elucidated.38 In other species, mutational changes in the dihydrofolate reductase gene leading to changes in the affinity for trimethoprim and/or overproduction of dihydrofolate reductase have been reported.39

MIC values of trimethoprim in MHB range from 0.002 to 0.63 mg/L. When performing MIC determinations in urine, the range increased to 2 to 100 mg/L. As the activity of trimethoprim is heavily influenced by the presence of folates and the degree of osmolality and acidity, all of which are factors that vary widely in urine, it is difficult to ascertain the predictive value of susceptibility testing when the isolate is categorized as susceptible to trimethoprim using standard AST. In vitro testing can, however, predict when trimethoprim should not be used, as the test can accurately distinguish between isolates with and without resistance mechanisms. Animal models and reports of clinical failures with in vitro susceptible E. faecalis strains indicate a lack of clinical success with trimethoprim in systemic infections. Due to the high trimethoprim concentrations in the urine, trimethoprim could be a therapeutic option for UTIs. The few clinical studies that exist have no control groups, and the number of trimethoprim-treated enterococcal UTIs is limited. However, the clinical studies indicate that there is clinical success with trimethoprim in some patients with enterococcal UTI. Although desirable, it seems difficult to envisage a susceptibility test procedure that takes into account individual differences in folate content, pH and/or osmolality. Even if the predictive value of a susceptible categorization is doubtful, an epidemiological cut-off value which on standard media can distinguish wild-type (WT  0.5 mg/L) from non-wild-type enterococci would be useful. In the ongoing harmonization process for European breakpoints, the currently agreed approach among breakpoint committees in Europe is to categorize wild-type enterococci as intermediate to trimethoprim

PK and pharmacodynamic modelling Whether the effect of trimethoprim best correlates with time above MIC (%T/MIC) or is concentration-dependent (AUC/ MIC) has not been studied. In order to obtain an estimate as to whether reasonable target levels can be reached, approximate AUC/MIC and %T/MIC were calculated for both serum and urine (Table 3). Hypothetical MIC values range from 0.5 mg/L (the highest MIC value of wild-type isolates on standard media40) to 100 mg/L (the highest MIC value of wild-type isolates on media with urine).24 For serum, the free trimethoprim concentration was used, but since the protein bound fraction in urine is unknown, the total trimethoprim concentration was used in these calculations. Though never determined for trimethoprim, we assumed that trimethoprim, similar to other nucleic acid synthesis inhibitors, would require a target AUC/MIC of 40 –60.41 For Gram-positive pathogens, the required %T/MIC is, in general, 30% to 40% for b-lactams, which we tentatively used for trimethoprim.42 Assuming a UTI and a trimethoprim 38

Review 16. Cohen J, Powderly WG. Infectious Diseases. St Louis, MO: Elsevier, 2004. 17. Nielsen ML, Laursen H, Stroyer I. Short term treatment of urinary tract infections with trimethoprim/sulfamethoxazole. Scand J Infect Dis 1970; 2: 211–4. 18. Meares EM Jr. Prostatitis: review of pharmacokinetics and therapy. Rev Infect Dis 1982; 4: 475–83. 19. Jodal U, Fellner H. Plasma and urine concentrations of trimethoprim–sulfadiazine (co-trimazine) in children given one dose per day. Scand J Infect Dis 1988; 20: 91 –5. 20. Stachowska B, Senczuk W. Studies on kinetics of sulfadiazine and trimethoprim excretion in man. Int J Clin Pharmacol Ther Toxicol 1987; 25: 81 –5. 21. Daily Med Current Medication Information. http://www.dailymed. nlm.nih.gov (12 February 2008, date last accessed). 22. Hamilton-Miller JM. Reversal of activity of trimethoprim against Gram-positive cocci by thymidine, thymine and ‘folates’. J Antimicrob Chemother 1988; 22: 35– 9. 23. Hill JM, Morse PA Jr, Gentry GA. Metabolism of deoxycytidine, thymine, and deoxythymidine in the hamster. Cancer Res 1975; 35: 1314–9. 24. Zervos MJ, Schaberg DR. Reversal of the in vitro susceptibility of enterococci to trimethoprim –sulfamethoxazole by folinic acid. Antimicrob Agents Chemother 1985; 28: 446–8. 25. Brumfitt W, Hamilton-Miller JM. Changing role of co-trimoxazole in the treatment of recurrent urinary infections: a comparison with Augmentin. Br J Clin Pract 1985; 39: 346–51. 26. Brumfitt W, Hamilton-Miller JM, Ludlam H et al. Comparative trial of trimethoprim and co-trimoxazole in recurrent urinary infections. Infection 1982; 10: 280–4. 27. Kasanen A, Anttila M, Elfving R et al. Trimethoprim. Pharmacology, antimicrobial activity and clinical use in urinary tract infections. Ann Clin Res 1978; 10 Suppl 22: 1–39. 28. Sitzen W, Rugendorff EW. Co-trimazine once daily in urinary tract infections in comparison with co-trimoxazole given twice daily—a double-blind randomized study. Infection 1981; 9: 91 –5. 29. Stratford BC, Dixson S. Results of treatment of 108 patients using trimethoprim plus sulfamethoxazole. Med J Aust 1971; 1: 526 –31. 30. Crider SR, Colby SD. Susceptibility of enterococci to trimethoprim and trimethoprim –sulfamethoxazole. Antimicrob Agents Chemother 1985; 27: 71– 5. 31. Reid G, Howard L. Effect on uropathogens of prophylaxis for urinary tract infection in spinal cord injured patients: preliminary study. Spinal Cord 1997; 35: 605 –7. 32. Elsner HA, Kruger W, Laufs R et al. Septicemia due to susceptible Enterococcus faecalis despite prophylaxis with trimethoprim–sulfamethoxazole. Eur J Clin Microbiol Infect Dis 1997; 16: 620–2. 33. Goodhart GL. In vivo v in vitro susceptibility of enterococcus to trimethoprim–sulfamethoxazole. A pitfall. JAMA 1984; 252: 2748–9. 34. Chenoweth CE, Robinson KA, Schaberg DR. Efficacy of ampicillin versus trimethoprim–sulfamethoxazole in a mouse model of lethal enterococcal peritonitis. Antimicrob Agents Chemother 1990; 34: 1800–2. 35. Grayson ML, Thauvin-Eliopoulos C, Eliopoulos GM et al. Failure of trimethoprim–sulfamethoxazole therapy in experimental enterococcal endocarditis. Antimicrob Agents Chemother 1990; 34: 1792–4. 36. Farrell DJ, Morrissey I, De Rubeis D et al. A UK multicentre study of the antimicrobial susceptibility of bacterial pathogens causing urinary tract infection. J Infect 2003; 46: 94–100. 37. Jones ME, Karlowsky JA, Draghi DC et al. Epidemiology and antibiotic susceptibility of bacteria causing skin and soft tissue

and trimethoprim/sulfamethoxazole and that the R-breakpoint R . 1 mg/L will be helpful in identifying strains with acquired high-grade resistance to trimethoprim.43

Acknowledgements We are grateful to Annelie Brauner for critical reading of the manuscript.

Transparency declarations None to declare.

References 1. Moellering RC Jr. Vancomycin-resistant enterococci. Clin Infect Dis 1998; 26: 1196–9. 2. Taconelli E, Cataldo MA. Vancomycin resistant enterococci (VRE): transmission and control. Int J Antimicrob Agents 2008; 31: 99 – 106. 3. Amyes SG. Enterococci and streptococci. Int J Antimicrob Agents 2007; 29 Suppl 3: S43– 52. 4. Martins Teixeira L, da Glo´ria Siqueira Carvalho M, Facklam RR. Enterococcus. In: Murray PR, ed. Manual of Clinical Microbiology, 9th edn. Washington, DC: American Society for Microbiology, 2007; 430–42. 5. Decousser JW, Bourgeois-Nicolaos N, Doucet-Populaire F. Dalbavancin, a long-acting lipoglycopeptide for the treatment of multidrug-resistant Gram-positive bacteria. Expert Rev Anti Infect Ther 2007; 5: 557 –71. 6. Giamarellou H. Treatment options for multidrug-resistant bacteria. Expert Rev Anti Infect Ther 2006; 4: 601– 18. 7. Nordmann P, Naas T, Fortineau N et al. Superbugs in the coming new decade; multidrug resistance and prospects for treatment of Staphylococcus aureus, Enterococcus spp. and Pseudomonas aeruginosa in 2010. Curr Opin Microbiol 2007; 10: 436– 40. 8. Gordon KA, Jones RN. Susceptibility patterns of orally administered antimicrobials among urinary tract infection pathogens from hospitalized patients in North America: comparison report to Europe and Latin America. Results from the SENTRY Antimicrobial Surveillance Program (2000). Diagn Microbiol Infect Dis 2003; 45: 295– 301. 9. Hoban DJ, Bouchillon SK, Johnson JL et al. Comparative in vitro potency of amoxycillin– clavulanic acid and four oral agents against recent North American clinical isolates from a global surveillance study. Int J Antimicrob Agents 2003; 21: 425–33. 10. Hamilton-Miller JM. Antibiotic treatment of enterococcal infection. Antimicrob Agents Chemother 1989; 33: 2164. 11. Hamilton-Miller JM. Antibiotic treatment of enterococcal infection. Antimicrob Agents Chemother 1989; 33: 989. 12. Murray BE. Antibiotic treatment of enterococcal infections. Antimicrob Agents Chemother 1989; 33: 1411. 13. Grose WE, Bodey GP, Loo TL. Clinical pharmacology of intravenously administered trimethoprim –sulfamethoxazole. Antimicrob Agents Chemother 1979; 15: 447–51. 14. Kaplan SA, Weinfeld RE, Abruzzo CW et al. Pharmacokinetic profile of trimethoprim– sulfamethoxazole in man. J Infect Dis 1973; 128 Suppl: 547–55. 15. Bruun JN, Ostby N, Bredesen JE et al. Sulfonamide and trimethoprim concentrations in human serum and skin blister fluid. Antimicrob Agents Chemother 1981; 19: 82 –5.

39

Review infections in the USA and Europe: a guide to appropriate antimicrobial therapy. Int J Antimicrob Agents 2003; 22: 406– 19. 38. Frosolono M, Hodel-Christian SL, Murray BE. Lack of homology of enterococci which have high-level resistance to trimethoprim with the dfrA gene of Staphylococcus aureus. Antimicrob Agents Chemother 1991; 35: 1928– 30. 39. Huovinen P, Sundstrom L, Swedberg G et al. Trimethoprim and sulfonamide resistance. Antimicrob Agents Chemother 1995; 39: 279–89. 40. EUCAST. Antimicrobial Wildtype MIC Distributions of Microorganisms. http://www.eucast.org/WT_EUCAST.htm (12 February 2008, date last accessed).

41. Ambrose PG, Bhavnani SM, Owens RC Jr. Clinical pharmacodynamics of quinolones. Infect Dis Clin North Am 2003; 17: 529–43. 42. Ambrose PG, Bhavnani SM, Rubino CM et al. Pharmacokinetics–pharmacodynamics of antimicrobial therapy: it’s not just for mice anymore. Clin Infect Dis 2007; 44: 79 –86. 43. EUCAST. MIC-breakpoints for Miscellaneous Antimicrobials— Period of Consultation Ongoing. http://www.eucast.org (12 February 2008, date last accessed). 44. Drugdex. http://www.drugdex.com (12 February 2008, date last accessed). 45. Schwartz DE, Ziegler WH. Assay and pharmacokinetics of trimethoprim in man and animals. Postgrad Med J 1969; 45 Suppl: 32–7.

40