Trimethoprim-Sulfamethoxazole

Trimethoprim-Sulfamethoxazole

FRANKLIN R. COCKERILL III, M.D., Division ofInfectious Diseases and Internal Medicine and Section of Clinical Microbiology; RANDALL S. EDSON, M.D., Division ofInfectious Diseases and Internal Medicine

The antimicrobial combination of trimethoprim and snlfamethoxazole is active in vitro against various gram-positive and gram-negative bacteria. Clinically, it is useful for prophylaxis and treatment of selected infections of the genitourinary, respiratory, and gastrointestinal tracts. Trimethoprimsulfamethoxazole by itself or in combination with other antimicrobial agents is indicated for most Nocardia asteroides infections and is the antimicrobial agent of choice for Pneumocystis carinii pneumonia. The drug is relatively nontoxic in patients who do not have the acquired immunodeficiency syndrome (AIDS) and is available in both oral and intravenous forms. The native compounds and the metabolites of trimethoprim and sulfamethoxazole are excreted primarily in the urine. When the creatinine clearance is less than 30 mllmin, the dosage of trimethoprim-sulfamethoxazole should be adjusted.

Introduced in 1968, trimethoprim-sulfamethoxazole (TMPSMX) is one of the few effective, commercially available combination antibiotics. It is also known as co-trimoxazole and marketed as Bactrim or Septra. The therapeutic effectiveness of this antibiotic for numerous infections has contributed to its widespread use. MODE OF ACTION SMX is one of the sulfonamides, all of which competitively inhibit the modification of p-aminobenzoate into folic acid. More specifically, sulfonamides are competitive inhibitors of the bacterial enzyme responsible for the incorporation of p-aminobenzoate into dihydropteroic acid, the immediate precursor of folic acid. TMP, a diaminopyrimidine, competitively inhibits the activity of bacterial dihydrofolate reductase. The biochemical structures of TMP and SMX are shown in Figure 1, and their mode of action in the sequential inhibition of synthesis of folinic acid, necessary for microbial production of DNA, is shown in Figure 2. 1 The combination of TMP and SMX often produces a synerIndividual reprints of this article are not available. The entire Symposium on Antimicrobial Agents will be available for purchase as a bound booklet from the Proceedings Circulation Office at a later date. Mayo Clin Proc 66:1260-1269,1991

gistic bactericidal effect against many gram-positive and gram-negative bacteria that may not be present with either agent when used independently.' The effect of TMP-SMX may be diminished in patients who receive high doses of folinic acid.3 PHARMACOKINETICS The optimal synergistic ratio of serum concentrations of TMP to SMX against most susceptible bacteria is approximately 1:20.1 Steady-state serum concentration ratios of 1:20 (TMP:SMX) are achieved by using a fixed oral or intravenous combination of 1:5 (TMP:SMX). The components of commercially available preparations are shown in Table 1. Absorption.-After oral administration, TMP and SMX are absorbed as efficiently in combination as when administered independently. Absorption, distribution, metabolism, and excretion of both antibiotics follow first-order kinetics. In human volunteers given a single combined oral dose of 160 mg of TMP and 800 mg of SMX, Bach and associates" measured mean peak serum concentrations of 1.72 to 1.82 ug/ml of TMP and 36.5 to 38.5 ug/ml of SMX. All these subjects had normal renal function, and peak concentrations of TMP and SMX occurred at 1 and 4 hours, respectively, after administration.

1260

Mayo Clin Proc, December 1991, Vol 66

Peak serum or plasma concentrations of TMP and SMX occur more rapidly after intravenous than after oral administration. Because of variable oral absorption, peak concentrations of both antibiotics are often higher and more predictable after intravenous administration. After a single l-hour intravenous infusion of 160 mg of TMP and 800 mg of SMX, mean peak serum concentrations were 304 ± 0.3 ug/ml and 47.3 ± 2.7 ug/ml, respectively.' With repeated administration of intravenous doses at 8-hour intervals, mean plasma trough and peak concentrations ofTMP were 5.6 ± 0.6Ilg/ml and 8.8 ± 0.9Ilg/ml, respectively, and mean trough and peak concentrations of SMX were 70.7 ± 7.3 ug/ml and 105.6 ± 10.9 ug/ml, respectively. Distribution and Metabolism.- TMP is 45% and SMX is 66% bound to plasma protein. Tissue concentrations of SMX are usually less than concurrent serum or plasma concentrations. Fries and colleagues- have shown that the concentrations of SMX and TMP in most tissues, including inflamed meninges, are approximately 20% and 30 to 50%, respectively, of the concomitant plasma concentrations. TMP often penetrates extravascular tissues, especially fatty tissues, to a greater extent than does SMX. Concentrations of TMP in saliva, human breast milk, noninflamed prostatic tissue, seminal fluid, inflamed lung tissue, and bile often exceed those in serum.' Specifically, concentrations of TMP in prostatic fluid are usually at least 3 times the serum concentrations.?" Both TMP and SMX cross the human placenta. Minimal information is available about concentrations of either antibiotic in brain tissue. Studies in rhesus monkeys have shown brain concentrations of TMP and SMX to be approximately 50% and 5 to 15% of serum concentrations, respectively.'? Penetration of the cerebrospinal fluid by TMP and SMX in patients with noninflamed meninges is equivalent to about 20% and 12% of the serum concentration, respectively. In the cerebrospinal fluid, peak concentrations of TMP occur significantly earlier than peak concentrations of SMX (60 minutes versus 480 minutes after infusionj.U" Ten to 30% of TMP is metabolized. About 20% of SMX is metabolized by means of N4 acetylation or glucuronide conjugation.' The metabolites of both antibiotics are bacteriologically inactive. Excretion.-In patients with normal renal function, the plasma half-lives of TMP and SMX are approximately 11 and 9 hours, respectively.P Both the parent compounds and the metabolites of TMP and SMX are excreted in the urine; however, only the parent compounds of both drugs are excreted in the bile. When the creatinine clearance decreases to less than 30 ml/min, the dosage of TMP-SMX should be adjusted. The initial dose or loading dose remains unchanged. One recommendation for subsequent modification of the dose is to decrease the total dose per 24 hours by half

TRIMETHOPRIM-SULFAMETHOXAZOLE

1261

Trimethoprim

Fig. 1. At left, chemical structure oftrimethoprim (2,4-diamino-5[3,4,5-trimethoxybenzyl]pyrimidine). At right, chemical structure of sulfamethoxazole (3-fp-aminophenylsulfonamido]-5-methylisoxazole). (From Cockerill FR III, Edson RS: Trimethoprimsulfamethoxazole. Mayo Clin Proc 62:921-929,1987.)

(and to keep the frequency of administration constant) for a creatinine clearance from 15 to 30 ml/min. For a creatinine clearance of less than 15 ml/min, after the normal loading dose has been administered, subsequent total doses per 24 hours can be administered as a percentage of the loading dose that equals the percentage of renal function.v-" Furthermore, in this subgroup of patients, the dose can be either administered once daily or divided and given every 12 hours. Patients who undergo hemodialysis should receive a normal loading dose after each dialysis procedure and a repeated fractional dose as necessary every 24 hours between dialyses on the basis of peak and trough drug concentrations." Serum drug concentrations should be monitored in patients with renal insufficiency.

IPara-aminobenzoate I Sulfamethoxazole_- --

-1- ---

IFolic acid I Trimethoprim-----

---1----

\Folinic acid I

IPrecursorsl

.\

IPurines I

t

IDNAl Fig. 2. Diagram of mode of action of sulfamethoxazole and trimethoprim in inhibition of production of folinic acid. (From Cockerill FR III, Edson RS: Trimethoprim-sulfamethoxazole. Mayo Clin Proc 62:921-929,1987.)

1262 TRIMETHOPRIM-SULFAMETHOXAZOLE

Mayo Clin Proc, December 1991, Vol 66

Table I.-Commercially Available Preparations of Trimethoprim-Sulfamethoxazole Trade name

Preparation

Bactrim, Septra Bactrim, Septra Bactrim, Septra

Oral, one single-strength tablet Oral, one double-strength tablet Oral, liquid suspension, 1 teaspoon or5ml Intravenous, 5 ml

Bactrim, Septra

Trimethoprim (mg)

80

160

Sulfamethoxazole (mg)

400 800

40

200

80

400

From Cockerill FR III, Edson RS: Trimethoprim-sulfamethoxazole. Mayo Clin Proc 62:921-929, 1987.

SPECTRUM OF ACTIVITY, INDICATIONS, ing postcoital infections), administration of either one-half AND SUGGESTED DOSAGE single-strength tablet daily or one single-strength tablet on Table 2 shows the in vitro spectrum of activity of TMP-SMX alternate days is advised.r':" TMP-SMX is highly effective in acute bacterial prostatiagainst various gram-negative and gram-positive organisms tested in our laboratories. The susceptibilities of Neisseria tis when susceptible organisms are present. As mentioned gonorrhoeae, Streptococcus pneumoniae, and Haemophilus earlier, TMP accumulates in the prostate. When no pathogen influenrae are not shown. Howard and co-workers'? found is isolated-and particularly in men older than 35 years of that 98% of 874 strains of H. influenzae tested were suscep- age (in Whom Chlamydia is an unusual pathogen)-a trial of tible to TMP-SMX at concentrations of l ug/rnl ofTMP and TMP-SMX is reasonable. 16 ug/ml of SMX. Zackrisson and Brorson" reported that TMP-SMX is an effective alternative therapy for uncom95% of 180 strains of S. pneumoniae were sensitive to con- plicated gonococcal infections of the urogenital system and centrations of 0.5 ug/ml of TMP and 10.0 ug/ml of SMX. may be particularly useful with penicillinase-producing Most N. gonorrhoeae isolates are susceptible, although no strains of gonococci and in patients with multiple drug allerlarge series have been reported. Other microorganisms usu- gies. Various regimens have been highly successful (more ally susceptible to TMP-SMX include Brucella species, than 90% cure), including large single doses (four doubleChlamydia trachomatis, H. ducreyi, Moraxella (previously, strength tablets)" or nine single-strength tablets daily for 5 Branhamella) catarrhalis.t? Mycobacterium balnei days." In addition, TMP-SMX has been highly efficacious (marinum), M. kansasii, M. scrofulaceum, Nocardia asteroi- for treating oropharyngeal gonorrhea." TMP-SMX is inefdes, Pneumocystis carinii, Pseudomonas pseudomallei, and fective against syphilis; however, it seems promising for Salmonella typhi. Of note, TMP-SMX has virtually no treatment of lymphogranuloma venereum and chancroid (H. activity against anaerobes. The specific indications and ducreyii infections. TMP-SMX has been highly effective doses for TMP-SMX are summarized in Table 3 and dis- for treatment of concomitant C. trachomatis and N. cussed in the following text. gonorrhoeae infections of the genitourinary tract. 39,40 Most Genitourinary Tract Infections.- TMP-SMX is useful of the activity against C. trachomatis seems to be due to the for the treatment of chronic and recurrent infections of SMX component." the urinary tract caused by susceptible bacteria. Because of Gastrointestinal Tract Infections.-Because of increasthe emergence of TMP-SMX-resistant organisms, particu- ing numbers of ampicillin-resistant Shigella and Salmonella larly among Escherichia coli and Klebsiella species, alterna- strains, TMP-SMX may be considered an alternative antibitive empiric therapy (for example, quinolones) may be indi- otic for infections caused by these organisms. Anecdotal cated for urosepsis--especially for recurrent or relapsing reports, however, have described the existence of TMPurosepsis 20- 23-before culture and sensitivity results are SMX resistance among Shigella 42-45 and Salmonella available.v" strains." Most "short-course" antibiotic studies of young female TMP-SMX may be useful in treating enteric fever (S. patients with uncomplicated acute cystitis have shown excel- typhi and S. paratyphi), especially when chloramphenicollent results when TMP-SMX has been used: two double- resistant strains are isolated." Unfortunately, emerging restrength tablets as a single dose 27-32 or two double-strength sistance of Salmonella strains against TMP-SMX has been tablets daily for 3 days." Otherwise, conventional therapy noted." for female or male patients with cystitis is one doubleTMP-SMX may be effective therapy for infantile diarrhea strength tablet every 12 hours for 7 to 10 days. For prophy- caused by enteropathogenic E. COli. 49 The effectiveness of laxis against recurrent infections of the urinary tract (includ- TMP-SMX as prophylaxis against" and treatment of 51 trav-

Mayo Clin Proc, December 1991, Vol 66

eler's diarrhea has been demonstrated; however, alternative therapy with quinolones may be as beneficial.F TMP-SMX is ineffective against Campylobacter jejuni strains that may cause traveler's diarrhea." RespiratoryTractlnfections.-The activity ofTMP-SMX against S. pneumoniae and H. influenzae accounts for its usefulness in acute otitis media, sinusitis, bronchitis, and pneumonia. Specifically in acute otitis media, TMP-SMX may be particularly useful when ampicillin-resistant H. injluenzae isolates are sensitive to TMP-SMX.54-5? Prophylactically administered TMP-SMX also effectively decreases the recurrence of acute otitis media in children." Investigators have suggested that TMP-SMX is as effective as ampicillin for treatment of acute bronchitis" and as effective as doxycycline for prophylaxis against bacterial pulmonary infections in patients with chronic bronchitis and cystic fibrosis." Recent studies have implicated M. catarrhalis as an important cause of bronchitis and pneumonitis, especially in immunosuppressed patients. Because TMPSMX has excellent activity against M. catarrhalis, it is indicated for such infections. 19 P. carinii Pneumonia.-In immunosuppressed patients, P. carinii pneumonia is a life-threatening infection for which TMP-SMX is the antimicrobial agent of choice. The recommended starting dose is 20 mg/kg of TMP equivalent daily, divided into doses administered orally or intravenously at 6hour intervals. Often, however, this dose is excessive and must subsequently be decreased on the basis of serum levels of SMX. The serum concentration of SMX should be monitored so that peak levels of approximately 100 ug/ml can be achieved. The minimal duration of treatment should be 2 weeks in most immunosuppressed patients other than those with acquired immunodeficiency syndrome (AIDS).61 Most patients with AIDS should receive high-dose TMP-SMX for at least 3 weeks followed by maintenance therapy, although a shorter course (2 weeks) of high-dose therapy may be successful and result in fewer side effects.F Concurrent use of a corticosteroid for treatment of severe P. carinii pneumonia in patients with AIDS is suggesred.v-" Alternative therapy (for example, with pentamidine or dapsone) may be necessary in these patients who have severe reactions to TMP-SMX.65-6? Prospective studies have shown the usefulness of daily or thrice weekly administration of TMP-SMX (5 mg/kg and 25 mg/kg daily, respectively) in immunosuppressed patients who do not have AIDS.68,69 Prophylaxis is indicated in patients with human immunodeficiency virus infections and should be initiated when the CD4 helper cells decline to less than 200/mm3.?O In the only published prospective trial of primary prophylaxis against P. carinii pneumonia in patients with AIDS, TMPSMX administered as one double-strength tablet twice daily was shown to be highly effective in preventing occurrences

TRIMETHOPRIM-SULFAMETHOXAZOLE

1263

Table 2.---Susceptibility of Organisms to Trimethoprim Alone and to Trimethoprim-Sulfamethoxazole (TMP-SMX), Expressed as Cumulative Percentage of Isolates Inhibited-Mayo Clinic, 1989* Organismt Acinetobacter calcoaceticus var. anitratus Citrobacter diversus C. jreundii Enterobacter aerogenes E. agglomerans E. cloacae Escherichia coli Klebsiella oxytoca K. pneumoniae Morganella morganii Proteus mirabilis P. vulgaris Providencia rettgeri P. stuartii Pseudomonas aeruginosa P. cepacia P. fluorescens Serratia liquejaciens S. marcescens Staphylococcus saprophyticus Xanthomonas maltophilia

TMP-SMX Trimethoprimt (:5:0.5 and 9.5 J.Lg/ml)§ (:5:8 J.Lg/ml)§

100

78 100

100

100

96 89 96

95 88

37

67 99

100 85 82 60 81 71 I 94 2 92 86

NO I

67 98

96 87 89

82 74 69 43 I

100 7

100 83 83

22

*Results are for isolates from all sources. Breakpoints for susceptibility used in this summary represent clinical practices at the Mayo Clinic. Some of the breakpoints differ from those defined by the National Committee for Clinical Laboratory Standards (NCCLS). These differences are minor, and the percentage of strains susceptible would not be affected substantially by application of the NCCLS guidelines. ND = insufficient data (results from fewer than 10 isolates). tIn addition, the following microorganisms have been shown to be susceptible to trimethoprim-sulfamethoxazole: Brucella species, Chlamydia trachomatis, Haemophilus ducreyi, H. influenzae, Moraxella catarrhalis, Mycobacterium balnei (marinum), M. kansasii, M. scrofulaceum, Neisseria gonorrhoeae, Nocardia asteroides, Pneumocystis carinii, Pseudomonas pseudomallei, Salmonella typhi, Shigella species, and Streptococcus pneumoniae.

:j:Reported for isolates from urine, §Breakpoint minimal inhibitory concentration.

of Pneumocystis pneumonia." Daily therapy with one double-strength tablet or intermittent treatment (for example, thrice weekly) may also be beneficial." Recent experience suggests that TMP-SMX is as effective as or more effective than aerosolized pentamidine for prevention of second occurrences of P. carinii pneumonia in patients with AIDS. TMP-SMX is considerably less expensive that pentamidine, and the rate of upper lobe or extrapulmonary

Mayo Clin Proc, December 1991, Vol 66

1264 TRIMETHOPRIM-SULFAMETHOXAZOLE

Table 3.-Indications and Suggested Dosages for Trimethoprim-Sulfamethoxazole Dosage* Intravenous Oral Infection Genitourinary tract Upper urinary tract pyelonephritis Lower urinary tract Cystitis Single dose, female Conventional, female or male Urinary tract prophylaxis Asymptomatic bacteriuria (when treatment is indicated) Prostatitis Acute Chronic Venereal disease Neisseria gonorrhoeae (urethritis, cervicitis) Lymphogranuloma venereum Chancroid (Haemophilus ducreyi) Gastrointestinal tract Shigella Salmonella enteric fever Enteropathogenic Escherichia coli Adults Children Traveler's diarrhea prophylaxis Respiratory tract Otitis media Adults Children Acute bronchitis Prophylaxis against acute infectious exacerbations in chronic bronchitis Pneumocystis carinii pneumonia Treatment Prophylaxis

Nocardia asteroides infections

Tabletst

Frequency

Trimethoprim equivalent (mglkg/day)

Frequency

8-10

Every 6 h

Duration:j:

1 DS

Every 12 h

2DS

Once

1 DS liz SS Or 1 SS

Every 12 h Every day Every other day

7-10 days Variable Variable

1 DS

Every 12 h

7-10 days

1 DS Then 1 DS 1 DS

Every 6 h Every 12 h Every 12 h

4DS Or2DS 1 DS or 3 SS

Once Every 12 h Every 12 h

5 days 7-10 days

1 DS

Every 12 h

10 days

1 DS 1 DS

Every 6 h Every 6 h

8-10 8-10

Every 6 h Every 6 h

5-7 days 10-14 days

1 DS 5-7 mglkg/ day (liquid) 1 DS

Every 12 h Every 6 h

5-7

Every 6 h

5-7 days

Every 24 h

Duration of exposure

1 SS 8-10 mglkg/ day (liquid) 1 SS 1 SS

Every 6 h Every 8-12 h

7-10 days 7-10 days

Every 6 h Daily

7-10 days 7 days/mo or alternate weeks

2DS 1 DS

Every 6 h Twice daily, once daily, or thrice weekly§ Every 6 h

3 SS or 1 DS

10

Every 6 h

10-14 days

7-10 days 14-35 days Up to 12 wk

20

Every 6 h

2 wk (non-AIDS) 2-3 wk (AIDS)

10-15

Every 6 h

6 mo-l yr

*AIDS =acquired immunodeficiency syndrome. All doses are for adults unless otherwise specified. Oral doses: 1 single-strength tablet =80 mg of trimethoprim and 400 mg of sulfamethoxazole. 1 double-strength tablet = 160 mg of trimethoprim and 800 mg of sulfamethoxazole. tDS = double strength; SS = single strength. :j:Duration refers to the entire period of the treatment regimen, whether the initial treatment is intravenous and the subsequent treatment is oral or the entire treatment regimen is oral or intravenous therapy alone. §See text. Modified from Cockerill FR III, Edson RS: Trimethoprim-sulfamethoxazole. Mayo Clin Proc 62:921-929, 1987.

TRIMETHOPRIM-SULFAMETHOXAZOLE

Mayo Clin Proc, December 1991, Vol 66

pneumocystosis in patients who receive prophylaxis with pentamidine may be unacceptable. Prophylaxis with TMPSMX may also prevent toxoplasmosis infections in patients with AIDS.73 Untoward reactions in patients with AIDS may preclude prophylaxis with TMP-SMX; in such patients, inhaled pentamidine or TMP and dapsone may be indicated for prophylaxis or treatment." N. asteroides Infections.-TMP-SMX is a valuable antimicrobial agent for treatment of N. asteroides infections." Although in vitro susceptibility testing is difficult to perform and interpret, if resistance to TMP-SMX is demonstrated and the infection is poorly controlled, other antimicrobial agents should be used alone or in combination with TMP_SMX.76,77 The recommended initial daily dose is 10 to 15 mg/kg ofthe TMP component divided into doses administered every 6 hours, the higher-range doses being used for infections of the central nervous system. General Prophylaxis in Immunosuppressed Patients (Those Without AIDS).-In most studies in which prophylaxis with TMP-SMX has been used, a decreased incidence of bacterial infections in patients with granulocytopenia and a decreased incidence of P. carinii pneumonia during immunosuppressive therapy have been demonstrated.P:" Recent studies have reported the emergence of resistant Enterobacteriaceae in patients treated prophylactically with TMP_SMX.78,80.82.84.8S The importance of this finding is unknown. In selected patients, short oral courses of TMPSMX are perhaps beneficial for limited sterilization of the gut (that is, elimination of Enterobacteriaceae and retention of intestinal anaerobes). For example, patients with neutropenia who undergo bone marrow transplantation and who are at high risk for development of serious gram-negative infections might benefit from such a regimen, although alternative antimicrobial agents such as quinolones administered prophylactically may be as effective." TMP-SMX may produce or exacerbate neutropenia, which may complicate the immune status of already immunosuppressed patients. Other Possible Indications.-Other uses for TMP-SMX are empiric at this time. Isolated cases of melioidosis (P. pseudomallei s." P. cepacia endocarditis," P. cepacia meningitis,"? brucellosis.P':? Legionella micdadei pneumonitis,93,94 Listeria monocytogenes meningitis.v" Isospora belli gastroenteritis," donovanosis (granuloma inguinale),99 Wegener's granulomatosis.P"!" and Whipple's disease'?' have been ameliorated or cured with use of this combination drug. Theoretically, TMP-SMX should be advantageous against malaria-causing species and Toxoplasma gondii, but clinical experience is lacking." In vitro susceptibility data demonstrate inhibition of some mycobacteria by TMP-SMX. M. kansas ii, M. balnei (marinum), and M. scrofulaceum are moderately sensitive,

1265

Table 4.-Adverse Reactions Attributed to Trimethoprim-Sulfamethoxazole in 1,121 Patients* Reaction

Patients No. %

Alimentary tract Upper (nausea, vomiting,anorexia) Lower (diarrhea)

36 6

3.2 0.5

Skin (erythema,urticaria, itch)

38

3.4

4 2 2 1 1 1

0.4 0.2 0.2 <0.1 <0.1 <0.1

Other Increase in serum creatinineconcentration Fever Vertigo Superinfection(oral Candida infection) Renal tubular acidosis Thrombocytopenia

*Nopatient in this studyhad acquiredimmunodeficiency syndrome (AIDS).

From Jick.106 By permissionof the Universityof Chicago.

whereas M. tuberculosis and M. chelonae (formerly, chelonei) are generally resistant. Other mycobacteria show variable susceptibility. lOS Additional clinical studies will be necessary to assess the efficacy of TMP-SMX against susceptible mycobacteria.

ADVERSE REACTIONS Table 4 summarizes reactions to TMP-SMX, as observed by Jick 106 in 1,121 patients without AIDS. Serious adverse reactions associated with the use of TMP-SMX in patients without AIDS are rare; they include anaphylaxis, severe cutaneous eruptions, and hematologic effects such as thrombocytopenia, leukopenia, and hemolytic anemia. Leucovorin may overcome the bone marrow suppression associated with TMP-SMX therapy in patients without human immunodeficiency virus infection. TMP-SMX should not be given to patients with a demonstrated deficiency of folic acid or glucose-6-phosphate dehydrogenase. Severe cytopenias may occur with concomitant use of methotrexate; thus, this combination should be avoided. 107,108 More frequent but less serious side effects include nausea, vomiting, and diarrhea. In contrast with the data in Table 4, a much higher frequency of reactions (as high as 70%)-especially skin rashes, cytopenias, and hepatotoxicity-occurs in patients with AIDS.6S,109,11O Use of TMP-SMX is contraindicated in women who are pregnant. TMP-SMX may potentiate the effects of warfarin, phenytoin, tolbutamide, and chlorpropamide.'!' Furthermore, crystalluria may occur with use of high doses of TMP-SMX, particularly in patients who have severe renal insufficiency.

1266 TRIMETHOPRIM-SULFAMETHOXAZOLE

REFERENCES I. Reeves DS: Sulphamethoxazole/trimethoprim: the first two years. 1 Clin Pathol 24:430-437, 1971 2. Patel RB, Welling PG: Clinical pharmacokinetics of cotrimoxazole (trimethoprim-sulphamethoxazole). Clin Pharmacokinet 5:405-423,1980 3. Nunn PP, Allistone lC: Resistance to trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonia: implication of folinic acid. Chest 86: 149-150, 1984 4. Bach MC, Gold 0, Finland M: Absorption and urinary excretion of trimethoprim, sulfamethoxazole, and trimethoprim-sulfamethoxazole: results with single doses in normal young adults and preliminary observations during therapy with trimethoprim-sulfamethoxazole. 1 Infect Dis 128 (Suppl):S584-S598, 1973 5. Grose WE, Bodey GP, Loo TL: Clinical pharmacology of intravenously administered trimethoprim-sulfamethoxazole. Antimicrob Agents Chemother 15:447-451, 1979 6. Fries N, Keuth U, Braun IS: Untersuchungen zur Liquorgangigkeit von Trimethoprim im Kindesalter. Fortschr Med 93:1178-1183,1975 7. Robb CA, Carroll PT, Tippett LO, Langston JB: The diffusion of selected sulfonamides, trimethoprim, and diaveridine into prostatic fluid of dogs. Invest Urol 8:679-685, 1971 8. Winningham DG, Nemoy Nl, Stamey TA: Diffusion of antibiotics from plasma into prostatic fluid. Nature 219:139-143,1968 9. Meares EM lr: Observations on activity of trimethoprimsulfamethoxazole in the prostate. 1 Infect Dis 128 (Suppl): S679-S685, 1973 10. Craig WA, Kunin CM: Distribution of trimethoprim-sulfamethoxazole in tissues of rhesus monkeys. 1 Infect Dis 128 (Suppl):S575-S579, 1973 11. Dudley MN, Levitz RE, Quintiliani R, Hickingbotham 1M, Nightingale CH: Pharmacokinetics of trimethoprim and sulfamethoxazole in serum and cerebrospinal fluid of adult patients with normal meninges. Antimicrob Agents Chemother 26:811-814, 1984 12. Wang EEL, Prober CG: Ventricular cerebrospinal fluid concentrations of trimethoprim-sulfamethoxazole. 1 Antimicrob Chemother 11:385-389, 1983 13. Welling PG, Craig WA, Amidon GL, Kunin CM: Pharmacokinetics of trimethoprim and sulfamethoxazole in normal subjects and in patients with renal failure. 1 Infect Dis 128 (Suppl):S556-S566, 1973 14. Bourgault A-M, Van Scoy RE, Brewer NS, Rosenow EC III: Trimethoprim with sulfamethoxazole for treatment of infection with Pneumocystis carinii in renal insufficiency. Chest 74:91-92, 1978 15. Van Scoy RE, Wilson WR: Antimicrobial agents in adult patients with renal insufficiency: initial dosage and general recommendations. Mayo Clin Proc 62: 1142-1145, 1987 16. Craig WA, Kunin CM: Trimethoprim-sulfamethoxazole: pharmacodynamic effects of urinary pH and impaired renal function; studies in humans. Ann Intern Med 78:491-497, 1973 17. Howard AI, Hince Cl, Williams ID: Antibiotic resistance in Streptococcus pneumoniae and Haemophilus influenzae: report of a study group on bacterial resistance. Br Med 1 1:1657-1660,1978

Mayo CUn Proc, December 1991, Vol 66

18. 19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

Zackrisson G, Brorson l-E: Antibiotic sensitivity pattern of recent clinical isolates of Streptococcus pneumoniae. Acta Pathol Microbiol Scand (B) 89:25-28, 1981 Forsgren A, Walder M: Activity of common antibiotics against Branhamella catarrhalis, Haemophilus influenzae, pneumococci, group A streptococci, and Staphylococcus aureus in 1983. Acta Otolaryngol [Suppl] (Stockh) 407:43-49, 1984 Allais 1M, Preheim LC, Cuevas TA, Roccaforte IS, Mellencamp MA, Bittner Ml: Randomized, double-blind comparison of ciprofloxacin and trimethoprim-sulfamethoxazole for complicated urinary tract infections. Antimicrob Agents Chemother 32: 1327-1330, 1988 Cox CE: A comparison of enoxacin and co-trimoxazole in the treatment of patients with complicated urinary tract infections. 1 Antimicrob Chemother 21 (Suppl B): 113-118, 1988 Seidmon El, Krisch EB, Truant AL, Amy BG, Childs SI, Hurst AT, McCabe RE: Treatment of recurrent urinary tract infection with norfloxacin versus trimethoprim-sulfamethoxazole. Urology 35:187-193,1990 Chan MK, Wong WT, Yin PD, Cheng IKP: A double-blind controlled trial of norfloxacin versus cotrimoxazole in the treatment of urinary tract infections. Br 1 Clin Pract 43:6163, 1989 Tungsanga K, Chongthaleong A, Udomsantisuk N, Petcharabutr O-A, Sitprija V, Wong ECK: Norfloxacin versus co-trimoxazole for the treatment of upper urinary tract infections: a double blind trial. Scand 1 Infect Dis Suppl 56:28-34, 1988 Wong WT, Chan MK, Li MK, Wong WS, Yin PD, Cheng IKP: Treatment of urinary tract infections in Hong Kong: a comparative study of norfloxacin and co-trimoxazole. Scand J Infect Dis Suppl 56:22-27, 1988 Bow El, Rayner E, Louie TJ: Comparison of norfloxacin with cotrimoxazole for infection prophylaxis in acute leukemia: the trade-off for reduced gram-negative sepsis. Am 1 Med 84:847-854, 1988 Rubin RH, Fang LST, Jones SR, Munford RS, Slepack JM, Varga PA, Onheiber L, Hall CL, Tolkoff-Rubin NE: Singledose amoxicillin therapy for urinary tract infection: multicenter trial using antibody-coated bacteria localization technique. JAMA 244:561-564,1980 Ludwig P, Buckwold F, Harding G, Ronald A, Thompson L, Slutchuk M, Shaw J: Single-dose therapy of acute cystitis in adult females: prospective randomized comparison of four regimens. In Current Chemotherapy and Infectious Disease. Vol 2. Edited by JD Nelson, C Grassi. Washington, DC, American Society for Microbiology, 1980, pp 1297-1298 Tolkoff-Rubin NE, Weber D, Fang LST, Kelly M, Wilkinson R, Rubin RH: Single-dose therapy with trimethoprimsulfamethoxazole for urinary tract infection in women. Rev Infect Dis 4:444-448, 1982 Prentice RD, Wu LR, Gehlbach SH, Hanlon IT, ClappChanning NE, Finn AL: Treatment of lower urinary tract infections with single-dose trimethoprim-sulfamethoxazole, 1 Fam Pract 20:551-557, 1985 Counts GW, Stamm WE, McKevitt M, Running K, Holmes KK, Turck M: Treatment of cystitis in women with a single dose of trimethoprim-sulfamethoxazole. Rev Infect Dis 4:484-490,1982

Mayo CUn Proc, December 1991, Vol 66

32.

33.

34.

35.

36. 37. 38. 39.

40.

41. 42. 43. 44. 45.

46. 47. 48. 49.

Fihn SD, Johnson C, Roberts PL, Running K, Stamm WE: Trimethoprim-sulfamethoxazole for acute dysuria in women: a single-dose or lO-day course; a double-blind, randomized trial. Ann Intern Med 108:350-357, 1988 Trienekens TAM, Stobberingh EE, Winkens RAG, Houben AW: Different lengths of treatment with co-trimoxazole for acute uncomplicated urinary tract infections in women. BMJ 299: 1319-1322, 1989 Harding GKM, Buckwold FJ, Marrie TJ, Thompson L, Light RB, Ronald AR: Prophylaxis of recurrent urinary tract infection in female patients: efficacy of low-dose, thriceweekly therapy with trimethoprim-sulfamethoxazole. JAMA 242:1975-1977,1979 Stapleton A, Latham RH, Johnson C, Stamm WE: Postcoital antimicrobial prophylaxis for recurrent urinary tract infection: a randomized, double-blind, placebo-controlled trial. JAMA 264:703-706,1990 Svindland HB: Treatment of gonorrhoea with sulphamethoxazole-trimethoprim: lack of effect on concomitant syphilis. Br J Vener Dis 49:50-53, 1973 Lawrence A, Phillips I, Nicol C: Various regimens of trimethoprim-sulfamethoxazole used in the treatment of gonorrhea. J Infect Dis 128 (Suppl):S673-S(i78, 1973 Wulf HC, Bech-Thomsen N: Two-day trimethoprim-sulfamethoxazole treatment of pharyngeal gonorrhea. Sex Transm Dis 15:116-118,1988 Brunham RC, Kuo C-C, Stevens CE, Holmes KK: Treatment of concomitant Neisseria gonorrhoeae and Chlamydia trachomatis infections in women: comparison of trimethoprim-sulfamethoxazole with ampicillin-probenecid. Rev Infect Dis 4:491-499,1982 Stamm WE, Guinan ME, Johnson C, Starcher T, Holmes KK, McCormack WM: Effect of treatment regimens for Neisseria gonorrhoeae on simultaneous infection with Chlamydia trachomatis. N Engl J Med 310:545-549, 1984 Hammerschlag MR: Activity of trimethoprim-sulfamethoxazole against Chlamydia trachomatis in vitro. Rev Infect Dis 4:500-505,1982 Finlayson M: Shigella sonnei resistant to cotrimoxazole (letter to the editor). Can Med Assoc J 123:718; 721, 1980 Nelson JD, Kusmiesz H, Shelton S: Oral or intravenous trimethoprim-sulfamethoxazole therapy for shigellosis. Rev Infect Dis 4:546-550, 1982 Nikkah J, Mehr-Movahead A: Antibiotic resistance among Shigella species isolated in Tehran, Iran. Ann Trop Med Parasitol 82:481-483, 1988 Barg NL, Hutson FS, Wheeler LA, Thomson CJ, Amyes SG, Wharton M, Schaffner W: Novel dihydrofolate reductases isolated from epidemic strains of trimethoprimlsulfamethoxazole-resistant Shigella sonnei. J Infect Dis 162: 466-473, 1990 Murray BE: Resistance of Shigella, Salmonella, and other selected enteric pathogens to antimicrobial agents. Rev Infect Dis 8 (SuppI2):SI72-S181, 1986 Datta N, Richards H, Datta C: Salmonella typhi in vitro acquires resistance to both chloramphenicol and co-trimoxazole. Lancet 1:1181-1183, 1981 Bryan JP, Rocha H, Scheld WM: Problems in salmonellosis: rationale for clinical trials with newer l3-lactam agents and quinolones. Rev Infect Dis 8:189-207,1986 Thoren A, Wolde-Mariam T, Stintzing G, Wadstrom T, Habte D: Antibiotics in the treatment of gastroenteritis

TRIMETHOPRIM-SULFAMETHOXAZOLE

50.

51.

52. 53.

54.

55.

56. 57.

58.

59.

60. 61. 62.

63.

64.

1267

caused by enteropathogenic Escherichia coli. J Infect Dis 141:27-31, 1980 DuPont HL, Evans DG, Rios N, Cabada FJ, Evans DJ Jr, DuPont MW: Prevention of travelers' diarrhea with trimethoprim-sulfamethoxazole. Rev Infect Dis 4:533-539, 1982 DuPont HL, Reves RR,Galindo E, Sullivan PS, Wood LV, Mendiola JG: Treatment of travelers' diarrhea with trimethoprimlsulfamethoxazole and with trimethoprim alone. N Engl J Med 307:841-844,1982 DuPont HL, Ericsson CD, Robinson A, Johnson PC: Current problems in antimicrobial therapy for bacterial enteric infection. Am J Med 82 (Supp14A):324-328, 1987 Ericsson CD, DuPont HL, Mathewson 11,West MS, Johnson PC, Bitsura JAM: Treatment of traveler's diarrhea with sulfamethoxazole and trimethoprim and loperamide. JAMA 263:257-261, 1990 Schwartz RH, Rodriguez WJ, Khan WN, Mann R, Barsanti RG, Ross S: Trimethoprim-sulfarnethoxazole in the treatment of otitis media caused by ampicillin-resistant strains of Haemophilus influenzae. Rev Infect Dis 4:514-516, 1982 Pelton SI, Shurin PA, Klein JO, Finland M: Quantitative inhibition of Haemophilus influenzae by trimethoprimlsulfamethoxazole. Antimicrob Agents Chemother 12:649654, 1977 Feldman W, Momy J, Dulberg C: Trimethoprim-sulfamethoxazole v. amoxicillin in the treatment of acute otitis media. Can Med Assoc J 139:961-964, 1988 Feldman W, Sutcliffe T, Dulberg C: Twice-daily antibiotics in the treatment of acute otitis media: trimethoprim-sulfamethoxazole versus amoxicillin-clavulanate. Can Med AssocJ 142:115-118,1990 Principi N, Marchisio P, Massironi E, Grasso RM, Filiberti G: Prophylaxis of recurrent acute otitis media and middleear effusion: comparison of amoxicillin with sulfamethoxazole and trimethoprim. Am J Dis Child 143:14141418, 1989 Chodosh S, Eichel B, Ellis C, Medici TC: Comparison of trimethoprim-sulfamethoxazole with ampicillin in acute infectious exacerbations of chronic bronchitis: a double-blind crossover study. Rev Infect Dis 4:517-527, 1982 Hughes DTD, Russell NJ: The use of trimethoprim-sulfamethoxazole in the treatment of chest infection. Rev Infect Dis 4:528-532, 1982 Sattler FR, Remington JS: Intravenous trimethoprim-sulfamethoxazole therapy for Pneumocystis carinii pneumonia. Am J Med 70:1215-1221,1981 Eeftinck Schattenkerk JKM, Lange JMA, van Steenwijk RP, Danner SA: Can the course of high dose cotrimoxazole for Pneumocystis carinii pneumonia in AIDS be shorter? A possible solution to the problem of cotrimoxazole toxicity. J Intern Med 227:359-362, 1990 Gagnon S, Boota AM, Fischl MA, Baier H, Kirksey OW, La Voie L: Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 323:1444-1450,1990 Bozzette SA, Sattler FR, Chiu J, Wu AW, Gluckstein D, Kemper C, Bartok A, Niosi J, Abramson I, Coffman J, Hughlett C, Loya R, Cassens B, Akil B, Meng T-C, Boylen CT, Nielsen D, Richman DD, Tilles JG, Leedom J, McCutchan JA, California Collaborative Treatment Group: A controlled trial of early adjunctive treatment with cortico-

1268 TRIMETHOPRIM-SULFAMETHOXAZOLE

65.

66.

67.

68.

69. 70. 71.

72.

73.

74.

75. 76. 77.

78.

steroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 323:14511457, 1990 Small CB, Harris CA, Friedland GH, Klein RS: The treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Arch Intern Med 145:837840, 1985 Wharton JM, Coleman DL, Wofsy CB, Luce JM, Blumenfeld W, Hadley WK, Ingram-Drake L, Volberding PA, Hopewell PC: Trimethoprim-sulfamethoxazole or pentamidine for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a prospective randomized trial. Ann Intern Med 105:37-44,1986 Sattler FR, Cowan R, Nielsen DM, Ruskin J: Trimethoprirnsulfamethoxazole compared with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a prospective, noncrossover study. Ann Intern Med 109:280-287, 1988 Hughes WT, Kuhn S, Chaudhary S, Feldman S, Verzosa M, Aur RJA, Pratt C, George SL: Successful chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med 297:1419-1426,1977 Hughes WT, Rivera GK, Schell MJ, Thornton D, Lott L: Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med 316:1627-1632, 1987 Sande MA, Volberding PA (eds): The Medical Management of AIDS. Philadelphia, WB Saunders Company, 1988 Fischl MA, Dickinson GM, La Voie L: Safety and efficacy of sulfamethoxazole and trimethoprim chemoprophylaxis for Pneumocystis carinii pneumonia in AIDS. JAMA 259:1185-1189,1988 Raviglione MC, Nsah EN, Cortes H, Mariuz P, Sanjana V: Intermittent co-trimoxazole prophylaxis against Pneumocystis carinii pneumonia (letter to the editor). Lancet 336:180, 1990 Solbreux P, Sonnet J, Zech F: A retrospective study about the use of cotrimoxazole as diagnostic support and treatment of suspected cerebral toxoplasmosis in AIDS. Acta Clin Belg 45:85-96, 1990 Medina I, Mills J, Leoung G, Hopewell PC, Lee B, Modin G, Benowitz N, Wofsy CB: Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med 323:776-782, 1990 Smego RA Jr, Moeller MB, Gallis HA: Trimethoprimsulfamethoxazole therapy for Nocardia infections. Arch Intern Med 143:711-718,1983 Wallace RJ Jr, Septimus EJ, Musher DM, Martin RR: Disk diffusion susceptibility testing of Nocardia species. J Infect Dis 135:568-576, 1977 Cockerill FR III, Edson RS, Roberts GD, Waldorf JC: Trimethoprim/sulfamethoxazole-resistant Nocardia asteroides causing multiple hepatic abscesses: successful treatment with ampicillin, amikacin, and limited computed tomography-guided needle aspirations. Am J Med 77:558-560, 1984 Gualtieri RJ, Donowitz GR, Kaiser DL, Hess CE, Sande MA: Double-blind randomized study of prophylactic trimethoprim/sulfamethoxazole in granulocytopenic patients with hematologic malignancies. Am J Med 74:934-940, 1983

Mayo CUn Proc, December 1991, Vol 66

79.

80.

81.

82.

83.

84.

85.

86. 87. 88.

MartinoP, Venditti M, Petti MC, Mandelli F, SerraP: Cotrimoxazole prophylaxis in patients with leukemia and prolonged granulocytopenia. Am J Med Sci 287:7-9, May/June 1984 EORTC International Antimicrobial Therapy Project Group: Trimethoprim-sulfamethoxazole in the prevention of infection in neutropenic patients. J Infect Dis 150:372379, 1984 Kovatch AL, Wald ER, Albo VC, Prin W, Orlando SJ, Wollman MR, Phebus CK, Shapiro ED: Oral trimethoprim/ sulfamethoxazole for prevention of bacterial infection during the induction phase of cancer chemotherapy in children. Pediatrics 76:754-760,1985 Goorin AM, Hershey BJ, Levin MJ, Siber GR, Gelber RD, Flynn K, Lew M, Beckett K, Blanding P, Sallan SE: Use of trimethoprim-sulfamethoxazole to prevent bacterial infections in children with acute lymphoblastic leukemia. Pediatr Infect Dis 4:265-269, 1985 Fox BC, Sollinger HW, Belzer FO, Maki DG: A prospective, randomized, double-blind study of trimethoprimsulfamethoxazole for prophylaxis of infection in renal transplantation: clinical efficacy, absorption of trimethoprim-sulfamethoxazole, effects on the microflora, and the cost-benefit of prophylaxis. Am J Med 89:255-274, 1990 Guerrant RL, Wood SJ, Krongaard L, Reid RA, Hodge RH: Resistance among fecal flora of patients taking sulfamethoxazole-trimethoprim or trimethoprim alone. Antimicrob Agents Chemother 19:33-38, 1981 Murray BE, Rensimer ER, DuPont HL: Emergence of highlevel trimethoprim resistance in fecal Escherichia coli during oral administration of trimethoprim or trimethoprim-sulfamethoxazole. N Engl J Med 306:130-135, 1982 Verhoef J, Rozenberg-Arska M, Dekker A: Prevention of infection in the neutropenic patient. Rev Infect Dis 11 (Suppl 7):S1545-S1550, 1989 Morrison 1M: Chronic melioidosis. Proc R Soc Med 63:289-290,1970 Neu HC, Garvey GJ, Beach MP: Successful treatment of Pseudomonas cepacia endocarditis in a heroin addict with trimethoprim-sulfamethoxazole. J Infect Dis 128 (Suppl): S768-S770, 1973

89. 90. 91. 92.

93. 94.

Darby CP: Treating Pseudomonas cepacia meningitis with trimethoprim-sulfamethoxazole. Am J Dis Child 130:13651366, 1976 Lal S, Modawal KK, Fowle ASE, Peach B, Popham RD: Acute brucellosis treated with trimethoprim and sulphamethoxazole. Br Med J 3:256-257, 1970 Hassan A, Erian MM, Farid Z, Hathout SD, Sorensen K: Trimethoprim-sulphamethoxazole in acute brucellosis. Br MedJ 3:159-160,1971 Jacobs F, Abramowicz D, Vereerstraeten P, Le Clerc JL, Zech F, Thys JP: Brucella endocarditis: the role of combined medical and surgical treatment. Rev Infect Dis 12:740-744,1990 Rudin IE, Wing EJ: A comparative study of Legionella micdadei and other nosocomial acquired pneumonia. Chest 86:675-680, 1984 Rudin IE, Evans TL, Wing EJ: Failure of erythromycin in treatment of Legionella micdadei pneumonia. Am J Med 76:318-320, 1984

Mayo Clio Proc, December 1991, Vol 66

95. 96.

97. 98.

99. 100. 101. 102. 103.

Levitz RE, Quintiliani R: Trimethoprim-sulfamethoxazole for bacterial meningitis. Ann Intern Med 100:881-890, 1984 . Spitzer PG, Hammer SM, Karchmer AW: Treatment of Listeria monocytogenes infection with trimethoprim-sulfamethoxazole: case report and review of the literature. Rev Infect Dis 8:427-430, 1986 GUnther G, Philipson A: Oral trimethoprim as follow-up treatment of meningitis caused by Listeria monocytogenes. Rev Infect Dis 10:53-55, 1988 DeHovitz JA, Pape JW, Boney M, Johnson WD Jr: Clinical manifestations and therapy of Isospora belli infection in patients with the acquired immunodeficiency syndrome. N Engl J Med 315:87-90, 1986 Latif AS, Mason PR, Paraiwa E: The treatment of donovanosis (granuloma inguinale). Sex Transm Dis 15:27-29, 1988 Specks U, DeRemee RA: Granulomatous vasculitis: Wegener's granulomatosis and Churg-Strauss syndrome. Rheum Dis Clin North Am 16:377-397, May 1990 DeRemee RA, McDonald TJ, Weiland LH: Wegener's granulomatosis: observations on treatment with antimicrobial agents. Mayo Clin Proc 60:27-32, 1985 Israel HL: Sulfamethoxazole-trimethoprim therapy for Wegener's granulomatosis. Arch Intern Med 148:22932295, 1988 Spiera H, Lawson W, Weinrauch H: Wegener's granulomatosis treated with sulfamethoxazole-trimethoprim: report of a case. Arch Intern Med 148:2065-2066, 1988

TRIMETHOPRIM-SULFAMETHOXAZOLE 1269

104. Viteri AL, Greene JF Jr, Chandler JB Jr: Whipple's disease, successful response to sulfamethoxazole-trimethoprim. Am J Gastroenterol 75:309-310,1981 105. Wallace RJ Jr, Wiss K, Bushby MB, Hollowell DC: In vitro activity of trimethoprim and sulfamethoxazole against the nontuberculous mycobacteria. Rev Infect Dis 4:326-331, 1982 106. Jick H: Adverse reactions to trimethoprim-sulfamethoxazole in hospitalized patients. Rev Infect Dis 4:426-428, 1982 107. Ferrazzini G, Klein J, Sulh H, Chung 0, Griesbrecht E, Koren G: Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia. J Pediatr 117:823-826,1990 108. Groenendal H, Rampen FH: Methotrexate and trimethoprim-sulphamethoxazole-a potentially hazardous combination. Clin Exp Derrnatol 15:358-360, 1990 109. Jaffe HS, Abrams 01, Ammann AJ, Lewis 'BJ, Golden JA: Complications of co-trimoxazole in treatment of AIDS-associated Pneumocystis carinii pneumonia in homosexual men. Lancet 2:1109-1111, 1983 110. Wofsy CB: Use of trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonitis in patients with acquired immunodeficiency syndrome. Rev Infect Dis 9 (SuppI2):SI84-S191, 1987 111. Lawson DH, Paice BJ: Adverse reactions to trimethoprim-sulfamethoxazole. Rev Infect Dis 4:429-433,1982