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PubMed1982

Emergence of high-level trimethoprim resistance in fecal Escherichia coli during oral administration of trimethoprim or trimethoprim--sulfamethoxazole.

The effect of daily administration of trimethoprim (TMP), trimethoprim--sulfamethoxazole (TMP--SMX), or placebo on aerobically grown fecal gram-negative bacteria was monitored in 136 students from the United States during a two-week diarrhea-prevention study in Mexico. Unlike patients in other studies with these agents, who had urinary-tract infection or granulocytopenia, most persons in this study had no change in total fecal Enterobacteriaceae and had high-level TMP and SMX resistance in virtually all these strains. Escherichia coli was the predominant TMP-resistant organism isolated; 96 per cent of 165 TMP-resistant Esch. coli isolates were resistant to at least four antimicrobial agents, and 25 per cent were resistant to seven. TMP resistance was transferable in 40 ot 100 strains tested. Despite the lack of TMP resistance in other studies of prophylaxis, our results clearly demonstrate the remarkable capacity for emergence and dissemination of resistance to this agent.

Anti-Bacterial Agents↗
PubMed2003

Addressing antibiotic resistance.

Management of uncomplicated urinary tract infections (UTIs) has traditionally been based on 2 important principles: the spectrum of organisms causing acute UTI is highly predictable (Escherichia coli accounts for 75% to 90% and Staphylococcus saprophyticus accounts for 5% to 15% of isolates), and the susceptibility patterns of these organisms have also been relatively predictable. As a result, empiric therapy with short-course trimethoprim-sulfamethoxazole (TMP-SMX) has been a standard management approach for uncomplicated cystitis.However, antibiotic resistance is now becoming a major factor not only in nosocomial complicated UTIs, but also in uncomplicated community-acquired UTIs. Resistance to TMP-SMX now approaches 18% to 22% in some regions of the United States, and nearly 1 in 3 bacterial strains causing cystitis or pyelonephritis demonstrate resistance to amoxicillin. Fortunately, resistance to other agents, such as nitrofurantoin and the fluoroquinolones, has remained low, at approximately 2%. Preliminary data suggest that the increase in TMP-SMX resistance is associated with poorer bacteriologic and clinical outcomes when TMP-SMX is used for therapy. As a result, these trends have necessitated a change in the management approach to community-acquired UTI. The use of TMP-SMX as a first-line agent for empiric therapy of uncomplicated cystitis is only appropriate in areas where TMP-SMX resistance prevalence is <10% to 20%. In areas where resistance to TMP-SMX exceeds this rate, alternative agents need to be considered.

Adult↗
PubMed2003

An intraindividual comparative study of psoralen-UVA erythema induced by bath 8-methoxypsoralen and 4, 5', 8-trimethylpsoralen.

BACKGROUND: Limited work has been conducted on the characteristics of topical trimethylpsoralen (TMP) psoralen-UVA (PUVA) erythema. OBJECTIVE: We sought to determine the time-course and dose-response characteristics of erythema induced by topical TMP, and to compare these parameters with those for topical 8-methoxypsoralen (MOP) within patients. METHODS: After photosensitization of one forearm with topical TMP, test sites were exposed to a UVA dose series. The procedure was repeated on the other forearm using 8-MOP solution. Erythema was assessed visually and with a reflectance instrument every 24 hours for 7 days. RESULTS: TMP PUVA erythema followed a similar time course to 8-MOP PUVA erythema. The majority of patients were at maximal erythema at or beyond 96 hours. TMP PUVA had a significantly steeper dose-response curve at 48, 72, and 96 hours compared with 8-MOP PUVA. CONCLUSION: On the basis of these data, the optimal time to read the TMP minimal phototoxic dose is 96 hours. In view of the steeper dose-response curve for TMP PUVA, a lower UVA incremental regimen should be considered compared with that for 8-MOP PUVA.

Adult↗
PubMed1991

Pharmacokinetics of a sulphamethoxazole/trimethoprim formulation in pigs after intravenous administration.

Plasma disposition, metabolism, protein binding and renal clearance of sulphamethoxazole (SMZ) and trimethoprim (TMP) were studied in four pigs after intravenous administration at a dose of 40 and 8 mg/kg, respectively. SMZ and TMP were quickly eliminated (mean elimination half-lives: 2.7 and 2.4 h, respectively). SMZ was predominantly acetylated; no hydroxy and glucuronide derivates could be detected in plasma and urine. TMP was 0-demethylated into 4-hydroxytrimethoprim (M1) and 3-hydroxytrimethoprim (M4) metabolite and subsequently extensively glucuronidated. SMZ, TMP and its M1 metabolite were excreted predominantly by glomerular filtration, while N4-acetylsulphamethoxazole and glucuronide conjugates of the M1 and M4 metabolites of TMP were actively eliminated by tubular secretion. The proportional drug percentage being present in the urine as parent compound was 13.1% for TMP and 16.0% for SMZ. The glucuronide conjugates of the M1 and M4 metabolites formed the main part (81.5%) of urinary TMP excretion pattern.

Animals↗
PubMed2001

Resistance to trimethoprim-sulfamethoxazole.

Sulfonamides have a glorious history. In 1935, they were the first class of true antimicrobial agents with life-saving potency. Today, 66 years later, increased bacterial resistance to sulfonamides and to trimethoprim (TMP), a synthetic antimicrobial agent that is 30 years younger than sulfonamides, has limited their use to only a few indications. In the treatment and prophylaxis of patients with urinary tract infections, trimethoprim-sulfamethoxazole (TMP-SMZ) or TMP alone is still considered the first-line drug of choice, although increased bacterial resistance to these agents has been linked with treatment failure. TMP-SMZ has a possible role as a second- or third-line treatment for patients who have respiratory tract infections. In the developing world, where this inexpensive drug is widely used as first-line treatment, bacterial resistance has caused problems, especially with regard to the treatment of patients with severe respiratory tract infections. Use of TMP-SMZ as prophylaxis for Pneumocystis carinii infection has rapidly increased the multidrug resistance of bacterial pathogens found in human immunodeficiency virus-infected patients. Today, detailed and reliable knowledge on the resistance of bacterial pathogens to both TMP-SMZ and TMP is an essential requirement for the safe and effective use of these drugs in all clinical settings.

Drug Resistance, Microbial↗
PubMed2002

Prevalence and predictors of trimethoprim-sulfamethoxazole resistance among uropathogenic Escherichia coli isolates in Michigan.

Resistance among uropathogenic Escherichia coli to trimethoprim-sulfamethoxazole (TMP-SMX) has increased. Risk factors for resistance and the impact on clinical failure have been poorly described. We performed a retrospective cohort study of women with acute uncomplicated cystitis seen at a university health center and at primary care clinics in southeastern Michigan from 1992 to 1999. The prevalence of TMP-SMX resistance increased from 8.1% to 15.8% (P=.01). Women who had taken TMP-SMX recently were >16 times as likely as women who had not taken antibiotics recently to be infected with an isolate resistant to this agent; those who had taken any other antibiotic were more than twice as likely to be infected with a resistant isolate. Women infected with a TMP-SMX-resistant isolate who were treated with TMP-SMX were >17 times as likely to have treatment failure. Recent antibiotic use is a risk factor for infection with a TMP-SMX-resistant isolate; patients who are infected with a TMP-SMX-resistant isolate and who are treated with this agent are at a higher risk for clinical failure.

Adolescent↗
PubMed2004

Comparison of atovaquone and azithromycin with trimethoprim-sulfamethoxazole for the prevention of serious bacterial infections in children with HIV infection.

BACKGROUND: Trimethoprim-sulfamethoxazole (TMP-SMZ) has been used extensively for the prevention of Pneumocystis carinii (also referred to as "Pneumocystis jiroveci") pneumonia (PCP) and other opportunistic infections in human immunodeficiency virus (HIV)-infected children. Because the efficacy of TMP-SMZ for treatment of bacterial infections is limited, it is sometimes poorly tolerated, and there is risk of emergence of drug-resistant strains associated with widespread use, we evaluated a regimen that included atovaquone and azithromycin. METHODS: A randomized, double-blind, placebo-controlled trial was designed to determine whether atovaquone-azithromycin had equivalent efficacy to TMP-SMZ for the prevention of serious bacterial infections and to compare the long-term tolerance, PCP breakthrough rates, and nonserious bacterial infection rates among HIV-infected children aged 3 months to 19 years. Children qualified for PCP prophylaxis (on the basis of Centers for Disease Control and Prevention recommendations) were randomized to receive atovaquone-azithromycin or TMP-SMZ daily for >or=2 years. RESULTS: Data from 366 of the 369 eligible patients (median duration of follow-up, 3 years) showed that the estimated rates of serious bacterial infection-related events were lower among atovaquone-azithromycin recipients than among TMP-SMZ recipients (17.3 vs. 24.2 events per 100 patient-years; difference, 6.9 events per 100 patient-years; 95% confidence interval [CI], -0.22 to 14.12). Rates for all end points (serious bacterial infection, PCP, Mycobacterium avium complex infection, and serious and nonserious bacterial infection-related deaths) were 19.7 and 27.7 events per 100 patient-years, respectively (difference, 7.9 events per 100 patient-years; 95% CI, -0.28 to 15.54 events per 100 patient-years). The results marginally favored atovaquone-azithromycin therapy statistically. Atovaquone-azithromycin and TMP-SMZ therapies had similar adverse event profiles. CONCLUSIONS: We conclude that, in HIV-infected children, atovaquone-azithromycin is as effective as TMP-SMZ for the prevention of serious bacterial infections and is similarly tolerated.

AIDS-Related Opportunistic Infections↗
PubMed2002

Efficacy of trimethoprim-sulfamethoxazole for the prevention of bacterial infections in a randomized prophylaxis trial of patients with advanced HIV infection.

We compared the occurrences of several types of infections in HIV-infected patients participating in a randomized clinical trial of three treatment strategies given for the primary prevention of Pneumocystis carinii pneumonia (PCP) and toxoplasmosis. In a phase III open label trial, 842 patients with HIV infection and fewer than 200 CD4+ cells/mm(3) received zidovudine (standard dose) plus one of three randomly assigned prophylactic agents: trimethoprim-sulfamethoxazole (TMP-SMZ), or dapsone (DAP), or aerosolized pentamidine (AP). Patients developing intolerance to treatment were crossed over to another predefined prophylactic therapy. Patients were monitored for infections every other week for 8 weeks and then monthly until the study was completed. Primary statistical models were proportional hazards models adapted to recurrent end points. In an intent-to-treat analysis, compared with AP and DAP, TMP-SMZ significantly reduced the risk of any bacterial infection (combining all distinct types) (p = 0.02 and p = 0.01, respectively). When considering distinct types separately, compared with AP, TMP-SMZ significantly reduced the risk of infectious diarrhea (p = 0.04); compared with DAP, AP and TMP-SMZ significantly reduced the risk of sinusitis/otitis media (p = 0.03 and p = 0.04, respectively); compared with AP and DAP, TMP-SMZ significantly reduced the risk of a second occurrence of pneumonia (p = 0.04 and 0.02, respectively). For any bacterial infection, infection rates per 100 patient-years of follow-up were 31, 39, and 38 for TMP-SMZ, DAP, and AP, respectively. In patients with advanced HIV infection not taking highly active antiretroviral therapy, the treatment strategy that initiates prophylaxis with TMP-SMZ is superior to those initiating with AP or DAP for preventing any bacterial infection, with most of the advantage manifested through infectious diarrhea, sinusitis/otitis media, and pneumonia.

AIDS-Related Opportunistic Infections↗
PubMed1997

Monoclonal antibodies to thymidine glycol generated by different immunization techniques.

Monoclonal antibodies specific for thymidine glycol in oxidized DNA were generated by immunization with thymidine glycol monophosphate (TMP-OH) or thymidine glycol (T-OH), respectively, conjugated to keyhole limpet hemocyanin (KLH) or thyreoglobulin (TG). Forty-five clones (TMP-OH) and 70 clones (T-OH) were examined upon antibody production in ELISA. Four clones secreting IgG1, kappa, were characterized further. In several studies the antibodies derived from the immunization with TMP-OH were inhibited by various inhibitors. In descending order of effectiveness, they were thymidine glycol monophosphate (TMP-OH), thymidine glycol (T-OH), thymidine monophosphate (TMP), and thymidine (Thn). After immunization with T-OH, antibodies were inhibited in following order: T-OH > TMP-OH > TMP > Thn. Inhibition by the bases thymine, adenine, cytosine, and guanine were negligible. In ISB (Immuno Slot Blot) performed with OsO4-treated DNA (Poly-[dA-dT]) and amount of 70 fmol thymidine glycol was detectable. DNA had to be irradiated at a level of at least 20 Gy to detect any damage in ELISA but at a lower level of irradiation (10 Gy) in ISB by one of these antibodies, TPS-1. The antibodies obtained after immunization with hapten-protein are therefore capable of the detection of low frequency lesions in DNA generated by free radicals after radiation or oxidative stress.

Animals↗
PubMedDate not supplied

Prevention of infection in the neutropenic patient.

All adult patients with acute nonlymphocytic leukemia--either first diagnosed or in relapse--who were admitted to University Hospital (Utrecht) between 1 December 1978 and 1 November 1980 were randomly assigned to a control group or to a group that received trimethoprim-sulfamethoxazole (TMP-SMZ) prophylactically; those admitted between 30 November 1980 and 1 December 1981 received a regimen of TMP-SMZ plus colistin; those admitted from 1 December 1981 to 1 December 1983 were randomized to receive TMP-SMZ plus colistin or neomycin plus colistin; and those admitted after 1 December 1983 were randomized to receive either ciprofloxacin alone or TMP-SMZ plus colistin. All agents were capable of preventing infections. However, the use of TMP-SMZ alone led to an increase in the number of infections caused by multiresistant microorganisms. The combination of TMP-SMZ plus colistin was superior to that of neomycin plus colistin. The new quinolone derivative ciprofloxacin was more effective than TMP-SMZ and was well tolerated. Antimicrobial prophylaxis with agents that provide adequate levels of drug in tissue prevents infections in granulocytopenic patients and is superior to that with nonabsorbable agents.

Agranulocytosis↗
PubMedDate not supplied

Trimethoprim once daily vs. nitrofurantoin in treatment of acute urinary tract infections in young women, with special reference to periurethral, vaginal, and fecal flora.

College women with acute urinary tract infections were assigned randomly to three groups: 110 received trimethoprim (TMP), 300 mg once a day for seven days (group 1); 104 received TMP, 200 mg once a day for 10 days (group 2); and 108 received nitrofurantoin, 100 mg four times a day for 10 days (group 3). All primary urinary pathogens were sensitive to TMP, and 98.8% were sensitive to nitrofurantoin. A satisfactory clinical response was achieved by the end of therapy in each group. Bacteriologic cures occurred in 100.0% of the TMP groups and 99.0% of the nitrofurantoin group by the end of therapy. By four weeks after therapy, bacteriologic cure rates were 87.0% in group 1, 93.0% in group 2, and 82.0% in group 3. Bacteria responsible for the recurrences remained sensitive to TMP and nitrofurantoin. Patients with positive and negative tests for antibody-coated bacteria had similar responses to therapy. After therapy there was minimal emergence of Enterobacteriaceae resistant to TMP or nitrofurantoin in the fecal and urogenital flora. Both TMP and nitrofurantoin were tolerated well and were effective for treatment of acute urinary tract infections in women.

Adult↗
PubMedDate not supplied

The use of trimethoprim-sulfamethoxazole in the treatment of chest infections.

The use of combinations of trimethoprim (TMP) and sulfamethoxazole (SMZ) for the treatment of chest infections is described. A number of studies have shown that TMP-SMZ is effective treatment for exacerbations of chronic bronchitis. The long-term use of TMP-SMZ as chemoprophylaxis of chronic bronchitis is also described. Conventional doses of TMP-SMZ (320 mg of TMP and 1600 mg of SMZ) have proved most effective in the prevention of chronic bronchitis; the drug combination is nontoxic and does not lead to the emergence of any resistant organisms. The use of TMP-SMZ for the treatment of pneumonia has been previously described. TMP-SMZ has also been found effective for long-term use in the treatment of cystic fibrosis.

Adult↗
PubMedDate not supplied

Prevention of travelers' diarrhea with trimethoprim-sulfamethoxazole.

One hundred forty-seven students from the United States were given trimethoprim-sulfamethoxazole (TMP-SMZ; 160 mg of TMP and 800 mg of SMZ) twice daily for 21 days after their arrival in Mexico. They were watched for the development of diarrhea during the 21 days and for an additional eight days after the termination of TMP-SMZ therapy. Diarrheal illness occurred in 11 (16%) of 67 students taking TMP-SMZ and in 44 (55%) of 80 students receiving a placebo; the differences were significant (P less than 0.001). Milder symptoms not quite satisfying the criteria for illness were also less common in the group receiving the active drug: 23% vs. 69% (P less than 0.001). The drug appeared to prevent infection by fully virulent enterotoxigenic Escherichia coli (strains producing heat-stable toxin and those producing heat-labile toxin) and perhaps by shigella strains. During the eight days of follow-up after drug administration, 14 students (26%) who had taken TMP-SMZ and two (2.5%) who had taken the placebo experienced diarrhea (P less than 0.05). Twelve subjects (14%) in the TMP-SMZ group and one subject (1%) in the placebo group developed a generalized rash that necessitated discontinuance of the drug. The eruption occurred after 9-16 days of drug administration (mean, 10 days). This study shows that TMP-SMZ taken twice daily can prevent travelers' diarrhea for up to three weeks. Diarrhea will develop, however, if the drug is stopped while the risk remains.

Adult↗
PubMedDate not supplied

Trimethoprim-sulfamethoxazole therapy for Pneumocystis carinii pneumonitis in children.

Trimethoprim-sulfamethoxazole (TMP-SMZ) is effective in both the treatment and the prevention of Pneumocystis carinii pneumonitis. After initial evaluation in an animal model, TMP-SMZ was shown to be as clinically effective as pentamidine isethionate for the treatment of pneumonitis in children with cancer and to have minimal adverse effects. Treatment with TMP-SMZ (20 mg of TMP and 100 mg of SMZ per kg of body weight per day) was successful in three-fourths of patients tested. Administered prophylactically, TMP-SMZ (5.0 mg of TMP and 25 mg of SMZ per kg of body weight per day) prevented P. carinii infection in high-risk immunocompromised patients. Studies of the unstructured delivery of prophylactic TMP-SMZ have demonstrated the regimen to be feasible and effective, with a favorable benefit-risk ratio for a large number of children with cancer.

Child↗
PubMed1985

Comparative study of ceftriaxone and trimethoprim-sulfamethoxazole for the treatment of chancroid in Thailand.

A single dose of ceftriaxone (250 mg) administered intramuscularly was compared with trimethoprim-sulfamethoxazole (TMP-SMZ; 160/800 mg) administered orally twice daily for seven days or with a single dose of TMP-SMZ (640/3,200 mg) administered orally for the treatment of chancroid in men in Thailand. Haemophilus ducreyi was isolated from 79 (48%) of 164 men with a clinical diagnosis of chancroid. For men with ulcers that were culture positive for H. ducreyi, rates of cure were 100% in 25 men treated with ceftriaxone, 87% in 23 men given TMP-SMZ for seven days, and 55% in 31 men given TMP-SMZ in a single dose. For men with ulcers that were culture negative for H. ducreyi, rates of cure were 100% in 29 men treated with ceftriaxone, 66% in 32 men given TMP-SMZ for seven days, and 63% in 24 men given TMP-SMZ in a single dose. The MIC50 of the three antibiotics for 94 isolates of H. ducreyi were as follows: 0.004 micrograms/ml for ceftriaxone, 16 micrograms/ml for trimethoprim, and greater than 512 micrograms/ml for sulfamethoxazole. Our study indicates that ceftriaxone in a single dose of 250 mg is effective, but that TMP-SMZ, even when given in a standard seven-day regimen, is not effective treatment for chancroid in Thailand.

Administration, Oral↗
PubMed1989

Emergence of highly trimethoprim-sulfamethoxazole-resistant Shigella in a native American population: an epidemiologic study.

Resistance to trimethoprim-sulfamethoxazole (TMP-SMX) emerged among Shigella isolates from the Navajo Reservation in the southwestern United States in 1985, years after this antimicrobial agent came into common use. In the study area, TMP-SMX resistance increased dramatically from 3 per cent in 1983 to 21 per cent in 1985. Resistance was polyclonal and occurred in both S. sonnei and S. flexneri. No single plasmid was common to all resistant strains. However, all 28 TMP-SMX resistant isolates examined were resistant to ampicillin and streptomycin and had minimum inhibitory concentrations to sulfamethoxazole of greater than or equal to 4,096 micrograms/ml and to trimethoprim of greater than or equal to 1,024 micrograms/ml. The authors found that 28 of 101 Navajo children with gastrointestinal symptoms who were not taking antimicrobials had TMP-SMX-resistant aerobic fecal flora. To determine risk factors for acquiring resistant strains, they compared 40 case-patients with TMP-SMX-resistant Shigella to 66 controls with TMP-SMX-sensitive Shigella. Case-patients were more likely than controls to have used antimicrobials recently (p = 0.004) and to be hospitalized for shigellosis (p = 0.05). These findings suggest that polyclonal highly TMP-SMX-resistant Shigella emerged by transfer of trimethoprim resistance genes from aerobic bowel flora to endemic Shigella strains, that use of antimicrobials can lead to symptomatic shigellosis and thus the persistence of trimethoprim-resistant Shigella, and that appropriate therapy of shigellosis on the reservation is now a major challenge.

Adolescent↗
PubMedDate not supplied

Intravenous trimethoprim-sulfamethoxazole alone or combined with tobramycin for infections in cancer patients.

A total of 120 episodes of infection in 113 cancer patients were treated with intravenous trimethoprim-sulfamethoxazole (TMP-SMX) alone (92 episodes) or with TMP-SMX plus continuous infusion tobramycin (28 episodes). The overall response rates were 47% and 75%, respectively. The majority of episodes had failed to respond to prior antibiotics. Pneumonia was the most common infection, and Klebsiella pneumoniae was the most common pathogen. TMP-SMX plus tobramycin cured 86% of episodes of septicemia and 76% of episodes of pneumonia, whereas TMP-SMX alone cured 20% and 42%, respectively. The initial neutrophil count did not appear critical in determining the outcome of infection. It was the change in the neutrophil count during the infection that appeared important. The outcome of infection was less favorable where abnormal renal and/or hepatic functions were documented. The sensitivity of the organism in vitro to TMP-SMX and/or tobramycin correlated well with the in vivo response. Intravenous TMP-SMX was well tolerated with a 4% incidence of reversible toxicity. A 15% incidence of renal toxicity was attributable to tobramycin. Intravenous TMP-SMX appears to be useful antimicrobial regimen for the therapy of infections caused by susceptible organisms in cancer patients.

Adolescent↗
PubMedDate not supplied

Antibiotic treatment of acute shigellosis: failure of cefamandole compared with trimethoprim/ sulfamethoxazole and ampicillin.

Intravenously administered ampicillin (AMP), trimethoprim-sulfamethoxazole (TMP-SMX) and cefamandole (CEF) were evaluated in 30 children with shigellosis: 11 children received AMP, 10 TMP-SMX, and 9 CEF for a maximum of five days. Discharge criteria included; afebrile greater than 12 hrs, less than 9 stools/day, absence of seizures, and adequate oral intake. AMP or TMP-SMX patients required significantly fewer median days to meet discharge criteria than those who received CEF. AMP and TMP-SMX patients had fewer median days with fever (one day each) compared with CEF (five days). On day five, 7 of 8 CEF, 3 of 10 AMP and 2 of 9 TMP-SMX treated patients remained culture positive. Inhibitory concentrations against all Shigella isolates from CEF patients all were less than or equal to 0.4 microgram CEF/ml. Intravenous TMP-SMX was equivalent to AMP in treatment of children with shigellosis, while CEF was ineffective despite in vitro activity. Clinical and bacteriologic responses were achieved with AMP and TMP-SMX in the majority of patients with less than 5 days of intravenous therapy.

Ampicillin↗