Trimethoprim-sulfamethoxazole (TMP-SMX), also known as co-trimoxazole, is a combination of two antimicrobial agents that act synergistically against a wide variety of bacteria.
The two components, TMP and SMX, work sequentially to inhibit enzyme systems involved in the bacterial synthesis of tetrahydrofolic acid (THF). Reduced availability of THF inhibits thymidine synthesis, which in turn inhibits DNA synthesis.
Maximal synergistic action occurs when microorganisms are susceptible to both component drugs. However, bacteria that are resistant to one drug component, but remain fully susceptible to the other drug, can still be inhibited by the combination.
TMP-SMX is effective against a wide variety of aerobic gram-positive and gram-negative bacteria, Pneumocystis, and some protozoa.
SPECTRUM OF ACTIVITY
TMP-SMX is effective against a wide variety of aerobic gram-positive and gram-negative bacteria, P. jirovecii, and some protozoa. As examples:
- Most methicillin-resistant Staphylococcus aureus are susceptible to TMP-SMX, particularly those that are community-acquired (eg, USA300 clone).
- Certain nosocomial pathogens are frequently inhibited by TMP-SMX. These include Burkholderia cepacia (formerly Pseudomonas cepacia), Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia) and Serratia marcescens.
However, many pathogens are typically resistant to TMP-SMX. These include Pseudomonas aeruginosa, Bacteroides fragilis (and most other anaerobes), Mycobacterium tuberculosis, Treponema pallidum, Campylobacter, penicillin-resistant pneumococci, and rickettsiae. In addition, resistance can develop among previously susceptible bacteria, using the mechanisms described above.
Bioavailability of TMP-SMX is approximately 85 percent for both compounds; absorption of TMP-SMX is not affected by food or other medications.
Dosing of TMP-SMX is based on the trimethoprim component.
The more common adverse reactions to TMP-SMX involve the gastrointestinal tract (nausea, vomiting) and skin (rash and pruritus).
Life-threatening effects, which are more likely to occur in HIV-infected patients and older adults, include neutropenia, uncommon severe dermatologic reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis.
TMP-SMX should be avoided during certain stages of pregnancy.
TMP-SMX can interact with a variety of drugs that may require adjustment of therapy and/or more frequent monitoring.
Sudden death, possibly due to hyperkalemia, has been reported among older patients who were prescribed TMP-SMX while also receiving spironolactone, an angiotensin converting enzyme (ACE) inhibitor, or an angiotensin receptor blocker (ARB). As an example, in a case-control study of individuals taking ACE inhibitors or ARBs, those who received TMP-SMX had an increased seven-day risk of sudden death compared with those who received amoxicillin (adjusted odds ratio 1.38, 95% CI: 1.09 to 1.76) 【BMJ. 2014;349:g6196】. However, these studies have substantial limitations, and higher quality evidence is needed to confirm these findings.
Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study.
- OBJECTIVE: To determine whether the prescription of co-trimoxazole with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker is associated with sudden death.
- DESIGN: Population based nested case-control study.
- SETTING: Ontario, Canada, from 1 April 1994 to 1 January 2012.
- PARTICIPANTS: Ontario residents aged 66 years or older treated with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. Cases were those who died suddenly shortly after receiving an outpatient prescription for one of co-trimoxazole, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantoin. Each case was matched with up to four controls on age, sex, chronic kidney disease, and diabetes.
- MAIN OUTCOME MEASURE: Odds ratio for the association between sudden death and exposure to each antibiotic relative to amoxicillin, after adjustment for predictors of sudden death according to a disease risk index.
- RESULTS: Of 39 879 sudden deaths, 1027 occurred within seven days of exposure to an antibiotic and were matched to 3733 controls. Relative to amoxicillin, co-trimoxazole was associated with an increased risk of sudden death (adjusted odds ratio 1.38, 95% confidence interval 1.09 to 1.76). The risk was marginally higher at 14 days (adjusted odds ratio 1.54, 1.29 to 1.84). This corresponds to approximately three sudden deaths within 14 days per 1000 co-trimoxazole prescriptions. Ciprofloxacin (a known cause of QT interval prolongation) was also associated with an increased risk of sudden death (adjusted odds ratio 1.29, 1.03 to 1.62), but no such risk was observed with nitrofurantoin or norfloxacin.
- CONCLUSIONS: In older patients receiving angiotensin converting enzyme inhibitors or angiotensin receptor blockers, co-trimoxazole is associated with an increased risk of sudden death. Unrecognized severe hyperkalemia may underlie this finding. When appropriate, alternative antibiotics should be considered in such patients.
CMAJ. 2015 Mar;187(4):E138-43. Epub 2015 Feb 2.
Trimethoprim-sulfamethoxazole and risk of sudden death among patients taking spironolactone.
- BACKGROUND: Trimethoprim-sulfamethoxazole increases the risk of hyperkalemia when used with spironolactone. We examined whether this drug combination is associated with an increased risk of sudden death, a consequence of severe hyperkalemia.
- METHODS: We conducted a population-based nested case-control study involving Ontario residents aged 66 years or older who received spironolactone between Apr. 1, 1994, and Dec. 31, 2011. Within this group, we identified cases as patients who died of sudden death within 14 days after receiving a prescription for trimethoprim-sulfamethoxazole or one of the other study antibiotics (amoxicillin, ciprofloxacin, norfloxacin or nitrofurantoin). For each case, we identified up to 4 controls matched by age and sex. We determined the odds ratio (OR) for the association between sudden death and exposure to each antibiotic relative to amoxicillin, adjusted for predictors of sudden death using a disease risk index.
- RESULTS: Of the 11 968 patients who died of sudden death while receiving spironolactone, we identified 328 whose death occurred within 14 days after antibiotic exposure. Compared with amoxicillin, trimethoprim-sulfamethoxazole was associated with a more than twofold increase in the risk of sudden death (adjusted OR 2.46, 95% confidence interval [CI]1.55-3.90). Ciprofloxacin (adjusted OR 1.55, 95% CI 1.02-2.38) and nitrofurantoin (adjusted OR 1.70, 95% CI 1.03-2.79) were also associated with an increased risk of sudden death, although the risk with nitrofurantoin was not apparent in a sensitivity analysis.
- INTERPRETATION: The antibiotic trimethoprim-sulfamethoxazole was associated with an increased risk of sudden death among older patients taking spironolactone. When clinically appropriate, alternative antibiotics should be considered in these patients.