Contemporary unconventional clinical use of co-trimoxazole

Authors

  • E. Goldberg,

    1. Infectious Diseases Unit, Rabin Medical Centre, Beilinson Hospital, and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Petah-Tiqva, Israel
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  • J. Bishara

    1. Infectious Diseases Unit, Rabin Medical Centre, Beilinson Hospital, and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Petah-Tiqva, Israel
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Corresponding author: J. Bishara, Infectious Diseases Unit, Rabin Medical Centre, Beilinson Hospital, Tel-Aviv, Petah-Tiqva 49100, Israel
E-mails: jihadb@clalit.org.il; bishara@netvision.net.il

Abstract

Clin Microbiol Infect 2012; 18: 8–17

Abstract

In the late 1960s, the combination of trimethoprim and sulphamethoxazole (co-trimoxazole) was introduced into clinical practice and used to treat many infectious diseases, such as urinary tract infections, respiratory infections, sexually transmitted diseases, Gram-negative sepsis, enteric infections and typhoid fever. Subsequently, co-trimoxazole was reported to be effective against numerous bacterial, fungal and protozoal pathogens, including Nocardia, Listeria monocytogenes, Brucella, Stenotrophomonas maltophilia, Burkholderia, Coxiella burnetii, Tropheryma whipplei, atypical mycobacteria, and Pneumocystis jirovecii. Among protozoal infections, in addition to toxoplasmosis, co-trimoxazole has been used to treat susceptible Plasmodium falciparum, Cyclospora and Isospora infections. Several retrospective and prospective studies have demonstrated good clinical outcome with co-trimoxazole in treating invasive methicillin-resistant Staphylococcus aureus infections. We summarize herein the accumulated evidence in the literature on the new, ‘unconventional’ clinical use of co-trimoxazole during the last three decades. In the era of widespread antibiotic resistance and shortage of new antibiotic options, large-scale, well-designed studies are needed to explore the tremendous potential concealed in this well-established drug.

Introduction

In the era of rapidly escalating antibiotic resistance, along with stagnation of novel antimicrobial production, better compliance with infection control measures and rational use of new antimicrobial agents has become more crucial than ever. In addition, every older antimicrobial agent in our arsenal should be maximally ‘squeezed’.

Trimethoprim–sulphamethoxazole (co-trimoxazole) is a well-established compound that is extensively used for various indications in countries with limited resources, offering an additional option in the battle against many pathogens, owing to its low cost, acceptable toxicity profile, availability by both oral and intravenous routes, and bactericidal activity. In the 1930s, a promising new compound was found to possess antimicrobial qualities, especially in animal models. This compound, Prontosil, was one of the first sulphonamide dyes to demonstrate antistreptococcal activity together with a good safety profile [1]. Several modified sulphonamide preparations were produced in later years, improving the safety and specific anti-infectious activity in different sites, such as the central nervous system (CNS), respiratory tract and urinary tract [2].

Trimethoprim was first synthesized during the 1950s, and immediately demonstrated antibacterial activity in vitro [3]. During the next decade, it was used in different clinical settings, such as chronic bronchitis, staphylococcal pneumonia, Gram-negative bacteraemia and urinary tract infections [4].

Because of the closely related mechanisms of action, the combination of trimethoprim and sulphamethoxazole (Fig. 1) was investigated immediately, and was found to be synergistic [4].

Figure 1.

 Trimethoprim–sulphamethoxazole molecular structure.

During the first 2 years of clinical experience, co-trimoxazole was reported to be effective in different clinical conditions, such as urinary tract infections, respiratory tract infections, sexually transmitted diseases, Gram-negative sepsis and typhoid fever [5]. However, widespread use of this drug has led to increasing resistance rates among enteric and respiratory pathogens, peaking during the 1990s [6]. Gradually, its use in these ‘conventional’ settings diminished, while other clinical uses were being explored.

During the last three decades, co-trimoxazole re-emerged as an effective treatment for numerous pathogens, including bacteria, fungi and parasites. Its effectiveness has been well documented in some studies, whereas in others the data are sparse and of low quality.

In this review, we present updated data regarding the ‘unconventional’ use of this drug, other than for nocardiosis, toxoplasmosis and Pneumocystis jiroveci pneumonia. Table 1 summarizes the reported literature on the clinical use of co-trimoxazole during the past three decades.

Table 1.   Summary of the reported literature on the clinical use of co-trimoxazole in the last three decades
PathogenReferencesSample sizePresentationSpecial populationComparator
TypeNo.
  1. ALL, acute lymphoblastic leukemia; Ami, amikacin; Amo, amoxycillin; Amp, ampicillin; Aug, augmentin; Azt, aztreonam; Benz. Pen., benzathine penicillin; CA-MRSA, community-acquired methicillin-resistant Staphylococcus aureus; Cef, ceftriaxone; Ceft, ceftazidime; CGD, chronic granulomatous disease; Chlor, chloramphenicol; Chlo, chloroquine; CI, confidence interval; Cip, ciprofloxacin; Cla, clarithromycin; Clin, clindamycin; CLL, chronic lymphocytic leukemia; Clox, cloxacillin; CNS, central nervous system; Cot, co-trimoxazole; Dox, doxycycline; Gen, gentamicin; HIV, human immunodeficiency virus; HSCT, hematopoietic stem cell transplantation; ICU, intensive-care unit; Imi, imipenem; Iso, isoniazid; ITP, idiopathic thrombocytopenic purpura; IVDU, intravenous drug user; Ket, ketoconazole; Lin, linezolid; MAC, mycobacterium avium complex; Mer, meropenem; Min, minocycline; Moxal, moxalactam; MRSA, methicillin-resistant Staphylococcus aureus; MSM, men who have sex with men; MSSA, methicillin-sensitive Staphylococcus aureus; NA, not assessed; Oflo, ofloxacin; Pen, penicillin; Pip, piperacillin; Plaq, plaquenil; PT, piperacillin–tazobactam; RA, rheumatoid arthritis; Rif, rifampin; RR, relative risk; SP, sulphadoxine–pirimethamine; S/P, status post; Strep, streptomycin; TC, ticarcillin–clavulanate; Tei, teicoplanin; Tet, tetracycline; UTI, urinary tract infection; Van, vancomycin; VAP, ventilator associated pneumonia; VP, ventriculoperitoneal.

Bacterial pathogens
 ActinomycesCase series316ActinomycetomaNACure with Cot + Gen + Dox
7ActinomycetomaNACure with Cot + Pen, Gen, Amo
Case report11CutaneousNACure
 BrucellaCase series628Epididymo-orchitisNA75–90% cure with Cot + Rif or Dox
7EndocarditisNACure with Cot + Tet + Strep
5EndocarditisNACure with Cot + Tet + Strep/Gen
14NeurobrucellosisNAAll alive, 8/14 no sequelae with Cot + Rif, Tet, Strep
33Skeletal brucellosisNA94% improved, 6% relapsed (Cot with Rif)
2MeningitisNACure with Cot + Rif/Dox
Retrospective2415BrucellosisNA13.8% relapse with Cot + Rif
2.5% relapse with Cot + Dox
92BrucellosisPregnantNAProtective against spontaneous abortion RR 0.14 (95% CI 0.06–0.37; p <0.0001)
Case report43EndocarditisNACure with Rif and/or Dox/Gen
1Breast abscessNACure with Dox
Meta-analysis1415BrucellosisNACot recommended as second line
RCT2280BrucellosisCot + Rif vs. Cot + DoxLess relapse with Dox than with Rif
Cure in 52/64 with Cot
330BrucellosisCot vs. Dox, Dox + Rif, Dox + StrepComparable to all regimens, inferior to Strep + Dox
Prospective116BrucellosisChildrenNA100% cure with Cot + Rif
 ListeriaCase report112Brain abscessMultiple myelomaNASuccess with Cot + Gen
ITPNASuccess with Cot
2MeningitisRANASuccess with Cot
NASuccess with Cot
1Vascular graft infectionAortic graftNASuccess with Cot + Aug
1EndocarditisNASuccess with Cot + Rif + Tei
1Spinal cord abscessNAClinical stabilization with Cot
1Bacteraemia and meningitisALLNAImproved after Cot was added
1TenosynovitisNASuccess with Amo + Gen + Cot
2BacteraemiaAIDSNASuccess with Cot
Liver transplantNASuccess with Cot
1OsteomyelitisCLLNASuccess with Cot
1Septic arthritisRANASuccess with Cot
1SepsisPregnantNASuccess with Cot + Amp + Gen
Case series18MeningoencephalitisNA100% cure with Cot alone
Case–control190ListeriosisSolid organ transplantationNAOR for listeriosis with Cot prophylaxis 0.07 (p 0.029)
Retrospective122MeningoencephalitisAge, alcohol, lymphoma, leukaemia, myelomaAmp ± Gen vs. Amp + Cot56% failure28.5% death
6.7% failure6.7% death
 AeromonasCase report41PneumoniaLung transplantNA
1ColitisMSMNA
1Pyomyositis NA
1Gastroenteritis NA
Case series25Foot traumaNAOne received cot as maintenance: successful
18Travellers’ diarrhoeaNATwo received Cot: both recovered
 StenotrophomonasCase report71VAPHead injuryNASuccessful treatment but recurrence
NASuccess
2EndocarditisVP shuntNASuccess with Cot + TC
2MeningitisPreterm babyNASuccess with Cot + Cip
NeurosurgeryNASuccess with Cot + Cip
1SepsisLiver transplantNASuccess with Cot + Min
1PeritonitisDialysisNASuccess with Cot + Gen
1OsteomyelitisS/P discectomyNASuccess with Cot + TC
 Retrospective26BacteraemiaHSCTNASuccess with Cot + Oflo
33SepsisICU patientsNA45.5% mortality with Cot alone or in combination
Systematic review113Skin infectionsHaematological malignancyNA9/13 patients recovered with Cot ± Ceft, TC, Cip, Azt, Moxal
 AchromobacterCase series24UTINATwo cured, one relapse, one lost to follow-up with Cot
4BacteraemiaCancerNAAll responded to treatment
Case report11Pulmonary infectionNASuccess with Cot + Pip
 Burkholderia pseudomalleiCase report111Neck abscessNACure with Ceft, Aug
1PericarditisNACure with Ceft, Dox, Aug
1ArthritisNACure with Ceft, Dox, Chlor
2ProstatitisNACure with Imi–Ceft, Dox, Aug
1Co-infection with Mycobacterium aviumNACure with Ceft, Dox, Chlor
1OsteomyelitisNACure with Ceft, Dox
2Lung massNACure with Ceft ± Dox
1Transverse myelitisNACure with Ceft
1Adrenal abscessNACure with Ceft
Case series35Cranial melioidosisNA83% cure with Ceft
2Liver abscessNATwo died with Ceft
9MelioidosisNAAll cured with Ceft, Mer, Aug
RCT3241Severe melioidosisCeft + Cot vs. CeftNo difference in mortality, more treatment change with Ceft alone
180MelioidosisCot + Dox vs. Cot + Dox + ChlorCot + Dox was as effective and showed more tolerance
102Severe melioidosisCef–Sul + cot vs. Ceft + CotNo difference in mortality, success or tolerance
 Burkholderia cepaciaCase report21Liver abscessCGDNASuccess
1MeningitisInfantNASuccess
Case series23MeningitisChildrenNASuccess
5EndocarditisIVDUNASuccess with polymyxin
 Coxiella burnetiiRetrospective253Acute Q-feverPregnancyNALong-term Cot therapy decreased obstetric complications, chronic Q-fever and placental infection
20EndocarditisNASuccessful treatment in 19/20 with Cot + Tet
Case series23EndocarditisNASuccess with Cot + Dox following valve replacement
5EndocarditisNASuccess with Cot + Tet
Case report12EndocarditisNASuccess with Cot but relapse
EndocarditisNASuccess with Cot + Tet
 Tropheryma whippleiCase series44EndocarditisNASuccess with Cot maintenance following Cef + Gen
2Classic Whipple’s diseaseNASuccess with Cot
18EndocarditisNA16/18 cured with Cot and Ceft, Cip, Dox, Plaq, Van, Gen
12Cerebral diseaseNA7/10 improved or stable with Cot + Cef, Amp, Amo, Strep, Dox, Rif
4EndocarditisNASuccess with Cot + Cef, Pen, Gen
Case report72EndocarditisNASuccess with Cot + Dox + Plaq
NASuccess with Cot + Cef
1Cerebral diseaseNASuccess with Cot + Cef
1OphthalmicRenal transplantNASuccess with Cot + Cef + Van
1Whipple’s diseaseNAFailure with Cot, resistance identified.
1Cerebral diseaseNASuccess with Cot + Mer
1Cerebral diseaseNARelapse with Cot after 14 months
Prospective cohort114Classic Whipple’s diseaseNA1/14 died, 3 did not respond to Cot, 10 improved but 5 failed late and 5 relapsed (Gen, Amo, Cef, PT as induction)
RCT140Whipple’s diseaseMer vs. Ceft with Cot maintenanceCure in 39/40 patients, 1 required change in therapy
Retrospective152Whipple’s diseaseNASuccess with 15/16 treated with Cot alone or with Pen + Strep
Comparative study (retrospective)130Whipple’s disease12 Cot vs. 22 Tet1/12 dead with Cot
6/22 dead with Tet
Success in 12/13 with Cot treatment cycle, and in 13/22 with Tet treatment cycle
 KlebsiellaCase series110DonovanosisNASuccess in all patients
 Granulomatis (donovanosis)Prospective1116DonovanosisNASuccess in 100%, recurrence in 2
Case report21Sclerosing granuloma inguinaleNASuccess
1Penile donovanosisNAFailure
 Staphylococcus aureusRetrospective738MRSA bacteraemia38 Cot vs. 76 Van25/38 survived with Cot
45/76 survived with Van
One relapse with Cot, 9 relapses with Van
54Skin and soft tissue—CA-MRSACot vs. 20 Clin26% failure with Cot, 25% failure with Clin
415Skin and soft tissue—CA-MRSAChildren215 Cot97.7% did not return to hospital with Cot
200 Clin96.5% did not return to hospital with Clin
6Acute otitis mediaChildrenNA6/6 cured with Cot + topical antibiotics
18Skin and soft tissue—CA-MRSANA14/18 cured with Cot ± Rif
27MRSA infections—skin (15), bacteraemia (4), renal abscess (3), arthritis (2), endocarditis (1), psoas abscess (1), meningitis (1)NA26/27 cured with Cot (one bactaeremia failed)
RCT713ImpetigoAboriginal children7 Cot vs. 6 Benz Pen7/7 cured with cot (5 MSSA and 2 CA-MRSA)
5/6 cured with Benz Pen (5 MSSA and 1 CA-MRSA)
190Uncomplicated skin abscess88 Cot vs. 102 placebo (all cases underwent drainage)17% failure with Cot
26% failure with placebo
9% recurrence with Cot
28% recurrence with placebo
149Uncomplicated skin abscessChildren73 Cot vs. 76 placebo (all cases underwent drainage)4.1% failure with Cot
5.3% failure with placebo
12.9% recurrence with Cot
26.4% recurrence with placebo
48Osteomyelitis28 Cot + Rif 8 weeks vs. 22 Clox 6 weeksSuccess in 24/27 with Cot + Rif
Success in 19/21 with Clox
34Skin and soft tissue infection14 (8 MRSA) Cot vs. 20 (15 MRSA) DoxSuccess in 6/8 MRSA with Cot
Success in 15/15 MRSA with Dox
40Ventilated severe burn patients—prophylaxis for MRSA pneumonia21 CotMRSA pneumonia in 1/21 with Cot, in 7/19 with placebo
19 placeboSuccess in MSSA:
43 Cot16/22 with Cot, 31/32 with Van
101MSSA + MRSA infectionsIVDU58 VanSuccess in MRSA: 21/21 with Cot, 26/26 with Van
Case report22EndocarditisPregnancy, IVDUNASuccess only after Cot was added to Van + Rif
1EndocarditisNAFailure with Lin, success with Cot + Gen
Case series12Infected bronchiectasisNACure when added to other antibiotics
3MRSA meningitisNA2/3 survived with Cot + Van
Prospective217Infected orthopaedic implantsNA10/17 cured with Cot alone
6/7 cured with implant removal
6OsteomyelitisNA5/6 cured with Cot
 MycobacteriumCase report41Mycobacterium tuberculosisImmunocompromisedNAClinical improvement with Cot
1Line sepsis with Mycobacterium fortuitumLeukaemiaNACure with Cot + Cip + Ami + Cla
1M. fortuitum lung abscessNACure with Cot
1M. fortuitum meningitisNACure with Cot + Rif
Case series22M. fortuitum skin infectionNACure with Cot
3Fish tank granuloma—Mycobacterium marinumNACure with Cot
Retrospective224M. marinum skin infectionNA13/19 improved with Cot
69Prophylaxis for M. avium complexHIVNA5/5 improved with Cot + Min
6/17 developed MAC infection with Cot prophylaxis
34/52 developed MAC infection with no prophylaxis
Protozoa
 AcanthamoebaCase report21CNS abscessLiver transplantNACure with Cot + Rif
3MeningitisNA2/3 survived with Cot + Rif + Ket
 PlasmodiumRCT857Uncomplicated Plasmodium falciparumChildrenCot + artesunate vs. Chlo + artesunate100% cure both groups
181Uncomplicated P. falciparumChildrenCot + artesunate vs. amodiaquine + artesunate100% cure both groups
218Recurrent uncomplicated malariaChildrenRif + Cot + Iso vs. mefloquin vs. quinine + SPClinical failure 0%, parasitological failure 9%
Clinical failure 0%, parasitological failure 0%
Clinical failure 1%, parasitological failure 3%
205Malaria pneumoniaChildrenCot vs. SPClinical and parasitological success 87%
Clinical and parasitological success 80%
98Uncomplicated P. falciparumChildrenCot (3 days) vs. Cot (5 days) vs. ChloCure rate 88.2%
Cure rate 84.8%
Cure rate 74.2%
268Uncomplicated malariaChildrenCot vs. SPCure rate 96.7%
Cure rate 94.5%
61Uncomplicated P. falciparumChildrenRif + Cot + Iso vs. chloroquine41/41 cured with no recurrence
7/20 cured with no recurrence
165Plasmodium vivax malariaChildrenCot vs. Chlo100% cured with both treatments
Faster parasite clearance with Chlor
 IsosporaCase report61DiarrhoeaHIVNADeath after 1 month
1DiarrhoeaThymomaNACure with recurrence
1DiarrhoeaIntestinal transplantNACure, no recurrence
1DiarrhoeaLiver transplantNACure, no recurrence
1DiarrhoeaRenal transplantNACure, no recurrence
1DiarrhoeaLymphomaNACure, no recurrence
Retrospective226DiarrhoeaHIVNAAll cured, 9 relapsed
20DiarrhoeaHIVNAAll cured, 47% recurrence, all responded to Cot
RCT222DiarrhoeaHIVCot vs. CipCure in 10/10 with Cot
32Prophylaxis following Isospora diarrhoeaHIVCot vs. SP vs. placeboCure in 9/12 with Cip, 3 failures cured with Cot
No recurrence
No recurrence
50% recurrence
 CyclosporaRetrospective26Travellers’ diarrhoeaNAAll cured
7Travellers’ diarrhoeaNAAll cured
Case series15DiarrhoeaNAAll cured
Case report11DiarrhoeaNACure
RCT320DiarrhoeaHIVCot vs. CipCure in 9/9 with Cot
Cure in 7/11 with Cip, 4 failures cured with Cot
19DiarrhoeaChildrenCot vs. placeboShorter time to clinical and parasitological remission with Cot
40DiarrhoeaCot vs. placebo94% cure with Cot
12% cure with placebo
Prospective18Travellers’ diarrhoeaNAAll improved with Cot ± quinolones

Bacterial Pathogens

Actinomyces

Evidence of in vitro susceptibility of Actinomyces to co-trimoxazole exists in the literature [7]. However, very few clinical data are available. Several case series describe successful treatment of actinomycetoma and skin infections with co-trimoxazole [8,9], usually in combination with other drugs, such as penicillin, ampicillin, gentamicin and doxycycline.

Aeromonas hydrophila

Aeromonas spp. have good in vitro susceptibility to co-trimoxazole [10], although there is a wide range of susceptibility, depending on the specific species and geographical location. There are sparse clinical data showing successful treatment of mainly gastroenteritis and skin and soft tissue infections with co-trimoxazole used as monotherapy [11,12], but they are derived from case series and case reports only.

Achromobacter

This emerging nosocomial pathogen shows over 75% susceptibility to co-trimoxazole in vitro. Clinical data consist of small case series [13,14] and case reports demonstrating good clinical outcome in most patients, especially in bacteraemia and urinary tract infection.

Stenotrophomonas maltophilia

This pathogen is a growing threat to hospitalized patients, especially if they are immunosuppressed. Susceptibility to co-trimoxazole has been known and reported for a long time. Clinical information has been derived from numerous case reports, including cases of endocarditis and meningitis. Retrospective studies have demonstrated clinical success in cases of bacteraemia or sepsis [15,16]. A systematic review of skin infections with this pathogen in patients with haematological malignancy demonstrated good cure rates [17]. However, resistance is already developing, and may limit the use of co-trimoxazole in this setting [18].

Brucella

This common zoonotic pathogen has been successfully treated with co-trimoxazole since the 1970s. However, owing to a lack of robust evidence, it is considered to be a second-line treatment [19]. The data derive from many case reports and case series dealing mainly with brucella endocarditis or CNS infection, usually in combination with other drugs such as rifampicin, doxycycline and gentamicin. Several retrospective and prospective studies have demonstrated the efficacy of co-trimoxazole in brucellosis, including in children [20] and pregnant women [21]. Two randomized controlled trials (RCTs) evaluated co-trimoxazole in the treatment of brucellosis. However, in one study, co-trimoxazole was included in both treatment arms [22]. The other study compared six different treatment regimens, including co-trimoxazole alone. All treatment arms were comparable, except for streptomycin plus doxycycline. In light of this information, co-trimoxazole can be considered as a treatment option for brucellosis, especially in pregnant women.

Burkholderia

Burkholderia cepacia  This Gram-negative pathogen causes severe infections, especially in patients with cystic fibrosis and chronic granulomatous disease. It is highly resistant to many antibiotics, but in vitro data show good sensitivity to co-trimoxazole. Clinical data derive from case reports and case series [23,24] only, and show good clinical response. No large-scale trial was found in the literature.

Burkholderia pseudomallei  This is the causative agent of melioidosis. It is a Gram-negative pathogen that is common in Southeast Asia, causing serious infections such as pneumonia, sepsis, intra-abdominal abscesses and skin infections, among both locals and returning travellers. Co-trimoxazole plays an important role in the treatment of this pathogen, although not as monotherapy, as most of the case reports and case series describe drug combinations, especially with ceftazidime. Two RCTs compared different regimens that included co-trimoxazole [25,26]. Another randomized trial compared the combination of co-trimoxazole and ceftazidime with ceftazidime alone, and found no significant difference in efficacy. However, there were fewer treatment changes with co-trimoxazole.

Listeria monocytogenes

Since the 1980s, co-trimoxazole has been used successfully in the treatment of L. monocytogenes, a Gram-positive bacillus that causes serious infections such as sepsis and meningitis, especially in older and immunosuppressed patients. Case reports and a case series demonstrated efficacy of co-trimoxazole in treating listeriosis, both in combination with other drugs (such as gentamicin, amoxycillin and rifampicin) and as monotherapy. A case–control study in solid organ transplant patients demonstrated that co-trimoxazole prophylaxis was a significant protective factor against listeriosis [27]. A retrospective study in patients with Listeria meningoencephalitis demonstrated superiority of co-trimoxazole with ampicillin over gentamicin with ampicillin [28]. Thus, co-trimoxazole is a legitimate option in the treatment of Listeria infections.

Coxiella burnetii

Very few data are available concerning the use of co-trimoxazole in Q-fever. Case reports showed success of co-trimoxazole alone or in combination with tetracyclines in the treatment of Q-fever endocarditis. A retrospective analysis of Q-fever endocarditis demonstrated good cure rates with co-trimoxazole and tetracycline [29]. Another retrospective study demonstrated the efficacy of prolonged co-trimoxazole therapy in pregnant women with acute Q-fever, preventing obstetric complications, chronic Q-fever and placental infection [30]. More data are required to assess the importance of co-trimoxazole in the treatment of Q-fever.

Tropheryma whipplei

This causative agent of Whipple’s disease has been treated with different drug combinations, including co-trimoxazole, especially as long-term maintenance therapy. Numerous case reports and case series showed the efficacy of co-trimoxazole in the treatment of CNS disease and classic Whipple’s disease, either alone or in combination with ceftriaxone, or doxycycline and others. One RCT compared meropenem with ceftriaxone as initial treatment of Whipple’s disease. Both groups received co-trimoxazole maintenance therapy, with excellent results [31]. Two retrospective studies demonstrated good results with co-trimoxazole alone or in combination with penicillin and streptomycin [32,33]. However, one prospective study [34] and some case reports raised the question of resistance to co-trimoxazole in patients with relapses or failures. Bearing this in mind, co-trimoxazole may still be considered as an important therapeutic option in Whipple’s disease.

Klebsiella granulomatis

Donovanosis is a sexually transmitted disease caused by K. granulomatis, formerly known as Calymmatobacterium granulomatis. Donovanosis is a rare condition limited to very few geographical locations, such as Papua New Guinea, South Africa, India and Brazil. Successful treatment with co-trimoxazole was documented in the early 1980s, both in a case series [35] and in a prospective study of 116 patients [36]. Although some recurrences and failures were documented in these studies [37], co-trimoxazole is considered to be a second-line choice in the European guidelines for the treatment of donovanosis [38].

Methicillin-resistant Staphylococcus aureus (MRSA)

S. aureus, especially MRSA, is one of the most important and problematic pathogens, both in healthcare-associated and in community-acquired infections. The mortality rate of inpatients with S. aureus infection is five times higher than in other patients. One of the factors contributing to the high mortality rate is the scarcity of effective and safe treatments, especially in the case of MRSA [39]. The last decade has revealed a growing incidence of community-acquired MRSA, affecting healthy individuals and spreading quickly across the globe.

Co-trimoxazole has been shown to be active against S. aureus (including MRSA) in vitro. Its components have synergistic bactericidal activity against S. aureus [40]. In our centre, the susceptibility of nosocomial bloodstream MRSA isolates to co-trimoxazole increased from 31% in 1988 to 92% in 1997 [41]. The same trends in susceptibility to co-trimoxazole were observed in the USA [42,43].

However, clinical evidence of co-trimoxazole efficacy against MRSA in vivo is very limited. There are a few case reports and case series demonstrating the efficacy of co-trimoxazole in MRSA endocarditis and pulmonary infection when used with other drugs. Surprisingly, we found seven randomized controlled trials, seven retrospective studies and two prospective studies evaluating co-trimoxazole in different staphylococcal infections. One RCT demonstrated the efficacy of co-trimoxazole in preventing MRSA pneumonia in severe burn patients [44]. Two other RCTs demonstrated that co-trimoxazole treatment prevented recurrences after drainage of community-acquired MRSA uncomplicated skin abscesses in adults and children [45,46]. Other skin and soft tissue infections and osteomyelitis caused by S. aureus were investigated in three RCTs, which indicated equal efficacy with co-trimoxazole and other antibiotics (penicillin, cloxacillin and doxycycline) [47–49]. The only RCT comparing co-trimoxazole with vancomycin was performed in the 1990s on intravenous drug abusers with S. aureus bacteraemia. Vancomycin showed superiority in methicillin-sensitive S. aureus infections, but was equal to co-trimoxazole in MRSA infections [50]. Several other small retrospective and prospective studies demonstrated good clinical outcome with co-trimoxazole in skin and soft tissue infections, infected orthopaedic implants, osteomyelitis and otitis media. In a retrospective cohort study comparing co-trimoxazole with vancomycin in the treatment of MRSA bacteraemia, we found similar mortality rates in both groups, and a lower relapse rate in the co-trimoxazole group [39]. Overall, it appears that co-trimoxazole is a promising option in treating MRSA, although well-designed RCTs comparing it with vancomycin are required.

Mycobacterium

In vitro susceptibility of different mycobacteria, including Mycobacterium tuberculosis, to sulphonamides and subsequently to co-trimoxazole has been investigated for decades, with varying results. However, there are several case reports and case series showing the efficacy of co-trimoxazole in infections with Mycobacterium fortuitum, Mycobacterium marinum and even M. tuberculosis [51]. A retrospective study showed a good clinical response to co-trimoxazole in patients with M. marinum skin infections. Another retrospective study demonstrated the efficacy of co-trimoxazole in the prevention of Mycobacterium avium complex infections in human immunodeficiency virus (HIV) patients. No prospective trials are available.

Protozoa

Malaria

This common parasite can cause serious infections in adults and children. Evidence of in vitro susceptibility to co-trimoxazole, especially for Plasmodium falciparum, has existed in the literature for decades. In HIV patients, there is a known relationship between prophylaxis with co-trimoxazole and a decrease in the incidence of malaria [52–54]. Eight RCTs assessed the efficacy of co-trimoxazole in the treatment of malaria, all of them in children, and most of them in uncomplicated P. falciparum infections. Two of these studies examined the combination of co-trimoxazole with rifampin and isoniazid in the treatment of uncomplicated malaria. This combination proved to be effective and safe as compared with chloroquine, mefloquine or quinine–sulphadoxine–pyrimethamine [55,56]. Two other studies compared co-trimoxazole–artesunate with other drug combinations (chloroquine–artesunate and amodiaquine–artesunate) in the treatment of uncomplicated P. falciparum infections, and showed excellent results in both groups [57,58]. The remaining studies demonstrated equal or superior efficacy of co-trimoxazole alone as compared with chloroquine or sulphadoxine–pyrimethamine in P. falciparum [59–61] and Plasmodium vivax [62] infections. Although the data are relevant for a specific population, co-trimoxazole is an excellent and relatively unknown treatment option for malaria.

Acanthamoeba

This parasite can cause devastating CNS infections, with very few effective treatment options. Case reports describing successful treatment usually include combinations of multiple drugs, including co-trimoxazole [63,64].

Isospora belli

Immunosuppressed individuals, specifically HIV patients, are the target of this parasite, which causes gastrointestinal infections. Co-trimoxazole has been used as a treatment for this pathogen since the 1980s, with several case reports and two retrospective studies demonstrating successful treatment. One small RCT compared co-trimoxazole with ciprofloxacin in HIV patients with isosporiasis, and showed excellent results with co-trimoxazole [65]. Another RCT demonstrated the efficacy of co-trimoxazole in the prevention of isosporiasis after the initial episode in HIV patients [66]. These data are reflected in the CDC guidelines, which recommend co-trimoxazole as the treatment of choice for isosporiasis in HIV patients [67].

Cyclospora

Adult travellers to endemic areas are the main targets of this pathogen, which is considered to be a cause of traveller’s diarrhoea, as well as diarrhoea in immunocompromised hosts. Numerous case reports and a few retrospective and prospective studies showed success with co-trimoxazole in diarrhoea caused by Cyclospora. Three RCTs compared co-trimoxazole with ciprofloxacin or placebo for the treatment of Cyclospora infections. Co-trimoxazole was an effective treatment, with a low recurrence rate [65,68,69]. This information makes co-trimoxazole a first-line treatment for Cyclospora infections.

Conclusions

Co-trimoxazole is a mixture of trimethoprim and sulphamethoxazole, which act synergistically to produce bacteriostatic and bactericidal effects against a wide range of Gram-positive and Gram-negative bacteria and some protozoa. Although most information on its efficacy derive from case reports and case series, accumulated data indicate that this old antimicrobial agent has great potential in treating a drug-resistant super-bug, MRSA, as well as several other emerging pathogens.

One of the crucial questions is whether the above-mentioned indications will remain anecdotal or whether a real chance exists for the strategic use of this ‘forgotten drug’. Large-scale trials are urgently needed to explore the many hidden potentials of this agent.

Transparency Declaration

Nothing to declare.

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