Description of the drug KO-TRIMOXAZOL (KO-TRIMOKSAZOL)

Co-trimoxazole

Pharmacokinetic interaction

Trimethoprim is an organic cation transporter 2 (OCT2) inhibitor and a weak inhibitor of the CYP2C8 isoenzyme. Sulfamethoxazole is a weak inhibitor of the CYP2C9 isoenzyme.

Systemic exposure to drugs transported by OCT2 (eg, dofetilide, amantadine, memantine and lamivudine) may be increased when trimethoprim-sulfamethoxazole is coadministered.

Trimethoprim-sulfamethoxazole and dofetilide should not be used simultaneously. Trimethoprim inhibits the renal excretion of dofetilide, increases the area under the concentration-time curve AUC by 103% and the maximum concentration of dofetilide by 93%. Increasing concentrations of dofetilide may cause serious ventricular arrhythmias with QT prolongation, including torsades de pointes.

Patients receiving amantadine or memantine have an increased risk of developing nervous system adverse events (such as delirium and myoclonus).

Systemic exposure to drugs predominantly metabolized by CYP2C8 (e.g. paclitaxel, amiodarone, dapsone, repaglinide, rosiglitazone and pioglitazone) may be increased when trimethoprim-sulfamethoxazole is co-administered.

Paclitaxel and amiodarone have a low therapeutic index; their simultaneous use with trimethoprim-sulfamethoxazole is not recommended.

Dapsone and trimethoprim-sulfamethoxazole may cause the development of methemoglobinemia, as there is a potential for their pharmacokinetic and pharmacodynamic interactions. Patients receiving dapsone and trimethoprim-sulfamethoxazole should be closely monitored for the development of methemoglobinemia. If necessary, alternative therapy should be prescribed. Patients receiving repaglinide or pioglitazone should be regularly monitored for the development of hypoglycemia.

Systemic exposure to drugs predominantly metabolized by CYP2C9 (e.g. coumarins (warfarin, acenocoumarol), phenytoin and sulfonylureas (glibenclamide, gliclazide and glipizide)) may be increased when trimethoprim-sulfamethoxazole is co-administered.

Blood clotting should be monitored in patients receiving coumarins. Co-trimoxazole may inhibit the hepatic metabolism of phenytoin. After administration of standard doses of trimethoprim and sulfamethoxazole, an increase in the half-life of phenytoin by 39% and a decrease in its clearance by 27% were observed. Patients receiving phenytoin should be monitored for phenytoin toxicity. Patients receiving sulfonylurea derivatives (glibenclamide, gliclazide and glipizide) should be monitored for the development of hypoglycemia.

The drug Co-trimoxazole can reduce the effectiveness of oral contraceptives. During therapy with Co-trimoxazole, women are recommended to use additional methods of contraception.

The simultaneous use of trimethoprim-sulfamethoxazole and indomethacin may cause an increase in the concentration of sulfamethoxazole in the blood plasma.

Co-trimoxazole may increase serum digoxin concentrations, especially in elderly patients, so monitoring of serum digoxin concentrations is necessary.

Pharmacodynamic interactions and interactions with unknown mechanism

The incidence and severity of myelotoxic and nephrotoxic adverse events may be increased with concomitant use of trimethoprim-sulfamethoxazole and other drugs that have a myelosuppressive effect or can cause renal impairment (nucleoside analogues, tacrolimus, azathioprine or mercaptopurine). Patients receiving such drugs concomitantly with trimethoprim-sulfamethoxazole should be monitored for the development of hematologic and/or renal toxicity.

Concomitant use with clozapine should be avoided, since the latter is known to cause agranulocytosis.

In elderly and senile patients, with the simultaneous use of certain diuretics (mainly thiazide), an increase in the number of cases of thrombocytopenia was observed.

In patients receiving diuretics, platelet levels in the blood should be regularly monitored.

Patients receiving trimethoprim-sulfamethoxazole and cyclosporine after renal transplantation may experience a reversible deterioration in renal function.

Sulfonamides, including sulfamethoxazole, may compete for protein binding and renal transport of methotrexate, thereby increasing free methotrexate concentrations and systemic effect.

Cases of pancytopenia have been described in patients taking trimethoprim and methotrexate. Trimethoprim has low affinity for human dehydrofolate reductase, but may increase the toxicity of methotrexate, especially in the presence of risk factors such as old age, hypoalbuminemia, renal impairment, bone marrow suppression, and in patients receiving high doses of methotrexate. To prevent myelosuppression, such patients should be prescribed folic acid or calcium folinate.

It can be expected that when trimethoprim-sulfamethoxazole is co-administered to patients receiving pyrimethamine for malaria prophylaxis in doses greater than 25 mg per week, they may develop megaloblastic anemia. Caution should be exercised during the simultaneous use of trimethoprimasulfamethoxazole and drugs that increase the concentration of potassium in the blood serum (such as ACE inhibitors, angiotensin receptor blockers, potassium-sparing diuretics and prednisolone), due to the potassium-sparing effect of trimethoprimasulfamethoxazole.

Laboratory research

Trimethoprim-sulfamethoxazole and, in particular, trimethoprim, which is part of it, may affect the results of determining the concentration of methotrexate in serum, carried out by the competitive protein binding method using bacterial dihydrofolate reductase as a ligand. However, there is no effect when determining methotrexate using the radioimmunoassay method.

Trimethoprim and sulfamethoxazole can also affect the results of the Jaffe test (determination of creatinine by reaction with picric acid in an alkaline medium), and in the normal range the results are overestimated by approximately 10%.

Description of the drug KO-TRIMOXAZOL (KO-TRIMOKSAZOL)

With the simultaneous use of co-trimoxazole, the effect of indirect anticoagulants is significantly enhanced due to slower inactivation of the latter, as well as their release from plasma proteins.

When used simultaneously with some sulfonylurea derivatives, the hypoglycemic effect may be enhanced, which is associated with an increase in the concentration of the free fraction of co-trimoxazole.

The simultaneous use of co-trimoxazole and methotrexate may lead to increased toxicity of the latter (in particular, the appearance of pancytopenia) due to its release from plasma proteins.

Under the influence of butadione, indomethacin, naproxen, salicylates and some other NSAIDs, it is possible to enhance the action of co-trimoxazole with the development of undesirable effects, since the active substances are released from their binding to blood proteins and their concentration increases.

Concomitant use of diuretics and co-trimoxazole increases the likelihood of developing thrombocytopenia caused by the latter, especially in elderly patients.

In the case of simultaneous administration of chloridine with co-trimoxazole, the antimicrobial effect is enhanced, since chloridine inhibits the formation of tetrahydrofolic acid, necessary for the synthesis of nucleic acids and proteins. In turn, sulfonamides inhibit the formation of dihydrofolic acid, which is a precursor of tetrahydrofolic acid. This combination is widely used in the treatment of toxoplasmosis.

The absorption of sulfamethoxazole and trimethoprim when taken together with cholestyramine is reduced as a result of the formation of insoluble complexes, which leads to a decrease in their concentration in the blood.

Reduces the intensity of hepatic metabolism of phenytoin (extends its T1/2 by 39%), increasing its effect and toxic effect.

With simultaneous use of co-trimoxazole with pyrimethamine in doses exceeding 25 mg/week, the risk of developing megaloblastic anemia increases.

May increase serum digoxin concentrations, especially in elderly patients; monitoring of serum digoxin concentrations is necessary.

The effectiveness of tricyclic antidepressants when taken in combination with co-trimoxazole may be reduced.

Patients receiving co-trimoxazole and cyclosporine after kidney transplantation may experience a reversible deterioration in renal function, manifested by an increase in creatinine levels.

When used simultaneously with ACE inhibitors, especially in elderly patients, hyperkalemia may develop.

Trimethoprim, by inhibiting the renal transport system, increases the AUC of dofetilide by 103% and the Cmax of dofetilide by 93%. With increasing concentrations, dofetilide may cause ventricular arrhythmias with prolongation of the QT interval, including tachycardia. Simultaneous use is contraindicated.

MODERN VIEWS ON THE USE OF CO-TRIMOXAZOLE

L.S. Strachunsky, R.S. Kozlov

"Clinical pharmacology and therapy", 1997; vol.6, no.2, pp.27-31 (printed with permission of the editor)

Co-trimoxazole (trimethoprim/sulfamethoxazole, Bactrim, Biseptol, Septrin) is one of the most well-known antibacterial drugs for the treatment of mild and moderately severe community-acquired respiratory and urinary tract infections, and intestinal infections. In addition, it is often used for nosocomial infections. Co-trimoxazole causes a large number of adverse reactions, and therefore it is advisable to discuss modern views on the use of this drug.

Rationality of combination

Trimethoprim, like sulfonamides, belongs to the group of antifolic drugs, which in therapeutic concentrations inhibit the synthesis of folic acid in prokaryotes and do not interfere with it in humans. This is due to the fact that bacterial dihydrofolate reductase (DHFR) is 50,000–100,000 times more sensitive to trimethoprim than animal and human DHFR. The “heart” of the combination is trimethoprim. Given the similar mechanism of action, sulfamethoxazole was chosen due to the similarity of pharmacokinetic parameters. Trimethoprim can also be used with other sulfonamides, such as sulfamonomethoxine (Sulfatone).

For more than 20 years, manual after manual has cited two main advantages of the combination of trimethoprim with sulfamethoxazole: (1) the synergism of the components and, as a result, the bactericidal effect of the combination; (2) slower development of resistance. However, both statements do not have sufficient grounds. The ratio of 1 part trimethoprim to 5 parts sulfamethoxazole was chosen to give a serum ratio of 1:20, respectively. It is in this case that in vitro

maximum synergism of the two drugs against pathogenic bacteria is noted [24]. However, this fundamental principle of the “design” of co-trimoxazole is currently seriously disputed [6]. Firstly, most clinical situations where co-trimoxazole is prescribed are not accompanied by bacteremia, so their ratio in tissues and biological fluids other than blood is of greater importance. Due to the different lipophilicity, the volume of distribution of trimethoprim (about 100 l) is more than 12 times greater than the volume of distribution of sulfamethoxazole (about 8 l), so the ratio of drug concentrations in tissues differs significantly from 1:20. In urine, for example, it can reach 1:1; however, there is no synergy. Secondly, the synergism may be of real importance for microorganisms more sensitive to sulfonamides than to trimethoprim. However, the doses and ratio of components are not always optimal, which requires, for example, at least doubling the standard doses of co-trimoxazole for gonorrhea or brucellosis. Therefore, it has been proposed to use a trimethoprim to sulfamethoxazole ratio of 3:1 for the treatment of gonorrhea [25]. Thus, synergism is mainly a laboratory phenomenon and does not have any significant significance for the clinical effectiveness of co-trimoxazole [6]. Trimethoprim may slow the development of sulfonamide resistance [6]. However, increased sensitivity to sulfonamides may also be explained by a decrease in selective pressure due to decreased use.

The sulfanilamide component of co-trimoxazole is of no value in most clinical situations, which is associated with the high resistance of community- and nosocomial microflora to sulfonamides. In fact, the advantage of co-trimoxazole over trimethoprim has been shown only for Pneumocystis infection [6]. In addition, it is the sulfonamide component that poses the risk of severe adverse reactions and drug interactions, which are especially common in patients with chronic diseases and the elderly [6]. That is why, since 1973, trimethoprim has been used as monotherapy for various infections.

Pharmacokinetics [21]

After oral administration, trimethoprim is well absorbed. When taken orally with the usual dose of trimethoprim (160 mg), the serum concentration reaches a peak (2 mg/l) after 1-2 hours, the half-life is 9-13 hours. Due to its lipophilicity, trimethoprim is quickly and well distributed in various organs and tissues, especially high concentrations are observed in the liver, kidneys, prostatic fluid and vaginal secretions. For inflamed meninges, trimethoprim, like sulfamethoxazole, penetrates well into the central nervous system, where its concentration is 25–40% of the serum concentration. Trimethoprim is excreted primarily in the urine and less in the bile; 60–80% of the dose is excreted unchanged in the urine within 24 hours, and the metabolites have biological activity. The concentration of trimethoprim in urine is many times higher than the inhibitory concentration for most uropathogens. In terms of absorption and excretion, sulfamethoxazole is close to trimethoprim. In case of renal failure, the elimination of sulfamethoxazole and trimethoprim slows down to 20–30 hours or more, which requires a change in the dosage regimen. Both drugs are removed by hemodialysis.

The second antifolate drug used in clinical practice since 1993 is brodimoprim. It has a similar spectrum of activity to trimethoprim, but differs from it in physicochemical and pharmacokinetic properties, in particular a longer half-life (35 hours). Experience with brodimoprim is still very limited [5].

Microbiology

Trimethoprim has pronounced bactericidal activity against many gram-positive cocci and gram-negative bacilli. Sulfamethoxazole is more active than trimethoprim only against N.gonorrhoeae, Brucella

spp.,
N.asteroides, C.trachomatis
. Co-trimoxazole has a wide spectrum of activity and acts on many gram-positive and gram-negative microorganisms (Table 1). The activity of co-trimoxazole against hospital strains of gram-negative bacteria, such as Enterobacter, Acinetobacter, Morganella, etc. is variable.

Table 1.

Activity spectrum of co-trimoxazole

* Including strains producing b-lactamases.

Depending on sensitivity to trimethoprim and sulfonamides, W. Brumfitt and J. Hamilton-Miller (1994) divided the microflora into 4 categories (Table 2). Category I includes bacteria for which in vitro

Synergism between trimethoprim and sulfamethoxazole has been shown, but it has not been clinically confirmed. Category II includes microorganisms that are more sensitive to sulfonamides than to trimethoprim. Category III includes bacteria resistant to both components and their combinations. And finally, category IV includes microorganisms that are sensitive to trimethoprim but resistant to sulfonamides: enterococci, sulfonamide-resistant strains of Escherichia coli. For bacteria included in category IV, there is no microbiological basis for supplementing trimethoprim with sulfonamides.

Table 2.

Distribution of microflora depending on sensitivity to trimethoprim and sulfonamides [6]

P. Huovinen et al. noted: “Trimethoprim, in the form of monotherapy or in combination with sulfamethoxazole, is a fairly effective and inexpensive drug. In recent years, there has been a dramatic increase in resistance to trimethoprim against the background of resistance to sulfamethoxazole. The mechanisms of resistance and its prevalence among pathogenic bacteria show significant evolutionary adaptation to trimethoprim and sulfamethoxazole" [2].

Our study showed that the domestic AGV environment is unsuitable for determining sensitivity to co-trimoxazole [30]. Due to the high content of thymidine in AGV, inhibition zones do not form around the discs, which can lead to incorrect interpretation of the results and the identification of false resistance. When determining sensitivity to co-trimoxazole, Mueller-Hinton agar and disks containing 1.25 μg trimethoprim and 23.75 μg sulfamethoxazole should be used [32].

Sulfonamides, being structural analogues of para-aminobenzoic acid, act as competitive inhibitors of dihydropteroate synthetase, necessary for folate biosynthesis. As a result, the formation of dihydropteroic acid, an intermediate product of the synthesis of folic acid, which is a substrate for the synthesis of bacterial nucleic acids, is disrupted. The most common mechanism of resistance to sulfonamides in clinical strains of Gram-negative bacteria is plasmid resistance, caused by the presence of alternative sulfonamide-resistant variants of dihydropteroate synthetase. Chromosomal mutations of the dhps gene encoding dihydropteroate synthetase, described in N.meningitidis, S.pneumoniae, B.subtilis

, lead to resistance to sulfonamides [14].

Trimethoprim is a competitive inhibitor of dihydrofolate reductase and disrupts one of the stages of nucleic acid synthesis - the formation of tetrahydrofolic acid from dihydrofolic acid. There are three chromosomally determined mechanisms of resistance to trimethoprim: (1) loss of thymine requirement; (2) overproduction of dihydrofolate reductase; (3) disruption of cell wall permeability. The fourth mechanism is plasmid resistance due to the development of trimethoprim-resistant variants of dihydrofolate reductase, which causes a high level of resistance to trimethoprim [2].

Co-trimoxazole is very widely used for the treatment of respiratory tract infections, so the problem of resistance of the main bacterial pathogens of these infections is of great interest. Penicillin-resistant pneumococci are resistant to co-trimoxazole in 75% of cases, and cefotaxime-resistant pneumococci are resistant to 95% of cases [28]. In general, an intermediate level of resistance to co-trimoxazole (MIC 1–2 μg/ml) is observed in 18% of pneumococci, and a high level (MIC ≥4 μg/ml) is observed in 7%. Although multidrug-resistant strains of S. pneumoniae

are usually resistant to co-trimoxazole, penicillin-sensitive strains are usually susceptible to this combination [18].
Resistance to co-trimoxazole is observed in both S.aureus
(especially hospital strains) and coagulase-negative staphylococci.
In an international collection of strains, 28% of methicillin-resistant S. aureus
(MRSA) are resistant to trimethoprim and 35% are resistant to sulfamethoxazole [12].
According to multicenter studies in Europe, it was found that the level of resistance of H. influenzae
to co-trimoxazole is highest in Spain (41%) and Italy (12%), while in other countries it did not exceed 8% [11].
In the United States, only 0.7% of H. influenzae
are resistant to co-trimoxazole.
The resistance level of Moraxella (Branhamella) catarrhalis
, which is the third most common pathogen of respiratory tract infections, is even lower than that of
H. influenzae
and
S. pneumoniae
[18].
Gonococci with chromosomal resistance to penicillin are often resistant to co-trimoxazole [21]. In a study of resistance to co-trimoxazole in more than 20,000 strains of E. coli
and 5,000 strains
of K. pneumoniae
, the level of resistance to this combination in Central Asia was 41% in
E. coli
and 23% in
K. pneumoniae
, and the level of resistance in Asia is much higher, than in the USA and Western Europe [17].
Resistance to co-trimoxazole in urinary tract infection pathogens increased in England from 1971 to 1992 from 3.4% to 21.5% in community settings and from 16.1% to 29.5% in hospitals [7]. In Denmark, resistance of E. coli
increased from 14.5% in 1972 to 28% in 1992, and of gram-negative flora in general to 25% [7]. However, sensitivity to co-trimoxazole remains quite high (higher than to ampicillin and tetracycline), which allows it to be recommended for the treatment of these infections [7]. Co-trimoxazole has long been the drug of choice for the treatment of shigellosis (dysentery). Currently, Shigella resistance to the drug is increasing dramatically. In the 70s - early 80s. the level of resistance in Shigella media was minimal; already in 1983-84. resistance reached 4–17%, in 1985 – 7–21%, and somewhat later resistance to trimethoprim amounted to 52% (depending on the species) [19].

Among Salmonella, the level of resistance to co-trimoxazole is quite low. The greatest resistance is observed in S.typhimurium

: in 1981, resistance to sulfamethoxazole in England was 26%, in 1988 - 30%;
to trimethoprim – 8 and 11%, respectively. In S. enteritidis
and
S. virchow,
resistance was significantly lower: from 2 to 14% and from <1 to 9% [2].
According to the US Centers for Disease Control and Prevention, in 1995–96. resistance of S. enteritidis
to co-trimoxazole was 5%,
S. typhimurium
– 2%, and resistance to sulfamethoxazole was 22% [27].

In a study of nasopharyngeal carriage of pneumococci in preschool institutions in Smolensk in 1994, 41.9% of isolated S. pneumoniae

were resistant to co-trimoxazole. In a multicenter study of the resistance of hospital flora, conducted in eleven centers in Russia in 1995, an average of 45% of strains of gram-negative bacteria isolated from patients from intensive care units were resistant to co-trimoxazole.

Adverse reactions

The frequency and spectrum of mild reactions do not differ from those when using other antibacterial drugs. Most often (in 1–4% of cases) a rash occurs, which in some cases may be the initial manifestation of Stevens-Johnson syndrome. Diagnostic difficulties are presented by fever when taking co-trimoxazole, which is sometimes accompanied by a rash. In these cases, it is necessary to carry out differential diagnosis with Stevens-Johnson syndrome, scarlet fever, viral infections, and Kawasaki syndrome [10].

In connection with the undesirable effects of co-trimoxazole, a special public committee was created in the UK, according to which 130 deaths associated with the use of the drug were registered. The most dangerous are severe, potentially fatal skin reactions (mucocutaneous febrile syndromes) - toxic epidermal necrolysis syndrome (Lyell's syndrome) and Stevens-Johnson syndrome. When using sulfonamides and co-trimoxazole, the relative risk of their development is approximately 10–20 times higher than when using b-lactam antibiotics [3]. These reactions are caused mainly by the sulfonamide component and are much less common when using trimethoprim alone. Most often, skin reactions are observed in patients with AIDS during treatment of pneumonia caused by P.carinii

, especially after the 10th day of therapy. The severity of neutropenia, anemia, thrombocytopenia, pancytopenia can vary, even leading to death. Risk factors include old age, long courses of treatment, and glucose-6-phosphate dehydrogenase deficiency [20]. With parenteral administration of co-trimoxazole in high doses, there are numerous observations of the development of hyperkalemia [9]. Aseptic meningitis is more often observed with parenteral use and in patients with diffuse connective tissue diseases [8]. Coma, depression, damage to internal organs, and congenital deformities have been described.

Interactions have been noted with indirect anticoagulants, phenytoin, digoxin, oral sulfonylurea antidiabetic drugs, tricyclic antidepressants and many other drugs. Co-trimoxazole potentiates the inhibition of bone marrow hematopoiesis caused by immunosuppressants and cytostatics.

Indications for use

In 1995, restrictions on the use of co-trimoxazole were introduced in the UK [1], which were due to the risk of severe adverse reactions and a decrease in the effectiveness of the drug. The following indications for the use of co-trimoxazole are recommended:

• treatment and prevention of Pneumocystis pneumonia in children and adults, patients with AIDS and other immunodeficiencies;
• treatment and prevention of toxoplasmosis;
• treatment of nocardiosis;
• treatment of exacerbations of chronic bronchitis and urinary tract infections when the pathogen is sensitive to co-trimoxazole and there are serious reasons for its preference over monotherapy with trimethoprim or other antibiotics;
• treatment of acute otitis media in children if there are serious reasons for its preference over monotherapy with trimethoprim or other antibiotics;

Hospital-acquired infections caused by MRSA.

Despite the
in vitro
against MRSA [, ], its clinical effectiveness is variable and unpredictable [22]. In this regard, co-trimoxazole should not be considered as a reliable alternative to vancomycin. It can only be used if vancomycin is not available or is intolerant. Attempts have been made to use co-trimoxazole to treat MRSA carriers. In a double-blind study, combinations of rifampicin with co-trimoxazole were inferior in effectiveness to the combination of rifampicin with novobiocin [29].

Hospital infections caused by gram-negative microorganisms.

Co-trimoxazole is the best drug for treating the rare but multidrug-resistant pathogen of nosocomial infections
Stenotrophomonas maltophilia
(
Pseudomonas maltophilia, Xanthomonas maltophilia
) [23].
In addition, co-trimoxazole is active against another pathogen of nosocomial infections, Enterobacter cloacae
.
According to a multicenter study conducted in Russia in 1995 in 11 intensive care units, 89.3% of E. cloacae
were sensitive to co-trimoxazole.

Listeriosis.

Co-trimoxazole is one of the most effective treatments for listeriosis, as it penetrates well into cells (
Listeria monocytogenes
is an obligate intracellular parasite) and has a bactericidal effect. The effectiveness of therapy increases when co-trimoxazole is combined with ampicillin [4].

Wegener's granulomatosis

– a non-traditional indication for the use of co-trimoxazole. The effect of the drug was first noted by R. De Remee in 1975. In 1996, the anti-relapse effect of the drug was proven in a controlled, double-blind study [26]. Co-trimoxazole is prescribed to maintain remission after therapy with cytostatics and treatment is continued (960 mg 2 times a day) for several years. The mechanism of action of the drug in this disease is unknown.

A controversial indication for the use of co-trimoxazole is bacterial prostatitis

. Co-trimoxazole penetrates into the prostatic fluid relatively poorly due to the high pH during inflammation [13]. However, the concentration of trimethoprim in the prostate reaches the required therapeutic values, so it can be used to treat prostatitis in combination with rifampicin. When using this combination, synergism against prostatitis pathogens increases, and trimethoprim prevents the emergence of resistance to rifampicin [13]. However, after the advent of fluoroquinolones, the value of trimethoprim in the treatment of prostatitis decreased significantly.

Conclusion

Thus, in the second half of the 90s, the use of co-trimoxazole was limited to community-acquired forms of infections of the respiratory, urinary tract, and gastrointestinal tract. The condition for the use of co-trimoxazole is the sensitivity of the pathogen and the presence of serious reasons for its preference over monotherapy with trimethoprim or other antibiotics, and it is desirable to carry out short (no more than 5-7 days) courses of therapy. Co-trimoxazole is used for a number of specific diseases (pneumocystosis, nocardiosis) and certain forms of nosocomial infections caused by pathogens resistant to b-lactam antibiotics, fluoroquinolones and aminoglycosides ( S. maltophilia, E. cloacae

). The use of co-trimoxazole requires careful monitoring of adverse drug reactions, the underreporting of which can lead to death. From a microbiological, clinical and pharmacoeconomic point of view, for the vast majority of common infections that have traditionally served as an indication for the use of co-trimoxazole, preference should be given to monotherapy with trimethoprim or antibiotics of other groups.

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