Trimethoprim And Anti-Bacterial

Introduction

Trimethoprim (TMP) is an antibacterial drug that acts on specific targets. Trimethoprim belongs to a member of the diaminopyrimidines class of drugs. The drug was first synthesised in 1961 and used in 1962, but the drug only came to clinical practice in the year 1968 combined with sulphonyl sulfonamide. It has a broad range of antibacterial activity, is easy to manufacture, and low cost. TMP is used to treat various infections with reduced toxicity and has fewer side effects.¹ It is used to treat and prevent urinary tract infections caused by E. Coli and K. Pneumonia.² Both aerobic gram-positive bacteria and gram-negative bacteria are susceptible to trimethoprim.³ If it is combined with zinc it inhibits the infection of influenza A virus in chick embryos.⁴ Trimethoprim has antibacterial properties by preventing susceptible organisms from producing tetrahydrofolate, which is the active form of folic acid.⁵

Importance of trimethoprim as an antibacterial

Due to the wide range of broad-spectrum activity trimethoprim is used to treat both gram-positive and negative bacteria along with a couple of infections caused by protozoa.⁶ This drug is used to treat a wide range of ailments and is extremely inexpensive.⁷ Trimethoprim resistance has been identified in E. Coli is 39%, 26.7% of Klebsiella spp., and 41.9% of Proteus mirabilis.⁸

Mechanism of action

By directly competing with the enzyme dihydrofolate reductase, trimethoprim inhibits the enzyme and prevents tetrahydrofolate from being converted into its active form of folate. Synergetic anti-folate effects are created by the combination of sulfamethoxazole and trimethoprim; for the production of protein and synthesizing the purines for DNA tetrahydrofolate is mandatory.⁹ One important enzyme that catalyzes the NADPH-dependent reduction of 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate (THF) is known as dihydrofolate reductase (DHFR). Restricted cell development results from the partial depletion of intracellular reduced folates caused by DHFR inhibition. Trimethoprim (TMP) [2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine] is an artificial, broad-spectrum antibacterial drug most powerful inhibitor of bacterial DHFR.¹⁰ The chemical structure of sulfamethoxazole is similar to para amino benzoic acid binds to dihydropteroate synthetase competitively, preventing PABA from being converted to dihydrofolic acid. Trimethoprim acts in the second step. TMP, an analogue of dihydrofolic acid, interacts with dihydrofolate reductase and prevents the synthesis of tetrahydrofolic acid. Bacterial growth is slowed down when two enzymes in the process that produce bacterial DNA are sequentially blocked.¹¹

Spectrum of activity

Both gram-positive and gram-negative bacteria are susceptible to the broad-spectrum bacteriostatic action of trimethoprim. When trimethoprim is used alone it works similarly to sulfamethoxazole in treating various urinary and respiratory tract infections. The primary indication for co-trimoxazole (trimethoprim & sulfamethoxazole) right now is acquired immunodeficiency syndrome (AIDS) patients because of its effectiveness against the protozoan Pneumocystis jirovecii, which causes pneumonia in these patients.¹² 

Most of the gram-positive aerobic cocci, such as Staphylococcus aureus, Staphylococcus epidermidis, Group A beta-haemolytic streptococci, Streptococcus agalactiae, Streptococcus viridans, and Streptococcus pneumoniae, shows inhibitory activity when treated with trimethoprim.  Gram-negative aerobic bacteria such as Escherichia coli and Klebsiella pneumonia are typically vulnerable to trimethoprim. Pseudomonas aeruginosa, clostridium perfringens shows uniform resistance to the drug trimethoprim.⁵

Pharmacological properties

It has been found that 20 parts of sulfamethoxazole to 1 part of trimethoprim is the ideal ratio of the two medications' levels for possible synergy. There are two forms of trimethoprim-sulfamethoxazole available one is oral and the other is indicated for intravenous use.¹³ If the drug is administered orally, both the components are rapidly absorbed through the gastrointestinal tract without being affected by the food or other drugs. However, trimethoprim is more broadly dispersed throughout the body and absorbed more quickly than sulfamethoxazole.¹⁴ Due to this uneven dispersal, a broad range of concentration is attained in various tissues and body fluids. Both medications are present in high concentrations in the prostatic fluid, bile, cerebral fluid, and sputum.¹⁵ The half-life of the drugs is 8 to 10 hours and slightly metabolized in the liver.¹⁶ Approximately 10% to 30% of trimethoprim is metabolised to an inactive form before being eliminated in the urine largely unchanged.¹⁷ 

Therapeutic use of trimethoprim

Urinary tract infection 

Trimethoprim and sulfamethoxazole are used to treat lower urinary tract infections; it is extremely effective for sensitive bacteria. Trimethoprim-sulfamethoxazole is very successful in the treatment of simple lower urinary tract infections. When the pathogenic microbes belong to the Enterobacteriaceae family, the preparation has been demonstrated to have a greater therapeutic impact than each of its components when administered separately. At least three days of medication is more likely to help treat acute, uncomplicated urinary tract infections, while single-dose therapy (320 mg trimethoprim with 1600 mg sulfamethoxazole in adults) is effective in some situations.^18,19

Bacterial infections in the respiratory tract 

In acute exacerbations of chronic bronchitis, trimethoprim-sulfamethoxazole works effectively. It seems that giving 800–1200 mg of sulfamethoxazole plus 160–240 mg of trimethoprim twice a day can reduce fever, sputum purulence and volume, and bacterial count. Since trimethoprim-sulfamethoxazole does not destroy the pathogen, it is not a recommended treatment for streptococcal pharyngitis. It works well for susceptible strains of H. influenzae and S. pneumoniae that cause acute maxillary sinusitis in adults and acute otitis media in children.²⁰

Miscellaneous infections 

Whipple's illness, infections caused by Stenotrophomonas maltophilia, and infections caused by the intestinal parasites Cyclospora and Isospora have all been successfully treated with trimethoprim-sulfamethoxazole. Depending on the disease's progression, Wegener's granulomatosis may react. Trimethoprim-sulfamethoxazole is used to treat methicillin-resistant strains of S. aureus.²⁰

Adverse effect of trimethoprim

Main Trimethoprim/sulfamethoxazole side effects include rash, photosensitivity, and folate insufficiency. 

The following is a list of the more typical adverse effects:²¹ 

• Loss of appetite 
• vomiting 
• Dyspepsia
• nausea 
• tongue pain or swelling 
• lightheadedness 
• hearing loss 
• lack of sleep 
• itching and rash
• photosensitivity 

Patients receiving trimethoprim/sulfamethoxazole for an unidentified sulfa allergy might get severe symptoms like anaphylaxis or less severe ones like hives, itchy eyes, swelling in the mouth and/or throat, and cramping in the abdomen.²²

Drug resistance

There are various possible mechanisms that underlie resistance. The microbial cell wall's relative impermeability to trimethoprim may be linked to the innate resistance of bacteria like Pseudomonas aeruginosa.²³ Dihydrofolate reductase (DHFR) enzymes that are naturally insensitive have been identified in various species, including Moraxella catarrhalis, Bacteroides species, Clostridium species, and Neisseria species. There have been reports of promoter mutation-induced chromosomal dihydrofolate reductase overproduction in E. coli. Resistance to trimethoprim in Staphylococcus aureus and Streptococcus pneumoniae has been attributed to a single amino acid alteration in the DHFR gene and modified DHFR encoded chromosomally. Alterations have been discovered in the coding and promoter regions of the DHFR genes in isolates of Haemophilus influenzae that are resistant to trimethoprim.²⁴ Time-kill experiments and animal models have both shown that gemifloxacin and trimethoprim-sulfamethoxazole together had synergistic bactericidal efficacy against community-acquired MRSA (CA-MRSA).²⁵ 

Combination therapy and other uses (Trimethoprim [TMP] – sulfamethoxazole [SMX])

For over 40 years TMP and SMX have been used together in therapeutic settings.²⁶ TMP and SMX together are marketed under different names (e.g., Bactrim and Septra) and are used to treat various kinds of bacterial infections of the gastrointestinal, urinary, and respiratory tracts. The folate biosynthesis pathway's subsequent steps are the focus of TMP and SMX. The effects of TMP and/or SMX on M. tuberculosis have not been extensively studied.²⁷ TMP-SMX resistance in M. tuberculosis was initially identified. >128 μg/ml was reported to be the minimum inhibitory concentration (MIC) of TMP against M. tuberculosis H37Ra.²⁸ Drug-sensitive and drug-resistant M. tuberculosis strains were shown to be susceptible to the TMP-SMX combination, as demonstrated by a study by Forgacs et al. Bacteriocidal activity was found with 2 and 38 μg/ml of TMP and SMX, respectively.²⁹ In the early stages, these two drugs were tested in different ratios, but finally, the fixed ratio of these drugs is 5:1 (SMX AND TMP).³⁰ The majority of immunocompromised patients who experience TMP-SMX-induced rhabdomyolysis are either HIV positive or on immunosuppressive drugs, according to a study reviewed.³¹

Conclusion

Trimethoprim (TMP) is a reliable and affordable antibacterial drug with a unique mechanism of action that lowers negative effects on human cells while specifically targeting bacterial cells. It is an essential tool for treating a wide range of illnesses, including respiratory tract infections, skin conditions, and urinary tract infections, due to its potent action against gram-positive and gram-negative bacteria. Furthermore, when paired with zinc, the ability to suppress influenza A virus infection indicates wider therapeutic uses beyond antibacterial therapy. 

However, the development in trimethoprim resistance, especially in important pathogens like E. Coli and Klebsiella species, highlights the importance of further investigation and close observation to combat bacterial resistance. 

Trimethoprim has a good safety profile and is effective in treating a variety of diseases, especially those associated with impaired immune systems. Trimethoprim is a foundation of antibacterial therapy and offers clinicians a dependable and efficient choice in the fight against infectious diseases, even in the face of challenges posed by bacterial resistance.