Antimicrobials trimethoprim

Since the first edition of this book was published there have been substantial advances in the treatment of human immunodeficiency virus (HIV) infection and the corollary acquired immunodeficiency syndrome (AIDS). Multiregimen antiretroviral therapy has allowed HIV/AIDS to be managed in a manner that was impossible in 1992. The development of successful treatments for HIV/AIDS and the effectiveness of antimicrobials, trimethoprim/sulfamethoxazole or dapsone, in the treatment of Pneumocystic carinii pneumonia (PCP) have reduced... 

Many patents have been issued on the use of pyrogaUol derivatives as pharmaceuticals. PyrogaUol has been used extemaUy in the form of an ointment or a solution in the treatment of skin diseases, eg, psoriasis, ringworm, and lupus erythematosus. GaUamine triethiodide (16) is an important muscle relaxant in surgery it also is used in convulsive-shock therapy. Trimethoprim (2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine) is an antimicrobial and is a component of Bactrin and Septra. Trimetazidine (l(2,3,4-trimethoxybenzyl)piperazine (Vastarel, Yosimilon) is used as a coronary vasodilator. l,2,3,4-Tetrahydro-6-methoxy-l-(3,4,5-trimethoxyphenyl)-9JT-pyrido[3,4- ]indole hydrochloride is useful as a tranquilizer (52) (see Hypnotics, sedatives, ANTICONVULSANTS, AND ANXIOLYTICS). Substituted indanones made from pyrogaUol trimethyl ether depress the central nervous system (CNS) (53). Tyrosine-and glycine(2,3,4-trihydroxybenzyl)hydrazides are characterized by antidepressant and anti-Parkinson activity (54). 

The sulfa dmgs are stiH important as antimicrobials, although they have been replaced in many systemic infections by the natural and semisynthetic antibiotics. They are of great value in third world countries where problems of storage and lack of medical personnel make appropriate use of antibiotics difficult. They are especially useful in urinary tract infections, particularly the combination of sulfamethoxazole with trimethoprim. Their effectiveness has been enhanced by co-adniinistration with dihydrofolate reductase inhibitors, and the combination of sulfamethoxazole with trimethoprim is of value in treatment of a number of specific microbial infections. The introduction of this combination (cotrimoxazole) in the late 1960s (1973 in the United States) resulted in increased use of sulfonamides. 

The majority of patients can be managed with oral antimicrobial agents, such as trimethoprim-sulfamethoxazole or the fluoroquinolones (ciprofloxacin, levofloxacin). When IV treatment is necessary, IV to oral sequential therapy with trimethoprim-sulfamethoxazole or a fluoroquinolone, such as ciprofloxacin or ofloxacin, would be appropriate. 

Gobel A, McArdell CS, Suter MJ et al (2004) Trace determination of macrolide and sulfonamide antimicrobials, a human sulfonamide metabolite, and trimethoprim in wastewater using liquid chromatography coupled to electrospray tandem mass spectrometry. Anal Chem 76(16) 4756-4764... 

Co-trimoxazole consists of trimethoprim and sulphamethoxazole combined because of their synergistic antimicrobial effects. Trimethoprim is a folate antagonist that poses a teratogenic risk. 

Trimethoprim has a broad spectrum of antimicrobial activity. It is 20-100 times more active than sulfamethoxazole with respect to most bacterial forms. Trimethoprim is active with respect to Gram-positive, aerobic bacteria such as Staphylococcus aureus, Staphylococcus epidermidis, and various types of Streptococcus and Listeria monocytogenes. Trimethoprim is inferior to sulfonamides against forms of Nocardia. It is active... 

Figure 2.5 Reported concentrations of various PPCPs in Wastewater effluents by several research groups. On the x axis are respective PPCPs that are primarily cosmetics (1 = HHCB, 2 = AHTN, 3 = acetophenone, 4 = camphor, 5 = isobomeol, 6 = skatol, 7 = celestolide, i.e., AHMI, 8 = Phantolide, i.e., AHMI), the lotion ingredient (9 = methyl salicylate), two disinfectants (10 = triclosan and 11 = trilocarban), antihypertensive (12 = dehydronifedipine, 13 = diltiazem, 14 = bezafibrate, and 15 = gemfibrozil), analgesics and anti-inflammatories (16 = naproxen, 17 = ibuprofen, 18 = codeine), antimicrobials (19 = chlortetracycline, 20 = erythromycin, 21 = novobiocin, 22 = oxytetracycline, 23 = sulfamethaxazole, 24 = thiabendazole, 25 = trimethoprim), anxiolytic sedative (26 = carbamazepine), antidiabetic (27 = metaformin), reproductive (28 = 17(3 estradiol, 29 = 17a-ethinyl estradiol), GIT (30 = cimetidine, 31 = ranitidine), and respiratory (32 = Albuterol). The concentrations were compiled from Boyd et al. (2003), Gagne et al. (2006), Glassmeyer et al. (2005), Halden and Pauli (2005), Huang and Sedlak (2001), Ricking et al. (2003), and Temes et al. (2003).

Halling-Sdrensen B., H.C. Holten Liitzhpft, H.R. Andersen, and F. Ingerslev (2000). Environmental risk assessment of antibiotics Comparison of mecillinam, trimethoprim and ciprofloxacin. Journal of Antimicrobial Chemotherapy 46(Suppl. Sl) 53-58. 

Because of development of resistance and availability of more advanced antimicrobial agents, the use of sulfonamides is limited. However they are used in combination with trimethoprim. The important therapeutic uses are ... 

Trimethoprim (a weak base) concentrates in prostatic fluid and in vaginal fluid, which are more acidic than plasma. Therefore, it has more antibacterial activity in prostatic and vaginal fluids than many other antimicrobial drugs. 

Nitrofurantoin is bacteriostatic and bactericidal for many gram-positive and gram-negative bacteria but P aeruginosa and many strains of proteus are resistant. There is no cross-resistance between nitrofurantoin and other antimicrobial agents and resistance emerges slowly. As Escherichia coli resistant to trimethoprim-sulfamethoxazole and fluoroquinolones has become more common, nitrofurantoin has become an important alternative oral agent for treatment of uncomplicated urinary tract infection. 

Many antimicrobial agents have similar pharmacokinetic properties when given orally or parenterally (ie, tetracyclines, trimethoprim-sulfamethoxazole, quinolones, chloramphenicol, metronidazole, clindamycin, rifampin, linezolid and fluconazole). In most cases, oral therapy with these drugs is equally effective, is less costly, and results in fewer complications than parenteral therapy. 

Other synergistic antimicrobial combinations have been shown to be more effective than monotherapy with individual components. Trimethoprim-sulfamethoxazole has been successfully used for the treatment of bacterial infections and Pneumocystis jiroveci (carinii) pneumonia. 3-Lactamase inhibitors restore the activity of intrinsically active but hydrolyzable 3-lactams against organisms such as S aureus and Bacteroides fragilis. Three major mechanisms of antimicrobial synergism have been established ... 

Cribb AE, Lee BL, Trepanier LA, et al. Adverse reactions to sulphonamide and sulphonamide-trimethoprim antimicrobials clinical syndromes and pathogenesis. Adverse Drug React Toxicol Rev 1996 15 9-50. 

Trimethoprim is most often compounded with the sulfa drug, sulfamethoxazole. The resulting combination, called co-trimoxazole, shows greater antimicrobial activity than equivalent quantities of either drug used alone (Figure 29.6). The combination was selected because of the similarity in the pharmacokinetics of the two drugs. 

The synergistic antimicrobial activity of co-trimoxazole results from its inhibition of two sequential steps in the synthesis of tetrahydro-folic acid sulfamethoxazole inhibits the incorporation of PABA into folic acid, and trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate (see Figure 29.5). Co-trimoxazole exhibits more potent antimicrobial activity than sulfamethoxazole or trimethoprim alone (seed Figure 29.6). 

Aminoglycosides are NOT indicated for the treatment of uncomplicated urinary tract infections these Infections respond to less toxic antimicrobial agents, such as trimethoprim-sulfamethoxazole. 

Humans cannot synthesise folic acid. Many bacteria, however, synthesise it from PABA this bacteria-specific pathway provides a target for synthetic antimicrobial agents like the sulphonamides and trimethoprim (Figure 20.4). Sulphonamides inhibit dihydropteroate syn-... 

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