Today, sulfonamides and trimethoprim are probably more commonly used in combination than separately. Therefore, this lecture will treat them together for the most part. Pharmacokinetics, adverse reactions, and certain clinical applications will be discussed separately for the two groups.
The sulfonamides are the venerable group of antimicrobials that started the antibacterial revolution in 1935. They are still used today although the specific agents have changed completely. Many derivatives were created by modifying the sulfanilamide structure and the list of clinically used sulfonamides used to be long. Now, however, the USPDI lists only a few sulfonamides for use in human medicine. The list for veterinary medicine is still quite long, but recent actions by the FDA/CVM to reduce the high frequency of violative sulfa residues in food products has put the industry in a state of flux.
The older sulfonamides did not survive because their poor water solubility led to problems in preparing acceptable dose forms and with crystallization in renal tubules. In addition to correcting these deficiencies, modern derivatives also tend to require less frequent administration leading to improved convenience and compliance.
A major development is the seemingly universal use of sulfas in the form of either sulfamethoxazole (human dose forms) or sulfadiazine (veterinary dose forms) combined with the 2,4-diaminopyrimidine derivative trimethoprim. Combinations of these sulfonamides with trimethoprim are synergistic and bactericidal whereas sulfonamides alone are static. Although clearly not a sulfonamide, trimethoprim will be discussed with them because of their close relationship. Another potentiated sulfa available in veterinary medicine is Primor, a combination of ormetoprim and sulfadimethoxine.
Sulfonamides have in common the p-aminobenzene sulfonamide group shown in the classical compound sulfanilamide. This group closely resembles p-aminobenzoic acid (PABA) a folic acid precursor. Chemical modifications of the basic structure have been made primarily to alter their pharmacokinetic properties to make them more convenient therapeutically and less toxic. In contrast to the beta-lactams and aminoglycosides, differences in antibacterial activity of various sulfonamide derivatives are not marked. One or two sulfonamides can be used in sensitivity testing to predict the activity of others.
Although the sulfonamides are amphoteric, they generally function as weak acids at physiologic pHs. Therefore, they are usually seen as sodium salts which have increased solubility as pH increases. This fact explains why alkalinization of urine has been traditionally recommended to reduce tubular crystallization. On the other hand, the high alkalinity (pH >> 8) of sulfonamide solutions precluded the older, less soluble derivatives, from being used by IM or SC injection because of sterile abscess formation.
Sulfonamides are often discussed as if they were a homogeneous group of compounds. Although this may be reasonable with respect to their antimicrobial activity, it is not true with respect to their pharmacokinetics. The pKas of various derivatives vary from 5.4 for sulfacetamide to 10.4 for sulfanilamide. The percent nonionized (diffusable form) in plasma at pH 7.4, therefore, ranges from 1.0 to 99.9. Clearly the rate of penetration of membranes by non-ionic diffusion will vary tremendously depending on the specific compound. As a result, it is common to divide the sulfonamides into application sub-groups, e.g., intestinal, systemic, urinary, or topical.
Trimethoprim is a bacteriostatic, weakly basic, highly lipid soluble member of the 2,4-diaminopyrimidines. It also has antiprotozoal activity and is used therapeutically alone, (e.g., as Proloprim[R] or Trimpex[R]) or in combination with a sulfonamide, for bacterial infections or Pneumocystis carinii lung infections. It has relatives, e.g., pyrimethamine, that are used as antimalarials.
Both sulfonamides and trimethoprim are bacteriostatic drugs, but together they are synergistic and bactericidal. This synergism has made the combination extremely popular in both veterinary and human medicine.
Sulfonamides and trimethoprim, alone and in combination, demonstrate three important modes of drug action; competition, false synthesis, and sequential blockade or inhibition. Both drugs acting individually are competitive inhibitors of specific enzyme reactions. False synthesis contributes to the effectiveness of some sulfonamides. Combinations of the two drugs result in synergistic sequential blockade.
Tetrahydrofolic acid (THF, FH-4) is required as a methyl donor in the conversion of dUMP to thymidine and in the synthesis of the purine ring. Depletion of THF, therefore, inhibits DNA and RNA synthesis and ultimately inhibits protein synthesis as well. The action of these drugs depletes THF by acting at two enzyme steps.
sulfihydropteroate synthase catalyzes the synthesis of dihydrofolic acid (pteroylglutamic acid, DHF, FH-2) from precursors that include p-aminobenzoic acid (PABA). Sulfonamides are structural and competitive analogs of PABA in this reaction and inhibit the formation of DHF when present in adequate concentrations. Because the action is competitive, increased concentrations of PABA can overcome the inhibition. Some sulfonamides may also serve as substrates for the synthase leading to analogs of reduced forms of pteroic acid that may inhibit subsequent steps. This represents false synthesis.
Dihydrofolic acid reductase (DHFR) catalyzes the reduction of DHF to THF in cells of bacteria, protozoans, and vertebrates. The DHFR substrate includes DHF which is newly synthesized by dihydropteroate synthase and that which is being recycled. DHF is formed from THF while it is acting as a methyl donor. Trimethoprim inhibits reduction of DHF to THF by binding to bacterial DHFR at concentrations 50,000 to 60,000 times lower than are required to inhibit the vertebrate enzyme.
It is easy to see why the combined, sequential, actions of sulfonamides and trimethoprim are synergistic. Sulfonamides decrease the de novo synthesis of DHF while trimethoprim is decreasing the conversion of new and recycled DHF to THF.
Specificity of these actions is due to unique and pharmacologic differences. Vertebrates do not have dihydropteroate synthase and, therefore, cannot synthesize folic acid. It must be supplied as part of their diet. Conversely, many bacteria and protozoans must form their own folic acid, thereby becoming susceptible to the action of the sulfonamides. The difference in binding affinity between bacteria and vertebrates accounts for the specificity of trimethoprim. This author does not know the relative trimethoprim binding affinity for Pneumocystis carinii versus vertebrate DHFR, but there is presumably a significant difference.
Concentration Required to Inhibit DHFR by 50%
DRUG RAT LIVER E. coli P. berghei
IC50(nM) IC50(nM) IC50(nM)
Pyrimethamine 700 2,500 ~0.5
Trimethoprim 260,000 5 70
GG8th p985. Original data from Ferone, Burchall & Hitchings, 1969
Resistance
Resistance to the sulfonamides is fairly common. Individual sulfonamides generally reflect the activity of the group so switching among sulfonamides for reasons other than toxicity or pharmacokinetics is not rational.
Resistance may be chromosomal, in which case it is innate to the organism. Clinical problems are more often related to plasmid borne resistance. Transferred (plasmid) resistance does not result in altered drug or accumulation of drug in the organism. Therefore, it must result from a change in the organism's dihydropteroate synthase (DHPtS) to alter drug binding, or development of the organism's ability to use preformed folic acid.
Clinical resistance may also be due to more mundane causes. Factors which increase the concentration of PABA, thymidine, purines, and methionine may decrease the effectiveness of the sulfonamides. All of these may be increased in pus. Sulfonamides are also highly protein bound and bind to tissue debris, thus effectively decreasing the concentration of active drug. The only remedy is an increased concentration of drug (within safe limits) and improved drainage of abscesses where possible.
Combinations of trimethoprim and sulfonamide overcome some of the problems mentioned above, but organisms do become resistant to the combination.
Pharmacokinetics, adverse effects and clinical application of the sulfonamides will be discussed separately from those of trimethoprim. However, points relevant to the combinations will be discussed here.
Sulfonamides are recommended and available in ophthalmic, oral, and parenteral dose forms. Ophthalmic forms are obviously intended to be used topically. Vaginal sulfonamides exist, but USPDI10th90 states that they have no proven efficacy and most authorities advise against their use. Two orally administered drugs used for their effects in or on the gastrointestinal tract will be discussed. The remainder of the discussion will focus on systemically active sulfonamides.
Sulfacetamide and sulfisoxazole diolamine (highly water soluble) are available for topical ophthalmic use. Both are sold in ointment and solution dose forms. Absorption is limited so systemic effects are nil. In some cases, e.g., chlamydial infections, this topical use is combined with systemic sulfonamides.
Poorly absorbed intestinal sulfas were intentionally created for their local effect in the tract. Phthalylsulfathiazole [Sulfathalidine[R] typified this category which is decreasingly used clinically. This drug is not mentioned in the USPDI11th 91.
Another sulfonamide that is used for its effect in and on the gut is sulfasalazine. This drug is primarily indicated for inflammatory bowel disease, e.g., ulcerative colitis. As the name implies, it bears resemblance structurally and mechanistically to the sulfonamides and salicylates. Approximately 33% is absorbed from the intestine and the remainder is metabolized to form sulfapyridine and mesalamine (5-aminosalicylic acid; 5-ASA). Most of the sulfapyridine so formed and 33% of the mesalamine are absorbed from the colon from which they are distributed to serous fluids (e.g., peritoneal fluids), connective tissue, liver, and intestinal wall. Its mechanism is unknown, but may be related to the antiinflammatory action of its metabolites. Sulfapyridine is also available as a single agent for use in treating dermatitis herpetiformis. It is not bacteriostatic and its mechanism is unknown.
The USPDI11th91 mentions only 3 systemic sulfonamides out of the seemingly myriads available. These are sulfacytine (Renoquid[R]), sulfamethoxazole (Gantanole[R]), and sulfisoxazole (Gantrisin[R]). Unfortunately, many more are still available in veterinary medicine although recent FDA/CVM actions may decrease this number. This discussion will focus on the three named plus sulfadiazine, Sulfamethoxazole is primarily available in combination with trimethoprim (Co-Trimoxazole[R], Bactrim[R], Septra[R]). A combination of sulfadiazine and trimethoprim (Tribrissen[R]) is available specifically for veterinary applications.
These sulfonamides are available primarily in oral dose forms because they are practically insoluble in water at pHs that may be reasonably used for injection. They are available as tablets and suspensions that are up to 90 to 100% absorbed. An intravenous preparation of sulfamethoxazole plus trimethoprim is available for infusion in patients with severe systemic bacterial diseases and those with Pneumocystis carinii pneumonia.
These sulfonamides (except sulfisoxazole) are widely distributed throughout the body entering even into the ocular fluids and CSF. The placenta is also crossed. Sulfisoxazole is largely limited to the extracellular fluids; CSF reaches 10 to 50% of plasma concentrations.
Protein binding of these sulfonamides is variably moderate to high. It is susceptible to interaction with other drugs and bilirubin. Impaired renal function decreases binding, thus increasing the plasma free drug concentration. Because of this protein binding, Vd estimates will appear to be lower than they should, not reflecting true distribution. For example, the Vd for sulfamethoxazole is 0.36 L/kg.
These sulfonamides are eliminated primarily by glomerular filtration with some tubular secretion. Alkalinization of the urine increases the elimination rate by decreasing back-diffusion from the tubule (think ion-trapping). It also increases the solubility of the drugs making them less likely to crystallize in the tubules although that is not as severe a problem with these entities as it was with previous generations of drugs.
Elimination half-lives in humans are as follows: sulfacytine, 4 hours; sulfamethoxazole, 6 to 12 hours (20 to 50 in end-stage renal failure); and sulfisoxazole 3 to 7 hours (6 to 12 hours in end-stage renal failure). Elimination half-lives of sulfadiazine in various species are as follows (in hours): cattle, 10.1; sheep, 7.2; swine, 2.9; and dogs, 3.9. Sulfadiazine has a half-life of 2.7 hours in horses when given in combination with trimethoprim. Dogs do not acetylate sulfonamides. Cribb'89
Dose intervals for the drugs have rough correlation with the elimination half-lives given above. For humans, sulfacytine and sulfisoxazole are given q6h (slow release forms are available for sulfisoxazole); sulfamethoxazole alone is given q8h to q12h; and sulfamethoxazole plus trimethoprim is given q12h.
Main veterinary drugs are:
Sulfadimethoxine (Albon[R]) is the only sulfonamide approved for cattle. There is a problem in swine in that withdrawal times are very long so sulfonamides must be used only in young animals. Sulfonamides are still used with tetracycline because of claimed "synergy" and they are cheap and effective. According to Dr. Bowersock (95) no sensitivity testing has been done on the combination.
Older sulfonamides still play a significant role in veterinary medicine. In addition to those mentioned earlier, one may see such drugs as sulfathiazole, sulfamethazine (Calf Span[R], Spanbolet II[R], Sulkamycin[R]), sulfamerazine, sulfabromomethazine (Sulfabrom[R]), sulfadimethoxine (Albon[R], Bactrovet[R]), sulfachlorpyridazine (Nefrosul[R], Vetisulid[R], Sonilyn[R]), and sulfamethoxypyridazine (Midicel[R], S.E.Z. sol'n[R]). The first three listed, plus sulfadiazine, are "classical" sulfas that were commonly used in triple sulfa mixtures that are now illegal in the US. Some were also available as feed additives.
Some sulfonamides, e.g., sulfadimethoxine, have been buffered to nearly neutral pH and are available in IM dose forms as well as the IV and oral forms. Sulfonamide solutions that have not been buffered are strongly alkaline and cause tissue necrosis and sterile abscess formation when injected IM or perivascularly. These strongly alkaline solutions should not be injected intraperitoneally. Intrauterine dose forms of sulfonamides alone and in combination with urea are available. The true benefit of adding urea to the intrauterine sulfonamide has been questioned, but it is claimed to increase the concentration of free sulfa and enhance its activity. Drug residues in milk constitute a frequent and important hazard of intrauterine sulfonamides. Because of the strong tissue binding for which sulfas are known, there is reason to doubt their efficacy in topical applications to abscesses as well as for the intrauterine applications.
Sulfonamides produce reactions in all three categories; biological, direct toxicity, and hyersensitivity.
Although not a prominent adverse effect, sulfonamides can produce disturbances in gastrointestinal flora because of their broad spectrum of activity. This would be more pronounced with the older drugs that are less well absorbed from the gastrointestinal tract. This would be manifest initially as a diarrhea.
Sulfonamides are too small to be immunogenic and require metabolic activation to a reactive intermediate before they function as haptens. Nevertheless, a review of the literature would reveal that nearly every conceivable type of hypersensitivity reaction has been associated with the sulfonamides. Hypersensitivity is still one of the more frequent adverse reactions with the sulfonamides, but is rarely serious. It may occur in up to 3% of patients and may be manifest as fever, itching, or skin rash.
The Stevens-Johnson syndrome (arthralgia and myalgia; redness to blistering of skin; weakness) is also a form of hypersensitivity reaction, but is less frequent.
Idiosyncratic reactions occur in some dogs. Reports indicate that Doberman's may be more likely than other breeds of dogs to exhibit hypersensitivity to the combination of sulfadiazine and trimethoprim.This hypersensitivity exhibits as a polyarthritis/fever syndrome. Hydroxylamine metabolites are intermediates in the biotransformation of sulfas in dogs and may be the reactive intermediates that form haptens. Doberman's have less ability to detoxify this intermediate than mixed breed dogs, perhaps accounting for the increased hypersensitivity seen in Dobermans.
Miscellaneous toxicities that are seen more frequently include dizziness, headache, and gastrointestinal disturbances such as diarrhea, anorexia, nausea, and/or vomiting
This is classically associated with the older sulfonamides, but is regarded as rare with newer derivatives when they are taken with copious quantities of water. With the older compounds it was also advised to alkalinize the urine to increase the solubility of the drug and its metabolites.
Triple sulfas (now considered inappropriate and/or illegal) were developed to combat the poor solubility and low potency (e.g., 150 mcg/mL are required versus less than one-tenth of this concentration for most antimicrobials) of the sulfonamides. They exploited the fact that the sulfonamides were additive with respect to antibacterial action, but not solubility. Thus, 50 mcg/mL, each, of sulfamethazine, sulfamerazine, and sulfadiazine would sum to 150 mcg/mL, sufficient to inhibit sensitive strains. Conversely, because of the Lawof Independent Solubilities, the effective concentration in the renal tubule was decreased to one-third of that which would be required if a single agent were used. This significantly reduced the potential for crystallization.
Photosensitivity may be seen. Patiets should minimize exposure to sunlight while taking sulfonamides.
This is a commonly known adverse effect in dogs.
Cardiovascular collapse leading to death has been noted on too rapid administration of intravenous forms of these drugs. It is not due to the alkalinity.
Tissue necrosis can be expected if solutions not intended for IM administration are accidentally injected into the tissues. This is because of the strongly alkaline solutions required to solubilize most of the sulfonamides.
These have been reported in association with the newer sulfonamides. USPDI indicates that these occur more often than rarely! One should be attentive to signs associated with these, including fever, paleness, sore throat, unusual bleeding or bruising, and unusual tiredness and weakness.
Some older sulfonamides were known to cause hematuria, but with newer derivatives this is rare. This hemolysis may be more likely in patients with reduced glucose-6-phosphate dehydrogenase. Some races are genetically predisposed to this condition. The tendency follows the sickle cell trait in Blacks, and people from the Eastern Mediterranean. Approximately 10% of US blacks have the trait. Patients with tendency toward porphyria may be more prone to an attack during sulfonamide therapy.
Drug interactions should be a concern. This is because most sulfonamides are highly protein bound and can either displace substances making those substances toxic or be themselves displaced and produce toxicity. The other source of drug interaction is their nature as sulfonamides. They could enhance the action of furosemide, thiazide diuretics, sulfonylureas (antidiabetics), or carbonic anhydrase inhibitors.
Sulfonamides are used in a broad range of infectious diseases because of their broad spectrum of activity which rivals that of the tetracyclines. Alone and in combination with trimethoprim, they are used as first line drugs in a wide variety of bacterial diseases, e.g., pneumonia, meningitis, and urinary tract infections, . Sulfonamide plus trimethoprim may be used IV for HIV infected patients suffering from Pneumocystis carinii pneumonia. Some sulfonamides have activity against intestinal coccidia. Sulfisoxazole has been recommended for treatment of chloroquine-resistant malaria in conjunction with chloroquine and/or other agents. Sulfadoxine (a rapidly absorbed, but slowly eliminated sulfonamide, half-life 100 to 230 hours) plus pyrimethamine (related to trimethoprim) is recomended for both prophylaxis and treatment of Plasmodium falciparum malaria, particularly in cases where chloroquine resistance is expected or proven.
Pharmacokinetics, adverse effects, and clinical application of trimethoprim, a diaminopyrimidine derivative, will be discussed separately from the sulfonamides. Nearly all of this information can be transferred to its combined use with the sulfonamides. Adverse effects where causation is not clear and clinical applications of the combinations are discussed with the sulfonamides.
As a single agent trimethoprim is available only in tablets for oral administration.
Trimethoprim is rapidly and essentially completely absorbed (90-100%) after oral administration.
A trimethoprim dose of 100 mg given to a mythical 70 kg human produces a peak plasma concentration of approximately 1 mcg/mL. Urinary concentrations are normally 90 to 100 mcg/mL, but may reach 200.
Trimethoprim is rapidly and widely distributed throughout the body including various secretions, prostate, bile, aqueous humor, and bone marrow. It apparently does not penetrate compact bone well. CSF concentrations are 30-50% of plasma concentrations. Concentrations in kidney, urine, and lung gnerally exceed those in plasma. Concentration in vaginal fluids may be up to three times higher than that in plasma. As might be expected from the latter, it also crosses the placenta. The Vd is 1.2 to 2.0 L/kg in humans. This high Vd is consistent with a weak base that crosses membranes readily and probably reflects the volume that would be observed in animals as well.
Trimethoprim is eliminated primarily by glomerular filtration and tubular secretion. Its plasma half-life in humans with normal renal function is 8 to 10 hours. In anuric patients, it may increase to 20 to 50 hours. Only about 10 to 20% is metabolized. The long half-life in the face of tubular secretion reflects the large Vd and, presumably, passive reabsorption from the nephron as the urine is concentrated. This is consistent with the observation that acidification of urine increases its removal and alkaline urine is associated with slower elimination. Note that this is opposite the sulfas.
When given as a single agent trimethoprim is administered orally to humans at a rate of 100 mg q12h or 200 mg q1d.
Trimethoprim is regarded as a safe drug. It may rarely cause blood dyscrasia that would result in unusual bleeding or bruising and signs of infection. Methemoglobinemia is also observed rarely. More common, but less serious effects include headache, mild signs of hypersensitivity, and unusual taste.
Trimethoprim is primarily used to treat urinary tract infections and is recommended as a first line agent. It is effective against a number of gram-positive and gram-negative pathogens, but not Pseudomonas aeruginosa. It has also been used in combination with dapsone as a treatment for pneumonia caused by Pneumocystis carinii.
Used for both skin (staph) and urinary tract infections (E. coli, Staph, etc.), Bordetella bronchiseptica and others. Also god for enteric infections. Expensive for use in food animals. (Bowersock 95)