Crystalluria sulfadiazine

Sulfonamides, such as sulfadiazine, in combination with pyrimethamine, are considered the treatment of choice of symptomatic toxoplasmosis. Patients should be well hydrated to prevent crystalluria this problem may be reduced with the use of triple sulfas (trisulfapyrimidine). Some regimens have included a sulfonamide (sul-fadoxine) in combination with pyrimethamine (Fansidar) for the treatment of chloroquine-resistant malaria caused by P. falciparum. 

Sulfonamides may precipitate in urine, especially at neutral or acid pH, producing crystalluria, hematuria, or even obstruction. This is rarely a problem with the more soluble sulfonamides (eg, sulfisoxazole). Sulfadiazine when given in large doses, particularly if fluid intake is poor, can cause crystalluria. Crystalluria is treated by administration of sodium bicarbonate to alkalinize the urine and fluids to maintain adequate hydration. Sulfonamides have also been implicated in various types of nephrosis and in allergic nephritis. 

SULPHONAMIDES METHENAMINE Risk of crystalluria Methenamine is only effective at a low pH, and this is achieved by acidifiers in the formulation. Sulfadiazine crystallizes in an acid environment Avoid co-administration... 

Simon DI, Brosius FC 3rd., Rothstein DM. Sulfadiazine crystalluria revisited. The treatment of Toxoplasma encephalitis in patients with acquired immunodeficiency syndrome. Arch Intern Med 1990 150(ll) 2379-84. 

A large bibliography exists from the 1940 s related to crystalluria and acute kidney injury associated with the use of sulfadiazine [1, 10, 11]. Sulfadiazine disappeared from clinical use for a long time until it re-emerged again in the AIDS era. More recently, the number of reports in adults and children has increased substantially because of the use of sulfadiazine and pyrimethamine, as the treatment of choice for cerebral toxoplasmosis associated with AIDS, other immunosuppressive states or specific infections [7, 12-35]. Acute kidney injury secondary to sulfadiazine crystalluria has been also reported in renal transplant patients [36, 37]. 

Figure 1. Sulfadiazine nephrotoxicity (crystalluria and acute renal failure). 35 year old man with AIDS and cerebral toxoplasmosis treated for 33 days with 4-6 g/dayofsulfadiazine.The patient received oral hydration and possibly had an episode of transient renal impairment during days 8-13. By day 29 of treatment, crystalluria, hematuria, flank pain, renal calculi, and acute renal failure developed. Urine was alkalinized late in the course.

Prevention of sulfadiazine nephrotoxicity is centered in minimizing crystalluria. This can be accomplished with a high fluid intake (up to 3 liters per day). This may increase solubility of the crystals up to threefold. Nonetheless, continued alkaliniza-tion of the urine with sodium bicarbonate (6 to 12 g/day), assuring that the urine pH is 7.5 or higher, can increase solubility several fold and is very effective. As always, awareness of the possibility of this complication is the best form of prevention. 

In accordance with the better urinary solubility of SMZ, in comparison to older sulfas or sulfadiazine, reports of renal dysfunction secondary to crystalluria are extremely rare [69-71]. Even this theoretical risk inherited from the experience with older sulfas and sulfadiazine, can be avoided by providing adequate... 

Sahai J, HeimbergerT, Collins K, Kaplowitz L, Polk R. Sulfadiazine-induced crystalluria in a patient with the acquired immunodeficiency syndrome a reminder.The American journal of medicine. 1988 Apr 84(4) 791-2. 

Molina JM, Belenfant X, Doco-LecompteT, Idatte JM, Modai J. Sulfadiazine-induced crystalluria in AIDS patients with toxoplasma encephalitis. AIDS (London, England). 1991 May 5(5) 587-9. 

De Jaureguiberry JP RP, Vey N, Jaubert D. Acute renal failure caused by sulfadiazine crystalluria in AIDS. An historical resurgent iatrogenic complication. Ann Med Interne. 1992 143 218-9. 

Hein R, Brunkhorst R,Thon WF, Schedel I, Schmidt RE. Symptomatic sulfadiazine crystalluria in AIDS patients a report of two cases. Clinical nephrology. 1993 May 39(5) 254-6. 

Dong BJ, Rodriguez RA, Goldschmidt RH. Sulfadiazine-induced crystalluria and renal failure in a patient with AIDS.The Journal of the American Board of Family Practice/American Board of Family Practice. 1999 May-Jun 12(3) 243-8. 

Renal stone formation, possibly also accompanied by intratubular precipitation of crystalline material, has been arare complication of drug therapy. Until the AIDS era, triamterene had been the drug most frequently associated with renal stone formation, with an incidence approximating 1 in 1500 users of triamterene-hydrochlorothiazide. However, it has been unclear whether triamterene or its metabolites actually initiated stone formation, or are passively absorbed onto the organic matrix of pre-existing calculi. Sulfadiazine is a poorly soluble sulfonamide that has caused symptomatic acetylsul-fadiazine crystalluria with stone formation and flank or back pain, hematuria, or renal insufficiency in up to 29% of patients treated with the drug. A high urine volume and urinary aUcalinization to... 

Portoles J, Torralbo A, Prats D, Blanco J, Barrientos A. Acute renal failure and sulfadiazine crystalluria in kidney transplant. Nephrol Dial Transplant 1994 9 180-181. 

Fewer than 0.1% of patients receiving sulhsoxazole suffer serious toxic reactions. The untoward effects prodnced by this agent are similar to those that follow the administration of other sulfonamides. Because of its relatively high solubility in the urine as compared with sulfadiazine, sulhsoxazole only infrequently produces hematuria or crystalluria (0.2 to 0.3%). Despite this, patients taking this drug should ingest an adequate quantity of water. Sulhsoxazole and all snlfonamides that are absorbed must be used with caution in patients with impaired renal function. Like all sulfonamides, sulhsoxazole may produce hypersensitivity reactions, some of which are potentially lethal. Sulhsoxazole currently is preferred over other snlfonamides by most clinicians when a rapidly absorbed and rapidly exaeted sulfonamide is indicated. 

In adults and children who are treated with sulfadiazine, every precaution must be taken to ensure fluid intake adequate to produce a urine output of at least 1200 mL in adults and a corresponding quantity in children. If this cannot be accomplished, sodium bicarbonate may reduce the risk of crystalluria. 

The combination o/pyrimethamine and sulfadiazine is the treatment of choice for toxoplasmosis (see Chapter 40). Pyrimethamine is given as a loading dose of 75 mg followed by 25 mg orally per day, with sulfadiazine I g orally every 6 hours, plus folinic acid 10 mg orally each day for at least 3-6 weeks. Patients should receive at least 2 L of fluid intake daily to prevent crystalluria. 

The incidence of crystalluria is low with more soluble agents (e.g., sulfisoxazole). Crystalluria has occurred in volume-depleted patients with the acquired immune deficiency syndrome (AIDS) who were given sulfadiazine for Toxoplasma encephalitis. Fluid intake should be sufficient to ensure a daily urine volume of at least 1.2 L (in adults). Urinary alkalinization may be helpful if urine volume or pH is unusually low. 

The prototype sulphonamide, sulfanilamide has a pKa of 10.4. Substimtion of an electron withdrawing group at the R position increases the acidity (decreased pKa) of the sulphonamido N-H. Subsequently, compounds with a pKa of 6-7 will be ionised at physiological pH (7.4) and can be useful in the treatment of systemic infection with decreased risk of crystalluria. This principle has been applied in the design of sulfadimidine (pKa 7.4) and sulfadiazine (pKit 6.5) (Fig. 22.39) by the addition of the electron withdrawing 4,6,-dimethylpyrimidine and pyrimidine, respectively. 

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