Sulfonamides

Sulfonamides See also Trimethoprim and co-trimoxazole

on Silver) is widely and successfully used in treating burns and leg ulcers [4,5]. Since sulfonamides are easily absorbed through skin lesions, the same adverse reactions can occur as after systemic use.

GENERAL INFORMATION

Sulfasalazine

The term “sulfonamide” is generic for derivatives of paraaminobenzenesulfonamide (sulfanilamide), which is similar in structure to para-aminobenzoic acid (PABA), a co-factor required by bacteria for folic acid synthesis. The sulfonamides act by competitive inhibition of the incorporation of PABA into tetrahydropteroic acid. Sulfonamides have a higher affinity for the microbial enzyme tetrahydropteroic acid synthetase than the natural substrate PABA. Sulfonamides have a wide range of antimicrobial activity against both Gram-positive and Gramnegative organisms [1]. In therapeutic dosages they have only a bacteriostatic effect, and as single agents therefore have a limited role in drug therapy [1]. Sulfonamides have been combined with trimethoprim or trimethoprim analogues, since such combinations result in a bactericidal effect [2]. Adverse reactions during the administration of sulfamethoxazole þ trimethoprim (co-trimoxazole, BAN) can be due to either compound. Although sulfonamides are thought to cause adverse reactions more often than trimethoprim, the culprit in the individual patient can only be determined by re-exposure to the individual agents. Based on their pharmacological properties and clinical uses, sulfonamides can be classified in four groups [1]:

A sulfonamide derivative with special use is sulfasalazine (salicylazosulfapyridine), which has been widely used to treat ulcerative colitis and regional ileitis (Crohn’s disease). It is a compound of sulfapyridine and 5-aminosalicylate, linked by a diazo bond. Sulfasalazine is broken down in the large bowel to sulfapyridine, which is absorbed systemically, and 5-aminosalicylate, which reaches high concentrations in the feces [6]. Sulfasalazine is not used for the antibacterial properties of the sulfapyridine, but for the local anti-inflammatory effect of 5-aminosalicylate in the gut. Because most of the adverse reactions are thought to be due to the absorbed sulfapyridine, the combination has largely been replaced in clinical practice by newer drugs that contain only 5-aminosalicylic acid (mesalazine), such as mesalazine itself and diazosalicylate (olsalazine). The aminosalicylates are covered in a separate monograph.

1 2 3 4

short- or medium-acting sulfonamides; long-acting sulfonamides; topical sulfonamides; sulfonamide derivatives used for inflammatory bowel disease.

Short- or medium-acting sulfonamides include the earliest varieties of azosulfonamides (Prontosil, Neoprontosil), sulfapyridine (Dagenan), sulfathiazole (Cibazol), sulfanilamide, and sulfadiazine. With the exception of sulfadiazine [3], these compounds are no longer used. Sulfadiazine and later compounds, including sulfafurazole (sulfisoxazole), sulfamethoxazole, sulfametrole, sulfacitine, and sulfamethizole, are rapidly absorbed and rapidly eliminated. Compared with the older generation they are more soluble, less toxic, and probably less allergenic. Sulfamethoxazole is a medium-acting sulfonamide that is combined with trimethoprim (as co-trimoxazole). Long-acting sulfonamides include sulfametoxydiazine, sulfadimethoxine, and other compounds, of which many are no longer available, as they were associated with severe hypersensitivity reactions. Although these compounds have the advantage of long administration intervals, their long half-lives (over 100 hours) can be deleterious in case of adverse reactions. A long-acting drug that is still widely used is sulfadoxine (N-(5,6-dimethoxy-4-pyrimidinyl)-sulfanilamide). It is primarily used in combination with pyrimethamine (Fansidar) for the treatment and prophylaxis of malaria. The topical use of sulfonamides has been discouraged, because of the high risk of sensitization. Nevertheless, sulfacetamide and sulfadicramide are still used topically for eye infections. Topical silver sulfadiazine (see monograph ã 2016 Elsevier B.V. All rights reserved.

General adverse effects and adverse reactions The frequency and severity of the adverse effects of sulfonamides correspond to those seen with other antibacterial agents (2–5%). Dose-related effects, which tend to be more troublesome than serious, include gastrointestinal symptoms, headache, and drowsiness. Crystalluria can occur, but urinary obstruction is rare. Hematological adverse reactions due to folic acid antagonism occur primarily in combination with trimethoprim. Hemolytic anemia occurs in patients with enzyme deficiencies and abnormal hemoglobins. Hypersensitivity is thought to be the mechanism of many adverse effects of the sulfonamides. They can be lifethreatening, and immediate withdrawal is recommended. The most important reactions include anaphylactic shock, a serum sickness-like syndrome, systemic vasculitis, severe skin reactions (Stevens–Johnson syndrome and toxic epidermal necrolysis), pneumonitis, hepatitis, and pancytopenia. Sulfonamides should not be used in the third trimester of pregnancy. In premature infants, they displace bilirubin from plasma albumin and can cause kernicterus. Carcinogenicity has not been reported with the use of sulfonamides.

Sulfanilamide and the history of adverse drug reactions The first major drug catastrophe in the 20th century history of the public control of drugs occurred in 1937 in the USA. A pharmacist introduced Elixir Sulfanilamide, which consisted of sulfanilamide dissolved in diethylene glycol. It had been tested for flavor, appearance, and fragrance, but not for safety. After taking the drug, over 100 patients died in severe pain; many were children, who were given Elixir Sulfanilamide for sore throats and coughs. Public outrage created support for proposed legislation to reinforce the

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public control of drugs that was pending in the US Congress [7]. This led to the US 1938 Food, Drug, and Cosmetic Act, which is still the country’s legal foundation for the public control of drugs and devices intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or animals. It has been a model for similar legislation in many other countries. The 1938 Food, Drug, and Cosmetic Act prohibited traffic in new drugs, unless they were safe for use under the conditions of use prescribed on their labels. The Act also explicitly required the labeling of drug products with adequate directions for use. The burden of proof of harm of new drugs was laid on the Federal Food and Drug Agency (FDA). Companies that wanted to manufacture and sell new drugs in interstate commerce had to investigate their safety and report to the FDA. Unless the FDA, within a specified period of time, found that the safety of a drug had not been established, the company could proceed with its marketing. The FDA was also authorized to remove from the market any drug that proved to be unsafe [8]. The US Supreme Court also established in 1941, in a legal case over drug adulteration, that responsible individuals in a company can be held personally accountable for the quality of the products manufactured by the company, and that distributors of pharmaceuticals are responsible for the quality of their products, even if they are manufactured elsewhere [9]. After World War II, the pharmaceuticals market changed radically, as many companies started industrial production of drugs that had previously been manufactured in pharmacies. Announcements of new industrially produced drugs were hailed as part of technological advancement, as significant a sign of progress as the launching of satellites and putting a man on the moon. However, public safeguards against the risks of drugs remained unchanged in most countries. Thus, control of the effects of drugs largely lay in the hands of the manufacturers, even though the responsibility for taking precautions rested with pharmacists and doctors.

DRUG STUDIES Observational studies In an open trial in 25 patients treated with sulfamethoxypyridazine (1 g/day) for mucous membrane pemphigoid unresponsive to topical steroid treatment, 12% of patients were withdrawn, 4% because of allergic reactions, the others because of significant hemolysis [10]. In children with acute uncomplicated Plasmodium falciparum malaria, pyrimethamine þ sulfadoxine (25 mg þ500 mg) and artesunate (4 mg/kg) were well tolerated, and no adverse reactions attributable to treatment were recorded [11].

Comparative studies In a randomized, open, multicenter study in 46 patients with sight-threatening ocular toxoplasmosis, those who took pyrimethamine þ sulfadiazine had significantly more adverse events, especially malaise, than those who took pyrimethamine þ azithromycin [12]. ã 2016 Elsevier B.V. All rights reserved.

ORGANS AND SYSTEMS Cardiovascular Of 98 patients with drug-induced long QT interval, one taking sulfamethoxazole carried a single-nucleotide polymorphism (SNP; found in about 1.6% of the general population) in KCNE2, which encodes MinK-related peptide 1 (MiRP1), a subunit of the cardiac potassium channel IKr [13]. Channels with the SNP were normal at baseline but were inhibited by sulfamethoxazole at therapeutic concentrations, which did not affect wild-type channels. Cardiovascular reactions can be due to sulfonamide myocarditis or systemic vascular collapse, owing to severe adverse events such as widespread skin disease. Sulfonamide myocarditis has been described in relation to earlier sulfonamides and occurs in combination with other hypersensitivity reactions [14].

Respiratory Respiratory reactions to sulfonamides include migratory pulmonary infiltrates, chronic pneumonia, asthma, and pulmonary angiitis. These reactions are thought to be mainly due to hypersensitivity, although the precise mechanisms are not well understood [15–17]. The link to the drug has been proven in most cases by recurrence after reexposure to the same sulfonamide or to co-trimoxazole. Pulmonary reactions have been described with most sulfonamides. Pyrimethamine þ sulfadoxine, used in malaria prophylaxis and treatment, also rarely causes pulmonary reactions [18–20]. The sulfapyridine moiety of sulfasalazine, used in inflammatory bowel disease, can produce adverse pulmonary reactions [21]. The time between the last drug exposure and the first clinical symptoms varies from hours to a few days, and the lung pathology disappears in most patients within a few days after withdrawal. Most commonly, pulmonary involvement presents with fever, dyspnea, cough, and shortness of breath. Clinical examination reveals coarse crackles in the lungs, and there may be pulmonary infiltrates in the chest X-ray. Pulmonary function tests may show bronchial obstruction [19–22], and arterial blood gases show hypoxemia [20,21]. Whereas bronchial obstruction is probably an immediate reaction (type I), pulmonary infiltrates may correspond to a type III reaction, similar to the mechanism responsible for extrinsic allergic alveolitis [21,22]. Eosinophilia is present in 8– 58% of cases [15,17,19,20,22,23]. Histologically, the lung tissue is infiltrated by inflammatory cells, and in most cases the alveoli contain numerous macrophages and eosinophils in a protein-rich edema fluid. Based on the predominant symptoms and their duration, four categories of sulfonamide-related pulmonary hypersensitivity reactions can be distinguished [24–26]: 1 transient or migratory pulmonary infiltrations associated with eosinophilia (Loeffler’s syndrome) [23,27–29]; 2 chronic eosinophilic pneumonia [24,28]; 3 asthma with pulmonary eosinophilia [15–17,22]; 4 allergic angiitis with pulmonary involvement [26]. In the first three of these, the adverse reaction is limited to the lung, whereas in the fourth the lung involvement is

Sulfonamides part of a systemic reaction. Syndromes such as allergic granulomatosis and angiitis (Churg–Strauss syndrome) or Wegener’s granulomatosis are not associated with the use of sulfonamides [26].

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This has even been seen in patients with extensive burns receiving topical mafenide [53]. Mafenide (Sulfamylon) and its metabolite para-sulfamoylbenzoic acid inhibit carbonic acid anhydrase, resulting in reduced reabsorption of bicarbonate and thus bicarbonate wasting.

Nervous system Neurological disturbances that have been attributed to sulfonamides include polyneuritis, neuritis, and optic neuritis [30,31]. Tremor and ataxia have been described with co-trimoxazole [32,33]. Aseptic meningitis can be separately caused by sulfonamides and trimethoprim. The occurrence of meningitis has been verified in most patients, with recurrence on re-exposure [34–43].

Sensory systems Eyes Drug induced uveitis is rare. Antibiotics that have been implicated include rifabutin and sulfonamides. Furthermore, nearly all antibiotics injected intracamerally have been reported to produce uveitis [44]. Topical administration of a corticosteroid and a cycloplegic (such as atropine) is suitable as initial treatment. Withdrawal of causative drugs is not always necessary [45]. Corneal ring formation has been described simultaneously with an erythematous rash in a patient known to have skin hypersensitivity [46].

Vision Transient myopia can be caused by topical or systematic sulfonamides [47–49].

Taste In unmedicated young and elderly volunteers and HIVinfected patients, sulfamethoxazole applied to the tongue was described as sour by young subjects but bitter by elderly subjects [50].

Electrolyte balance Although co-trimoxazole in therapeutic doses can cause hyperkalemia [54], it is thought to be caused by the potassium-sparing effects of trimethoprim [55].

Hematologic Sulfonamides have adverse effects on all bone marrowderived cell lines. The resulting disturbances include hemolytic anemia, folate deficiency anemia, neutropenia, thrombocytopenia, and pancytopenia. While adverse effects on erythrocytes are rare, the rates of leukopenia, neutropenia, and thrombocytopenia are highly variable. In a hospital drug monitoring program, leukopenia or neutropenia occurred in 0.4% of 1809 patients treated with cotrimoxazole [56], and thrombocytopenia of mild-tomoderate degree in 0.1% [56,57], similar to figures recorded in other studies [58,59]. Pancytopenia is an extremely rare form of adverse reaction to sulfonamides [60]. There were similar findings in children [61]. It is generally believed that trimethoprim is primarily responsible for neutropenia due to co-trimoxazole. Severe neutropenia often occurs in HIV-infected patients taking co-trimoxazole [62]. It seems to be due to either folic acid deficiency or immunological mechanisms.

Erythrocytes Sulfonamides rarely have adverse effects on erythrocytes. However, there are various mechanisms by which sulfonamide-induced hemolytic anemia can occur [63]:  abnormally high blood concentrations, due to large doses or

reduced excretion of the drug in patients with renal disease [64]

 acquired hypersusceptibility, as reflected by the development

Psychiatric Headache, drowsiness, lowered mental acuity, and other psychiatric effects can be caused by sulfonamides [51]. However, these adverse reactions are rare, and the causative role of the drug is usually not clearly established. Acute psychosis is rarely associated with cotrimoxazole.  An acute psychosis occurred in a 46-year-old woman who had

taken oral co-trimoxazole (160 þ 800 mg bd) for a urinary tract infection [52]. She started to have psychotic symptoms with bizarre behavior 10 days after starting therapy. After withdrawal and antipsychotic drug treatment, her mental state resolved to a stable premorbid level within 36 hours.

Metabolism Several sulfonamides, including co-trimoxazole in high doses, can produce hyperchloremic metabolic acidosis. ã 2016 Elsevier B.V. All rights reserved.

of a positive Coombs’ test [65,66]

 genetically determined abnormalities of erythrocyte metabo-

lism, for example deficiency of glucose-6-phosphate dehydrogenase or of diaphorase [67,68]  the presence of an abnormal, so-called “unstable”, hemoglobin in the erythrocyte, for example hemoglobin Zu¨rich [69,70], hemoglobin Torino [71], hemoglobin Hasharon [72], and hemoglobins H and M [70].

Simple and readily available in vitro methods have been used to demonstrate the pathogenetic mechanisms, including Coombs’ test, Harris’s test [73], a quantitative assay or screening for glucose-6-phosphate dehydrogenase activity after recovery [74,75], a test for Heinz bodies, the buffered isopropanol technique [76] to detect abnormal hemoglobins, and hemoglobin electrophoresis [63,68]. The direct antiglobulin (Coombs’) test can be negative in spite of an immune mechanism. If such a mechanism is suspected and the direct Coombs’ test is negative, the indirect Coombs’ test on the patient’s serum with the addition of the suspected sensitizing agent can be of

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diagnostic value [77]. Heinz bodies in the erythrocytes can be important for early differentiation of a sulfonamideinduced reaction, which could further progress to hemolytic anemia [78]. This result can also be of help in distinguishing this from other kinds of anemia. Sulfonamides are not directly associated with folate deficiency and megaloblastic anemias. Sulfasalazine can affect the absorption of folates, but inflammatory bowel disease can also be responsible for reduced folate absorption. Only in combination with trimethoprim are sulfonamides thought to deplete folate stores in patients with pre-existing deficiency of folate or vitamin B12 [79].

Leukocytes Since the days when chloramphenicol was more commonly used, it has been recognized that many antimicrobial drug are associated with severe blood dyscrasias, such as aplastic anemia, neutropenia, agranulocytosis, thrombocytopenia, and hemolytic anemia. Information on this association has come predominantly from case series and hospital surveys [80–82]. Some evidence can be extracted from population-based studies that have focused on aplastic anemia and agranulocytosis and their association with many drugs, including antimicrobial drugs [83,84]. The incidence rates of blood dyscrasias in the general population have been estimated in a cohort study with a nested case–control analysis, using data from a General Practice Research Database in Spain [85]. The study population consisted of 822 48 patients aged 5–69 years who received at least one prescription (in all 1 507 307 prescriptions) for an antimicrobial drug during January 1994 to September 1998. The main outcome measure was a diagnosis of neutropenia, agranulocytosis, hemolytic anemia, thrombocytopenia, pancytopenia, or aplastic anemia. The incidence was 3.3 per 100 000 person-years in the general population. Users of antimicrobial drugs had a relative risk (RR), adjusted for age and sex, of 4.4, and patients who took more than one class of antimicrobial drug had a relative risk of 29. Among individual antimicrobial drugs, the greatest risk was with cephalosporins (RR ¼14), followed by the sulfonamides (RR ¼7.6) and penicillins (RR ¼3.1). Agranulocytosis was not infrequent in the early sulfonamide era. The first cases were observed in association with sulfanilamide [86,87], Prontosil [86], sulfapyridine [87,88], sulfathiazole [89], sulfadiazine [89], and sulfasalazine [90]. Even with topical silver sulfadiazine, agranulocytosis as a consequence of systemic absorption has been reported [91]. Special observations in patients with agranulocytosis favor an immunological/allergic mechanism rather than a toxic one. Several points justify this view: 1 the sulfonamide is well tolerated by most patients during the initial phase of treatment; 2 sulfonamide concentrations in the serum, when determined, are not particularly high in patients with hematological complications; 3 in some patients, rashes, fever, and arthritis start concomitantly with or even before the appearance of leukopenia or agranulocytosis; 4 re-exposure to a single dose can be followed by a second episode of severe agranulocytosis; ã 2016 Elsevier B.V. All rights reserved.

5 an agglutinin for leukocytes has been identified in patients’ serum shortly after withdrawal of the drug [88]; 6 using in vitro techniques, positive reactions to the drug with the lymphocyte transformation test or inhibition of colony growth in bone marrow have been found [92,93]; however, the results of lymphocyte transformation tests must be interpreted with caution—sometimes they are positive in patients who have been exposed to the drug without any evidence of a hypersensitivity reaction. In two reviews of epidemiological studies of drug-induced agranulocytosis, co-trimoxazole and sulfasalazine were associated with a high risk of agranulocytosis (OR >5) [94,95]. In a combined analysis of three case–control studies the highest risk ratio was observed for sulfasalazine (OR ¼207; 95% CI ¼61, 708), antithyroid drugs, procainamide, and dipyrone.

Platelets Reports of drug-induced thrombocytopenia have been systematically reviewed [80]. Among the 98 different drugs described in 561 articles the following antibiotics were found with level I (definite) evidence: cotrimoxazole, rifampicin, vancomycin, sulfisoxazole, cefalotin, piperacillin, methicillin, novobiocin. Drugs with level II (probable) evidence were oxytetracycline and ampicillin. In another retrospective analysis of drug-induced thrombocytopenia reported to the Danish Committee on Adverse Drug Reactions, 192 cases caused by the most frequently reported drugs were included and analysed [96]. There were pronounced drug-specific differences in the clinical appearance. Early thrombocytopenia was characteristic of cases caused by sulfonamides and cotrimoxazole. These drugs also often caused hemorrhage. Accompanying leukopenia was observed in some cases associated with co-trimoxazole. There were no patientspecific factors responsible for the heterogeneity of the clinical appearance, and factors related to the physician seemed to be of little significance. Acute thrombocytopenia is rarely associated with the newer sulfonamides [5,97,98]. The structurally related sulfonylureas and thiazide diuretics can also cause allergic thrombocytopenia [99]. Although some in vitro tests have been reported to predict the occurrence of thrombocytopenia, none of these has been used routinely [100,101]. Furthermore, a negative test result with a drug does not definitely exclude it as the responsible allergen.

Salivary glands Salivary gland enlargement on repeated exposure to sulfafurazole (sulfisoxazole) has been described [102].

Gastrointestinal Nausea, vomiting, and anorexia occur in a few patients taking sulfonamides [1]. They are usually related to dosage, the disposition of the individual patient, and how the question concerning adverse reactions is asked.

Sulfonamides

Liver Increased activities of alanine aminotransferase and aspartate aminotransferase to over five times the upper limit of the reference range were reported in a randomized trial of sulfadiazine in toxoplasmic encephalitis [103]. Co-trimoxazole-induced hepatitis has been repeatedly reported. However, trimethoprim alone can also cause acute liver injury [104]. Three forms of liver injury may be related to sulfonamides: 1 hepatitis of the hepatocellular type [105–109]; 2 hepatitis of the mixed hepatocellular type accompanied by cholestatic features [110]; 3 chronic active hepatitis, possibly leading to cirrhosis [111]. The number of cases of sulfonamide hepatitis published annually fell markedly after 1947, with the introduction of the newer short-acting derivatives [110]. However, cases continue to be reported [112].  A 20-year-old woman, who took sulfadiazine 3 g/day, pyrimeth-

amine 50 mg/day, leucovorin 15 mg/day, and prednisolone 75 mg/day for toxoplasmosis retinitis, developed gastrointestinal disturbance and jaundice because of acute fulminant hepatitis complicated by hepatorenal syndrome, presumably caused by sulfadiazine. She improved after withdrawal of sulfadiazine and treatment with hemodialysis.

Children can also be affected by drug-induced liver disease [113]. Hitherto, the connection with a sulfonamide has always been investigated by administering a test dose. Immunological in vitro methods that show sensitization to the drug, for example the lymphocyte transformation test, are of limited value. In some patients the hepatic injury develops in connection with a general reaction, such as serum sickness-like syndrome, generalized vasculitis, or rash [114,115]. In patients with hypersensitivity, re-exposure can result in generalized malaise, nausea, back pain, and chills within one to several hours [107,111]. However, symptoms can be delayed for as long as several days [110]. Daily monitoring of liver function on re-exposure seems to be important, since subjective signs can be absent despite rising activities of serum aminotransferases and alkaline phosphatase [106]. Even in patients with chronic active hepatitis, the histopathology of the liver damage was indistinguishable from non-drug-induced pathology. The degree of piecemeal necrosis usually varies from one area to another. Antinuclear factor and lupus erythematosus factor were positive in some cases [111]. Early recognition of drug-induced liver disease is of great importance, since liver injury can be completely reversible after withdrawal.

Pancreas Pancreatitis has been attributed to sulfonamides. Sulfamethizole [35] and sulfasalazine [116] have been implicated by re-exposure. The 5-aminosalicylic acid moiety of sulfasalazine may also be responsible [117,118].

Urinary tract Renal complications that occur in relation to sulfonamide administration include crystalluria, tubular necrosis, ã 2016 Elsevier B.V. All rights reserved.

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interstitial nephritis, and glomerular lesions as part of a vasculitis syndrome. Sulfonamides and their metabolites are excreted in large amounts in the urine. They are relatively insoluble in the acid environment and tend to precipitate in the collecting tubules, calyces, and pelvis of the kidney, and possibly in the ureters. The course is typically benign but adequate hydration and alkalinization may be required [119]. Nephrocalcinosis can cause hematuria, renal colic, or acute renal insufficiency [120]. Urinary obstruction with anuria/oliguria was seen primarily with the earlier, less soluble sulfonamides. With the newer and more soluble sulfonamides crystal formation is rare, as is acute renal insufficiency due to other mechanisms. During recent years renal complications have been seen more often in patients with AIDS, because of the use of large doses of sulfonamides combined with trimethoprim against infection with Pneumocystis jirovecii (formerly Pneumocystis carinii) or Toxoplasma encephalitis. Reduced fluid intake and low urinary pH favor crystal formation, and so both adequate fluid intake (about 2 l/day for adults) and urine alkalinization are encouraged when larger doses of sulfonamides are used [62,120–125]. For the diagnosis of sulfonamide crystalluria, the Lignin test is recommended. At room temperature crystals can even be found in the urine of patients taking sulfamethoxazole, which is readily soluble [126].  A 48-year-old man with untreated HIV infection developed con-

fusion and dyspnea. He had a history of ischemic heart disease and hepatitis C infection [127]. His CD4 count was 50 x 106/l (reference range 400–1320). He was found to have Pneumocystis jirovecii pneumonia and cerebral toxoplasmosis and was given oral co-trimoxazole (320/1600 qds) for the Pneumocystis pneumonia and sulfadiazine (1.5 g qds) for the toxoplasmosis. Baseline renal function was normal. Later, the co-trimoxazole was withdrawn because of concurrent sulfadiazine treatment. On day 7, he developed macroscopic hematuria and profuse crystalluria. Renal function was normal, but 2 days later his creatinine rose to 250 mmol/l. Despite vigorous intravenous hydration the serum creatinine increased to 401 mmol/l. Renal tract ultrasound was normal but morphological examination of crystals confirmed the presence of a sulfonamide. Sulfadiazine was withdrawn and he recovered uneventfully within 1 month.

Sulfadiazine is a weak acid that will precipitate as crystals in the tubular lumen at a urine pH below 5.5; patients taking doses over 4 g/day should maintain a high oral fluid intake or receive adequate intravenous hydration. Bilateral flank pain and progressive oliguria developed over 3 weeks in a 47-year-old woman who took sulfadiazine for toxoplasmosis retinitis [128]. Only in a second CT scan (an unenhanced helical scan with very low attenuation for stones) was urolithiasis detected; sulfonamide crystals were found in the urine. Other renal complications reported with sulfonamides are:  acute tubular necrosis or tubulointerstitial nephritis [122,129];  interstitial nephritis [130], in some cases combined with granu-

lomatous lesions [131,132];

 acute vasculitis [133];  acute renal insufficiency in association with a serum sickness-

like syndrome, generalized vasculitis, or rashes in combination with hepatic damage [114].

Acute anuria or oliguria is often the first symptom, not only in patients with tubular necrosis or tubulointerstitial

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nephritis, but also in those with allergic vasculitis. Nonoliguric renal insufficiency can also occur. It is not yet clear whether tubular necrosis in association with sulfonamides is a toxic, collateral, or hypersusceptibility reaction. The unstable hydroxylamine metabolites of some sulfonamides can act as direct renal toxins. In a French analysis of 22 510 urinary calculi performed by infrared spectroscopy, drug-induced urolithiasis was divided into two categories: first, stones with drugs physically embedded (n ¼238; 1.0%), notably indinavir monohydrate (n ¼126; 53%), followed by triamterene (n ¼43; 18%), sulfonamides (n ¼29; 12%), and amorphous silica (n ¼24; 10%); secondly, metabolic nephrolithiasis induced by drugs (n ¼140; 0.6%), involving mainly calcium/vitamin D supplementation (n ¼56; 40%) and carbonic anhydrase inhibitors (n ¼33; 24%) [134]. Drug-induced stones are responsible for about 1.6% of all calculi in France. Physical analysis and a thorough drug history are important elements in the diagnosis. An HIV-positive patient with toxoplasmic encephalitis developed acute renal failure after treatment with sulfadiazine; renal ultrasound showed echogenic areas presumed to be sulfa crystals [135]. Crystalluria occurs in 45% of patients taking sulfonamides and acute renal insufficiency in 0.4–29% [136]. Hydration and urinary alkalinization can prevent and resolve crystal formation.

Skin Rashes are common during sulfonamide administration, and the rate increases with duration of therapy. Maculopapular reactions are most common and occur in about 1– 3% of patients [137–141]. In a survey of 5923 pediatric records, 3.46% of prescriptions for sulfonamides were followed by the development of a rash, although none was severe enough to require hospitalization [142]. Urticaria, fixed drug eruptions [140,143–146], linear A bullous dermatosis [147], erythema nodosum [148], photosensitivity reactions [149], and generalized skin reactions involving light-exposed areas [149–151] are less common. Topical silver sulfadiazine cause local reactions, consisting of rash, pruritus, or a burning sensation in 2.5% of patients [5,53].  Generalized cutaneous depigmentation after sulfamide therapy

occurred in a 41-year-old man [152]. Melanocytes were not seen on electron microscopy, but there were clear cells with the characteristics of Langerhans cells along the basal layer.

Other eruptions seen with sulfonamides include erythema multiforme and Stevens–Johnson syndrome [153] and exfoliative dermatitis [154]. In erythema multiforme, linear depositions of IgA at the dermoepidermal junction have been suggested to play a pathogenic role [141].  Linear IgA dermatosis with erythema multiforme-like clinical

features has been reported in a 19-year-old man several days after completion of a 5-day-course treatment with sulfadimethoxine (500 mg bd) for a flu-like syndrome [147]. Treatment with methylprednisolone (150 mg) with gradual dosage reduction was started. Slow improvement was followed by a flare-up after reduction to 80 mg/day. Therapy was changed to dapsone 100 mg/day, and there was a dramatic improvement.

The most severe skin reactions associated with sulfonamides are the severe forms of erythema multiforme, ã 2016 Elsevier B.V. All rights reserved.

Stevens–Johnson syndrome, and toxic epidermal necrolysis [154–161]. In a study from Cameroon, eight of ten patients with toxic epidermal necrolysis had taken sulfonamides (five sulfadoxine, three sulfamethoxazole); two patients died after taking sulfadoxine [162]. Mortality in drug-induced toxic epidermal necrolysis has been estimated to be about 20–30% [163,164], and in Stevens–Johnson syndrome 1–10% [34,153,156,157,160]. Some severe skin reactions start with a maculopapular rash or generalized erythema. The culprit drug is often either a long-acting formulation or a short-acting drug that has been continued over a long period. In both toxic epidermal necrolysis and Stevens–Johnson syndrome immediate withdrawal of the sulfonamide and all other non-essential drugs is required, as well as adequate supportive therapy with fluids, proteins, and electrolytes, in order to prevent renal insufficiency and respiratory distress syndrome [163,164]. Occasionally, toxic epidermal necrolysis must be distinguished from staphylococcal scalded skin syndrome (Lyell’s syndrome) by histology. In toxic epidermal necrolysis, there is subepidermal cleavage of the skin at the level of the basal cells, resulting in full-thickness denudation, whereas in scalded skin syndrome the split occurs in the upper epidermis near the granular layer just beneath the stratum corneum [165]. The role of sulfonamides as an etiological factor in the Stevens–Johnson syndrome is extremely difficult to evaluate, except for patients with re-exposure or in situations where the drug was given prophylactically for meningitis [156] or pneumonia [153,157,160,161]. In the first epidemiological study in 1968, 100 000 individuals were given prophylactic sulfadoxine (Fanasil) and 997 (1.0%) had skin reactions [156]. Of these, about 100 had severe reactions, such as erythroderma with jaundice, Stevens– Johnson syndrome, or toxic epidermal necrolysis; 11 died from these complications, that is about one in 10 000 patients treated with the probably causative drug. It is not known how many would have had similar skin reactions unrelated to the drug. However, the benefit to risk balance of meningitis prophylaxis clearly favored the use of sulfonamides [156]. A second report [153] showed an incidence of three cases of Stevens–Johnson syndrome in 480 healthy, newly recruited Bantu mineworkers treated prophylactically with sulfadimethoxine. In a third epidemiological study in Mozambique in 1981, 149 000 inhabitants in one town were given a single dose of sulfadoxine as mass prophylaxis in an attempt to stem an outbreak of cholera [157]; 22 patients with typical Stevens–Johnson syndrome were admitted to hospital over 18 days; three died. In one case toxic epidermal necrolysis caused by cotrimoxazole improved with high-dose methylprednisolone [166]. However, previous studies of the use of glucocorticoids in toxic epidermal necrolysis have given contradictory results. The combination of pyrimethamine and sulfadoxine, used for prophylaxis of chloroquine-resistant malaria (Plasmodium falciparum), causes severe skin reactions in one per 5000–8000 users, with fatal reactions in one per 11000– 25 000 users [167]. Even at the stage of early rash or generalized erythema, this therapy should be withdrawn [138]. In an open prospective study in 95 HIV-infected patients with successfully treated Pneumocystis jirovecii pneumonia, pyrimethamine þ sulfadoxine (25/500 mg)

Sulfonamides was given twice weekly to prevent relapse [168]. There were allergic skin reactions in 16 patients, resulting in permanent withdrawal in six. Two patients developed serious adverse reactions (Stevens–Johnson syndrome), both of whom had continued to take prophylaxis despite progressive hypersensitivity reactions. Most of the cutaneous adverse reactions to sulfonamides are associated with increased in vitro reactivity to sulfonamide metabolites, such as unstable hydroxylamines [169]. In some cases glutathione deficiency has been proposed as a major mechanism. This seems to be important in patients with AIDS, in whom glutathione deficiency is frequent, and in whom rashes are much more common than in other patients [170]. A predominance of slow acetylator phenotype has also been observed among patients with sulfonamide hypersensitivity reactions, and an association with the phenotypes HLA-A29, B-12, and DR-7 in patients with bullous cutaneous reactions [169,171–173] A mechanism for generalized drug-induced delayed skin reactions to sulfamethoxazole may be perforinmediated killing of keratinocytes by drug-specific CD4 þ lymphocytes [174]. The requirement of interferon gamma pretreatment of keratinocytes for efficient specific killing might explain the increased frequency of drug allergies in generalized viral infections such as HIV, when interferon gamma concentrations are raised.

Immunologic Sulfa allergy refers to a specific hypersensitivity response to a group of chemicals containing a sulfonamide moiety covalently bound to a benzene ring; drugs structurally similar to sulfonamides may cross-react, for example sulfonylureas, thiazides, and furosemide [175]. Sulfa allergy is most consistent with an immune-mediated reaction with delayed onset, 7–14 days after the start of therapy, characterized by fever, rash, and eosinophilia. IgG antibodies may be present and directed against proteins in the endoplasmic reticulum (about 80% of patients) or against the drug covalently bound to protein (about 5% of patients). High-dose methylprednisolone sodium succinate (250 mg every 6 hours for 48 hours) may not only alleviate the signs but also markedly attenuate the antibody response, as reported in a 19-year-old man [176]. Hypersusceptibility to sulfonamides has been proposed to be the mechanism for many adverse reactions, including anaphylactic shock, serum sickness-like syndrome, systemic allergic vasculitis, drug fever (up to 1–2% in some series), lupus-like syndrome, myocarditis, pulmonary infiltrates, interstitial nephritis, aseptic meningitis, hepatotoxicity, blood dyscrasias (agranulocytosis, thrombocytopenia, eosinophilia, pancytopenia), and a wide variety of skin reactions (urticaria, erythema nodosum, erythema multiforme, erythroderma, toxic epidermal necrolysis, and photosensitivity). Urticarial and maculopapular rashes are the most frequent adverse reactions to sulfonamides after gastrointestinal symptoms. Although hypersusceptibility is suspected to be the mechanism for these adverse effects, type I allergic reactions, which are induced by IgE antibodies, have been confirmed only rarely. It appears that with the older sulfonamides severe reactions were more frequent. ã 2016 Elsevier B.V. All rights reserved.

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In some patients who have immediate hypersensitivity reactions to sulfonamides, IgE has been found that can bind to an N4-sulfonamidoyl determinant (N4-SM) [177].

Prediction It is desirable to predict hypersusceptibility reactions to sulfonamides. IgE-induced in vitro reactions to sulfonamides have mainly been studied in the last 15 years [177–179]. A lymphocyte toxicity assay showed a positive result in about 70% of patients with a maculopapular rash, an urticarial reaction, or erythema multiforme [180]. This biochemical test determines the percent of cell death due to toxic metabolites. The same in vitro reaction using the hydroxylamine metabolite of sulfamethoxazole gave significantly different results in six patients with fever and rash with or without hepatitis than in control patients [175]. Unfortunately, in most adverse reactions it is not known whether the reaction is dose-related or allergic. Individual differences in metabolism predispose to idiosyncratic reactions, for example sulfonamides are metabolized by N-acetylation (mediated by a genetically determined polymorphic enzyme) and oxidation to potentially toxic metabolites [172,173]. Fever and rash were observed significantly more often in slow than in fast acetylators [172,173]. Systemic glutathione deficiency, with a consequently reduced capacity to scavenge such toxic metabolites, might contribute to these adverse reactions, particularly in patients with AIDS [181,182]. In a child with dihydropteridine reductase deficiency, a variant of phenylketonuria, adverse drug reactions occurred to cotrimoxazole [183]. Unfortunately, there are no reliable in vitro tests to predict idiosyncratic reactions in vivo [169,172,173,175,182].

Cross-reactivity The immunogenicity of sulfonamide antimicrobials may be due to the presence of an arylamine group at the N4 position of the sulfonamide molecule. Thus, allergic crossreactions between different sulfonamides can occur. Therefore, in cases of known hypersusceptibility to a specific sulfonamide exposure to other sulfonamides should be avoided. Cross-reactions can even occur with paraaminosalicylic acid and local anesthetics of the procaine type; however, the real frequency of these crosssensitivities is not known and their significance is undetermined. It should be noted that as many as 50% of patients with rash have recovered in spite of continued treatment with the same drug [184], and even agranulocytosis did not occur after later re-exposures to the causative agent [170].

Susceptibility factors In an in vitro study, plasma from HIV-positive patients was less able to detoxify nitrososulfamethoxazole than control plasma, suggesting that a disturbance in redox balance in HIV-positive patients may alter metabolic detoxification capacity, thereby predisposing to sulfamethoxazole hypersensitivity [185].

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Types of reaction Type I reactions: Anaphylactic shock occurs rarely with sulfonamides [175,177,178,186,187]. Anaphylaxis to a central venous catheter (ARROWg þ ard Blue Catheter) coated with chlorhexidine and sulfadiazine has been reported in a 50-year-old man [188]. Type III reactions: A serum sickness-like syndrome has been observed during sulfonamide administration. This diagnosis should be limited to patients with at least three of the symptoms of classical serum sickness, that is fever, rash, allergic arthritis, lymphadenopathy, and possibly leukopenia or neutropenia. Histologically, severe serum sickness-like syndrome seems to correspond to an allergic vasculitis [133,189]. Most of the descriptions of serum sickness-like syndrome with histopathological documentation have been associated with older sulfonamides that are no longer used [190]. In some severe forms of serum sickness-like syndrome, the reaction can be complicated by a number of unusual organ manifestations, including plasmacytosis, lymphocytosis, monoclonal gammopathy [191,192], interstitial myocarditis [14,34], allergic pneumonitis, nephropathy, liver damage, and nervous system disorders [133,189]. Lupus-like syndromes: Sulfonamides can cause three different clinical and biological syndromes similar or identical to systemic lupus erythematosus [193,194]: 1 exacerbation of pre-existing lupus erythematosus 2 triggering of lupus erythematosus in a susceptible patient 3 serum sickness-like syndrome resembling lupus erythematosus clinically and serologically. There may be positive LE cells and antinuclear factors. In exacerbation or triggering of lupus erythematosus, two pathogenetic mechanisms may be involved: 1 a reaction to the pharmacological properties of the drug, such as occurs with other drugs, such as hydralazine, phenytoin, procainamide, isoniazid, and practolol [193–198]; 2 a hypersensitivity reaction [194,199,200]. In type I reactions, exposure time, and especially re-exposure time, are usually longer than 1–2 months. In type II reactions, exposure is more variable, lasting from hours to days or up to 1–2 months [193–195]. Some patients with ulcerative colitis have developed arthropathy, possibly polyserositis, hematological abnormalities, and even loss of consciousness with positive LE cell and antinuclear antibody tests during treatment with sulfasalazine [195,197].

Diagnosis No diagnostic tests are available to confirm sulfonamide hypersensitivity, and while avoidance of the drug is generally appropriate when a previous hypersensitivity reaction is suspected, desensitization protocols are available for use in HIV patients in whom Pneumocystis jirovecii pneumonia prophylaxis or treatment is indicated [201].

jirovecii pneumonia and toxoplasmosis. Desensitization is successful in 75% of patients with AIDS [202–204]. However, the procedure is not completely safe and even anaphylactic shock can occur [178].

Body temperature Drug fever due to sulfonamides is usually accompanied by a skin reaction; however, fever without other manifestations can occur [172,173].

LONG-TERM EFFECTS Drug resistance Salmonella typhimurium DT104 is usually resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline. An outbreak of 25 culture-confirmed cases of multidrug-resistant S. typhimurium DT104 has been identified in Denmark [205]. The strain was resistant to the abovementioned antibiotics and nalidixic acid and had reduced susceptibility to fluoroquinolones. A swineherd was identified as the primary source. The DT104 strain was also found in cases of salmonellosis in Washington State, and soft cheese made with unpasteurized milk was identified as an important vehicle of its transmission [206].

SECOND-GENERATION EFFECTS Fertility Male infertility with oligospermia has been reported during treatment with sulfasalazine [207,208]. However, inflammatory bowel disease can also affect the maturation of spermatozoa [209].

Teratogenicity The sulfonamides appear to have little if any effect on early human development. This is indicated by the absence of case reports or epidemiological survey data during pregnancy. In one study of 50 282 mother-child pairs, 1455 were exposed to sulfonamides during the first 4 months; there was no increase in the relative risk of any malformation [210,211]. Malaria during pregnancy is associated with an increased risk of severe anemia and babies of low birth weight. Effective intermittent therapy with pyrimethamine þ sulfadoxine reduces parasitemia and severe anemia and improves birth weight in areas in which Plasmodium falciparum is sensitive to this combination. In an open, prospective trial in 287 pregnant women in the Gambia who were exposed to a single dose of a combination of artesunate and pyrimethamine þ sulfadoxine there was no evidence of a teratogenic or otherwise harmful effect [212].

Desensitization Desensitization has been tried with sulfonamides and especially co-trimoxazole. Desensitization with the combination seems to be essential in patients with AIDS, since co-trimoxazole is the first choice against Pneumocystis ã 2016 Elsevier B.V. All rights reserved.

Fetotoxicity Sulfonamides should not be given to pregnant women in the third trimester of pregnancy. They can displace

Sulfonamides bilirubin from plasma albumin and cause kernicterus (bilirubin encephalopathy) [213–216]. For the same reason, the administration of sulfonamides to lactating women or premature infants should be avoided. Successful treatment of neonatal hyperbilirubinemia with higher bilirubin concentrations has been established using exchange transfusion and phototherapy.

SUSCEPTIBILITY FACTORS Genetic The acetylator phenotype of a patient can affect the frequency and severity of adverse reactions to drugs that are metabolized by acetylation [68,172,173]. In patients with porphyria, sulfonamides should not be used [217].

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Barbiturates Sulfafurazole enhances the anesthetic effect of shortacting intravenous barbiturates, by competitive displacement from binding sites on plasma albumin [222].

Coumarin anticoagulants In an elderly woman taking warfarin, anticoagulation was potentiated when sulfisoxazole was given concurrently [223]. A similar case was reported in a 74-year-old man [224]. The authors suggested that this was due to displacement of warfarin from serum albumin, but it is more likely to have involved inhibition of warfarin metabolism by CYP2C9, which some sulfonamides (for example sulfaphenazole, sulfadiazine, sulfamethizole, and sulfafurazole) inhibit [225].

Phenytoin HIV infection Although patients with HIV infection are more likely to develop generalized skin reactions to sulfonamides, they can be used for prophylaxis and therapy.

Immunological factors Relative contraindications to sulfonamides are systemic lupus erythematosus and a known predisposition to lupus-like reactions. Allergic reactions to antimicrobials are frequent in patients with Sjo¨gren’s syndrome. They are especially susceptible to reactions to penicillins, cephalosporins, and sulfonamides, but reactions to macrolides and tetracyclines also seem to be over-represented in these patients [218].

DRUG ADMINISTRATION Drug administration route Sulfacetamide sodium (Albucid) in solutions stronger than 5% can cause burning and stinging when applied to the eyes, but this brief discomfort is usually tolerated without serious complaints. Sulfacetamide still compares favorably with newer antibiotics since it is effective against superficial ocular infections caused by a variety of microorganisms. However, serious allergic reactions can develop after ocular treatment [219]. The sulfonamides have a bacteriostatic rather than a bactericidal action. Many local anesthetics used in the eye are esters of para-aminobenzoic acid, and such drugs will interfere with the action of sulfonamides. Thus, to obtain the maximum effect from instillation of sulfonamide eye-drops, these drugs should not be used until the effect of the local anesthesia disappears.

In single dose experiments sulfaphenazole prolonged the half-life of phenytoin by 237% and reduced phenytoin metabolic clearance rate by 67% [226]. Sulfadiazine, sulfamethiazole, co-trimoxazole prolonged the half-life of phenytoin by 80%, 66%, 39%, and 51% respectively, and reduced phenytoin metabolic clearance rate by 45%, 36%, 27%, and 30% respectively. Sulfamethoxazole gave a small but significant prolongation of phenytoin half-life but no change in clearance. Sulfamethoxypyridazine, sulfadimethoxine, and sulfamethoxydiazine had no effects. Steady-state experiments confirmed the findings of the single-dose experiments. The authors suggested that sulfaphenazole, sulfadiazine, sulfamethizole, and cotrimoxazole inhibit the hepatic metabolism of phenytoin.

Sulfonylureas Hypoglycemia, often during the first hours of combining the two drugs, is the result of an important interaction between sulfonylureas and sulfonamides [227–230]. Tolbutamide is mainly metabolized by CYP2C9, which also has a role in the metabolism of sulfonamides. For example, the half-life of tolbutamide was increased from 9.5 to 29 hours by chronic sulfaphenazole and from 9.2 to 26 hours by a single dose of sulfaphenazole [231]. Interference by sulfonamides with the protein binding of sulfonylureas may contribute. Most reports of this interaction have described hypoglycemia with tolbutamide in combination with sulfaphenazole [227,228,231,232], sulfafurazole [228], or co-trimoxazole [230,233]. The inhibitory effect of sulfonamides on tolbutamide metabolism is mediated by CYP2C9 [225]. Chlorpropamide produces the same interaction [234]. The combination of gliclazide, fluconazole, and sulfamethoxazole can cause severe hypoglycemia [235].

DRUG–DRUG INTERACTIONS

INTERFERENCE WITH DIAGNOSTIC TESTS

Alkalis

Theophylline

Urine alkalinization increases the urinary excretion of sulfonamides [220,221].

Sulfamethoxazole distorts the results of high performance liquid chromatography used for detection of theophylline

ã 2016 Elsevier B.V. All rights reserved.

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plasma concentrations; the antibiotic should be withdrawn 24 hours before the procedure [236]. [18]

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