Delayed hypersensitivity reactions to sulphonamides: syndromes,pathogenesis and management

Sulphonamide antibiotics are a commonly used, and important, group of antibiotics in veterinary dermatology. However, many of the commonly used sulphonamides such as sulphamethoxazole, sulpha-diazine, or sulphasalazine are associated with idiosyncratic drug reactions in dogs. This paper will review the clinical syndromes, pathogenesis of sulphonamide hypersensitivity reactions and current methods for predicting these occurrences.     

Nephrotic syndrome associated with administration of sulfadimethoxine/ormetoprim in a dobermann

This case report describes sulphonamide-induced nephrotic syndrome in a young dobermann dog. The clinical signs and laboratory abnormalities resolved shortly after discontinuation of the sulphonamide antibiotic and with generalised supportive care. Since nephrotic syndrome typically carries a guarded prognosis in veterinary medicine and is poorly responsive to therapy, a thorough drug history should be an important part of the investigation of any animal with a protein-losing nephropathy.     

Sulphonamides: updates on use in veterinary medicine

Sulphonamides are the oldest class of antimicrobials and are still the drug of choice for many diseases in veterinary patients. They are classified based on their pharmacokinetics and pharmacodynamics. This article presents an overview of various sulphonamides in each classification, the mechanisms of bacterial resistance, and the effectiveness and maintenance of skin concentrations. Clinical indications, routes and frequency of administration, duration of therapy, compliance factors, cost, adverse drug reactions and drug interactions are described. Controversial topics such as current usage and recommendations for sulphonamide use in dermatology are also discussed.     

In vitro antimicrobial activity of hydroxy and N4-acetyl sulphonamide metabolites

Hydroxylated metabolites of sulphadimidine, sulphamerazine, sulphatroxazole, sulphamethoxazole, and sulphadiazine exhibited antimicrobial activity against Escherichia coli 28 PR 271 test strain ranging from 2.5 to 39.5 per cent of that of the parent drug. Trimethoprim addition potentiated the antimicrobial activity of these metabolites. N4-acetyl sulphonamide metabolites possessed no antimicrobial activity, nor did trimethoprim potentiated them.     

Keratoconjunctivitis sicca in the dog associated with the administration of salicylazosulphapyridine (sulphasalazine)

Thirteen cases of iatrogenic and bilateral keratoconjunctivitis sicca following the administration of the sulphonamide salicylazosulphapyridine (sulphasalazine) for the treatment of colitis were studied. No breed, age or sex incidence was noted in this series, unlike in keratoconjunctivitis sicca cases due to other causes. The lacrimotoxic effect of sulphasalazine was permanent except in one case and it is suggested that dogs on this drug should be monitored for tear secretion at regular intervals. Reports of a similar association between keratoconjunctivitis sicca and this drug and between the disease and other sulphonamides and compounds are discussed.     

Effect of Sulfakombin SPOFA on the dynamics of the extent of coccidiosis in small rabbit breeding operations

We determined the yearly changes in coccidiosis extensity applying the results of an examination of 2707 rabbits performed in the years 1981-1984. A field trial was conducted to study the efficiency of the Czechoslovak anticoccidic drug Sulfakombin Spofa administered to control coccidiosis in small rabbit breedings. We made the calculations to find out the optimum time of administration of sulphonamide substances. We discuss certain factors that influence in a decisive way the changes in coccidiosis extensity in rabbit breedings.     

In vitro antimicrobial activity of hydroxy and N4‐acetyl sulphonamide metabolites

Summary

Hydroxylated metabolites of sulphadimidine, sulphamerazine, sulphatroxazole, sulphamethoxazole, and sulphadiazine exhibited antimicrobial activity against Escheria coli 28 PR 271 test strain ranging from 2.5 to 39.5 per cent of that of the parent drug. Trimethoprim addition potentiated the antimicrobial activity of these metabolites. N₄‐acetyl sulphonamide metabolites possessed no antimicrobial activity, nor did trimethoprim potentiated them.     

Destructive cholangiolitis in seven dogs

Summary

In seven dogs presented with clinical signs and laboratory data suggestive of extrahepatic cholestasis, destructive cholangiolitis was diagnosed. The diagnosis was based on the absence of extrahepatic cholestasis at laparoscopy, laparotomy and/or post‐mortem examination, and the presence of specific liver lesions i.e. loss of bile ducts in the smaller portal areas. The disease is compared with drug‐induced (chlorpromazine) cholestasis in man. In two dogs clinical signs were preceded by longstanding respectively repeated sulphonamide medication.     

Comparative bacterial drug resistance in modern battery and free-range poultry in a tropical environment

A correlation between the use of antibiotics and drug resistance was found among Escherichia coli strains isolated from modern battery poultry at the University of Ibadan, Nigeria. All 1248 E coli strains from university poultry and 2196 strains from a commercial poultry farm in Ibadan were resistant to tetracycline, streptomycin and sulphonamide, the minimal inhibitory concentrations of these drugs being found to be several times those of the control E coli NCTC 10418. In contrast, all 2284 strains isolated from free-range town and village poultry were sensitive to these drugs. In the tropical developing countries with poor environmental sanitation and low personal hygiene, this situation has public health implications.     

Pharmacokinetics and renal clearance of sulphadimidine, sulphamerazine and sulphadiazine and their N4-acetyl and hydroxy metabolites in pigs

The effect of molecular structure on the drug disposition and protein binding in plasma, the urinary recovery, and the renal clearance of sulphamerazine (SMR), sulphadiazine (SDZ), and sulphadimidine (SDM) and their N4-acetyl and hydroxy derivatives were studied in pigs. Following IV administration of SDM, SMR and SDZ, their mean elimination half-lives were 12.4 h, 4.3 h and 4.9 h respectively. The plasma concentrations of parent sulphonamide were higher than those of the metabolites, and ran parallel. The acetylated derivatives were the main metabolites; traces of 6-hydroxymethylsulphamerazine and 4-hydroxysulphadiazine were detected in plasma. The urine recovery data showed that in pigs acetylation is the major elimination pathway of SDM, SMR and SDZ; hydroxylation became more important in case of SMR (6-hydroxymethyl and 4-hydroxy derivatives) and SDZ (4-hydroxy derivatives) than in SDM. In pigs methyl substitution of the pyrimidine side chain decreased the renal clearance of the parent drug and made the parent compound less accessible for hydroxylation. Acetylation and hydroxylation speeded up drug elimination, because their renal clearance values were higher than those of the parent drug.     

An in vitro investigation of predisposition to sulphonamide idiosyncratic toxicity in dogs

Sulphonamide idiosyncratic toxicosis has been reported in 28 dogs. Non-septic polyarthritis and fever occurring after 8 to 21 days therapy was the most common manifestation. Of 22 dogs with this syndrome, 7 were Doberman Pinschers. In humans, inherited decreased ability to detoxify sulphonamide hydroxylamine metabolites (as reflected in an in vitro mononuclear leukocyte (MNL) toxicity assay) has been associated with susceptibility to sulphonamide idiosyncratic toxicity. We have demonstrated that microsomes obtained from the liver of a dog were capable of metabolizing sulphamethoxazole to sulphamethoxazole hydroxylamine (SMX-HA). Production of SMX-HA was an NADPH dependent process and the yield was increased by the presence of 1 mmol/L ascorbic acid. SMX-HA was toxic to isolated MNL from mixed breed dogs (MBD) and Doberman Pinschers. The toxicity of SMX-HA to MNL from Dobermans was significantly different from that to MNL from MDB. MNL from 7 out of 15 Dobermans (including a dog with a history of an idiosyncratic reaction to a sulphonamide) had an LD-50 (concentration of SMX-HA required to produce 50% cytotoxicity in MNL) < 100 mol/L, while MNL from 0 out of 10 MBD had an LD-50 < 100 mol/L. These results suggest that the basis for the observed predisposition of Dobermans to sulphonamide idiosyncratic toxicity may be a limited capacity to detoxify the hydroxylamine metabolites of sulphonamides.     

Pharmacokinetics and urinary excretion of sulphadimidine in sheep and goats

Pharmacokinetics and urinary excretion of sulphadimidine were determined in sheep and goats following a single intravenous injection (100 mg/kg). The disposition of the drug was described in terms of exponential expression: C _p= Be ^-βt. Based on total (free and bound) sulphonamide level in plasma, pseudo-distribution equilibrium was rapidly attained and the half-life for elimination was 3.88 ± 0.64 h and 4.00 ± 0.34 h in sheep and goats, respectively. Body clearance, which is the sum of all clearance processes was 88 ± 19 and 55 ± 4 ml/kg/h in sheep and goats. Based on this study a satisfactory intravenous dosage regimen might consist of 100 and 60 mg sulphadimidine/kg body wt for sheep and goats and should be repeated at 12 h intervals. The influence of disease conditions on predicted plasma levels remain to be verified experimentally. Three-quarters of an intravenously injected dose of sulphadimidine was excreted in the urine of sheep and goats within 24 h of administration. The drug was mainly excreted as free amine while acetylated drug constituted 7 and 8% of total drug content in the urine of sheep and goats, respectively.     

Renal excretion of N4-acetyl sulphanilamide and N4-acetyl sulphadimidine in goats

The renal excretion of N⁴-acetyl sulphanilamide and N⁴-acetyl sulphadimidine was studied in 19 experiments with 6 goats during continuous intravenous administration of the 2 sulphonamide derivatives. Deacetylation of both compounds takes place to a small extent only. Further it is shown that both sulphonamide derivatives are bound to plasma proteins to a greater extent than sulphanilamide and sulphadimidine. The excretion of the N⁴-acetylated sulphonamides is compared with the renal excretion of creatinine. The non-protein-bound fraction of the 2 N⁴-acetylated sulphonamides is excreted by filtration and active tubular secretion. The renal clearances of the acetyl derivatives are higher than those of the parent compounds.     

Pharmacokinetics and renal clearance of sulphadimidine,sulphamerazine and sulphadiazine and their N4‐acetyl and hydroxy metabolites in pigs

Summary

The effect of molecular structure on the drug disposition and protein binding in plasma, the urinary recovery, and the renal clearance of sulphamerazine (SMR), sulphadiazine (SDZ), and sulphadimidine (SDM) and their N₄‐acetyl and hydroxy derivatives were studied in pigs. Following IV administration of SDM, SMR and SDZ, their mean elimination half‐lives were 12.4 h, 4.3 h and 4.9 h respectively. The plasma concentrations of parent sulphonamide were higher than those of the metabolites, and ran parallel. The acetylated derivatives were the main metabolites; traces of 6‐hydroxymethylsulphamerazine and 4‐hydroxysulphadiazine were detected in plasma.

The urine recovery data showed that in pigs acetylation is the major elimination pathway of SDM, SMR and SDZ; hydroxylation became more important in case of SMR (6‐hydroxymethyl and 4‐hydroxy derivatives) and SDZ (4‐hydroxy derivatives) than in SDM. In pigs methyl substitution of the pyrimidine side chain decreased the renal clearance of the parent drug and made the parent compound less accessible for hydroxylation. Acetylation and hydroxylation speeded up drug elimentation, because their renal clearance values were higher than those of the parent drug.     

Pharmacokinetics, renal clearance, tissue distribution, and residue aspects of sulphadimidine and its N4-acetyl metabolite in pigs

Pharmacokinetics and tissue distribution experiments were conducted in pigs to which sulphadimidine (SDM) was administered intravenously, orally, and intramuscularly at a dosage of 20 mg SDM/kg. SDM was acetylated extensively, but neither hydroxy metabolites nor their derivatives could be detected in plasma, edible tissues or urine. Following i.v. and two oral routes of administration, the N4-acetylsulphadimidine (N4-SDM) concentration-time curve runs parallel to that of SDM. The percentage of N4-SDM in plasma was in the range between 7 and 13.5% of the total sulphonamide concentration. The bioavailability of SDM administered in a drench was 88.9 +/- 5.4% and administered mixed with pelleted feed for 3 consecutive days it was 48.0 +/- 11.5%. The renal clearance of unbound SDM, which was urine flow related, was 1/7 of that of creatinine, indicating reabsorption of the parent drug. The unbound N4-SDM was eliminated three times faster than creatinine, indicating that tubular secretion was the predominant mechanism of excretion. After i.v. administration, 51.9% of the administered dose was recovered in urine within 72 h p.i., one quarter of which as SDM and three quarters as N4-SDM. Tissue distribution data obtained at 26, 74, 168, and 218 h after i.m. injection revealed that the highest SDM concentration was found in plasma. The SDM concentration in muscle, liver, and kidney ranged from one third to one fifth of that in plasma. The N4-SDM formed a minor part of the sulphonamide content in edible tissues, in which the SDM as well as the N4-SDM concentration parallelled the plasma concentrations. Negative results obtained with a semi-quantitative bioassay method, based on monitoring of urine or plasma, revealed that the SDM concentration levels in edible tissues were in that case below 0.1 mu/g tissue.     

Incidence of drug resistance and transmissible R factors in strains of E. coli isolated from faeces of healthy pigs

Two hundred and twenty-six strains of E. coli were isolated from faeces of 107 pigs at different ages and without clinical signs of infectious diseases. The resistance of the strains to sulphonamide, tetracycline, streptomycin, chloramphenicol, ampicillin, and nalidixic acid was determined. In 74 % of the animals the predominant E. coli flora was found to be resistant to one or more of the drugs mentioned. Fifty-three % of the strains were resistant. Multiple resistance was predominant among resistant strains (67 %). R factors transmissible to a sensitive strain of E. coli K12 W3132 were demonstrated in 28 %. The proportion of resistant strains was largest in young animals (0–14 weeks) accounting for 65 % of the strains isolated, as compared to 43 % of strains from pigs and sows (6 months or more). The incidence of resistance to sulphonamide, tetracycline, and streptomycin was high, whereas most of the strains were sensitive to ampicillin and chloramphenicol. All strains were sensitive to nalidixic acid.The incidence of resistance to antibiotics in a population of pigs to whom these drugs are not fed but applied as therapeutic agents solely seems rather high. When based on clinical findings only, the value is therefore questionable of sulphonamide, tetracycline and streptomycin treatment of infectious diseases caused by E. coli.     

Survey of disc diffusion antimicrobial sensitivity testing in avian bacteriology laboratories and the evaluation of a standardised method

A survey was conducted in which 15 laboratories involved in avian bacteriology tested the antimicrobial sensitivity of cultures of Staphylococcus aureus, S. epidermidis, Escherichia coli, Alcaligenes faecalis and Salmonella typhimurium, using the disc diffusion test as routinely practised in each laboratory. Up to 28 different antimicrobials or antimicrobial combinations were used. The most commonly tested agents were ampicillin, benzylpenicillin, chloramphenicol, erythromycin, furazolidone, neomycin, streptomycin, sulphonamide, tetracycline and trimethoprim/sulphonamide. Results between laboratories were compared according to the width of the zone of inhibition (annular radius) where 5 or more laboratories used the same disc content of a particular antimicrobial agent, and on whether a culture was interpreted as being sensitive or resistant to a particular agent. The variation in annular radii about the mean values were less than +/- 2 SD in 39.5% and greater than +/- 3 SD in 32.6% of 43 different antimicrobial/culture combinations involving 8 different agents. The range of annular radii measurements was greatest with trimethoprim/sulphonamide and streptomycin discs and with the S. epidermidis culture. Variation in the interpretation of test results was greatest with the Gram-negative bacteria, where for each of the more frequently tested agents at least one, commonly 2 and sometimes all 3 cultures were reported as sensitive and resistant to the same agent by different laboratories. The calibrated dichotomous sensitivity (CDS) test of Bell (1975, 1984) was evaluated as a standardised disc diffusion procedure and was found to be reproducible and accurate. Results obtained using antimicrobial agents calibrated for use in the CDS test were compared with results obtained in the survey using the same agents or agents showing identical resistance patterns.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies on an outbreak of intestinal coccidiosis in the dog

An outbreak of intestinal coccidiosis in the dog due to Isospora canis characterized by mild severe haemorrhagic diarrhoea of sudden onset, acute abdominal pain, anorexia, dehydration and relative polycythaemia is described. Although clinical recovery followed sulphonamide therapy, reinfection was common within 10 days of treatment.     

Immune-mediated hemolytic anemia associated with trimethoprim-sulphamethoxazole administration in a horse.

A 10-year-old, thoroughbred gelding was administered sulphonamide drugs during surgical treatment of guttural pouch mycosis. The horse became anemic and a diagnosis of immune-mediated hemolytic anemia was made after other causes of anemia had been ruled out. The anemia resolved after the drugs were withdrawn.     

Isolation of enterotoxigenic Escherichia coli from camels with diarrhoea.

E. coli serogroups 02, 08, 083, 0103 and 0120 were isolated from seven camels with diarrhoea of which 02, 08, and 083 were found to be enterotoxigenic on rabbit ligated ileal loop test. Out of 125 apparently healthy camels, 75 strains of E. coli were isolated. The majority of isolates were susceptible to gentamycin, nitrofurantoin, trimethoprim plus sulphonamide, neomycin, kanamycin and chloramphenicol.