R. HOLDINESS,
MACK M.D., PH.D.
From the Department of Pharmacology and Experimental American literature5; however, this drug has been
Therapeutics, Louisiana State University Medical Center, used extensively in Ethiopia, India, Pakistan,‘ East
New Orleans Louisiana
Afri~a,’,~and Brazil.’ Also listed in Table 1 are two
miscellaneous agents (AMK and PTA) that are used
in experimental treatment of TB infections.
280
No. 5 REACTIONS T O ANTI-TB DRUGS . Holdiness 28 1
Drug Comments
~
sents another subject in this study (37 years old, slow symptoms, although at least two reports exist in the
acetylator) with extensive acneiform lesions that literature in which the syndrome was noted in patieiits
evolved into inflammatory papules. Although not even though they were concomitantly receiving pyr-
conclusively proved, these data are consistent with idoxine h y d r ~ c h l o r i d e . ’ ~ ~INH-induced
” lupus ery-
the hypothesis that slow acetylators are predisposed thematosus (LE) syndromes have also been re-
to this type of drug reaction due to their genotype. This syndrome has mainly been noted to
A pellagra-like syndrome has been associated with occur with great frequency in slow acelylators of
I N H therapy,l5.l6 probably due to the competitive INH. In one study, 10 of 14 patients with LE were
inhibition of nicotinic acid by structurally similar INH, slow acetylators. In a second study, 17 of 25 patients
which leads to altered pyridoxine metabolism. Co- with idiopathic LE were slow acetylators.2’ This disease
administration of pyridoxine should prevent these can persist for a variable period of time, and remission
of the symptoms does not always occur. At least two
cases of Stevens-Johnson syndrome have been re-
ported with INH therapy.*’,” In both cases, the
classical lesions ot severe erythema multiforme dc>-
veloped after administration of drug regimens of
either INH-TAZ*’ or INH-SM”; the lesions disap-
peared after cessation of these agents. In both Cases,
rechallenge with a test dose o t INH reproduced the
symptoms and dermatitis and tever reappeared
Ritxnprcin
R I F i s a relatively nontoxic drug, dnd c utarieous
reactions are uw;llly mild and selt limiting Flushing
with pruritis has been noted m05t ctmmonl\ on thc,
face and scalp The eves ottcm become wvthen~itous
and watery l4 Urticarid and niaculopapular lesions
with orange tears and sweat have also becw observed
The treauencv ot reactionc varies in ditterent IIOPU
282 INTERNATIONAL IOURNAL OF DERMATOLOGY June 1985 Vol. 24
Second-line Drugs
Etharnbutol
reported to be possibly due to PZA admini~tration.~” to developing countries due to its toxic effects and
Figure 3 shows the lower legs of this patient, dem- the fact that it is an extremely cheap drug to manu-
onstrating the development of dusky brown hyper- facture. Far more toxic reactions have been observed
pigmentations following sunlight exposure. The pa- since the original report by Levantine and Almeyda.”
tient also developed a butterfly-shaped erythema In a recent study in Nigeria of TAZ in combination
over her face with slight anorexia and lethargy. Lab- with I N H or SM, toxic reactions were observed in
oratory investigations revealed normal levels of blood 14% of a total of 1,212 patients4‘ Another study in
nicotinic acid; this is to be expected when substrate Brazil’ found 71 cases of drug-related cutaneous
competition is the causative mechanism of the disease reactions in 1,890 patients (a case rate of 37.6/1,000).
contrary to pellagra caused by malnutrition4” (personal All skin eruptions occurred 2-92 days after initiation
communication with Dr. J. Jorgensen). of combined INH, SM, and TAZ therapy, and the
various eruptions were classified as mild (uncompli-
Third-line Drugs cated pruritis, acneiform eruption, mobilliform ery-
E thionarn ide thema), moderate (extensive rnaculoerythematous
eruptions, urticaria, purpura), and severe (erythro-
The use of ETA is limited by its adverse effects,
derma, Stevens-Johnson syndrome, Lyell’s disease).
most notably gastrointestinal irritation. A study by
Of the 71 cases, 34 were mild, 19 were moderate,
Tala and TevoIa4’ of 68 patients who were given ETA
and 18 were severe. Five deaths were recorded (a
for less than 8 months revealed 10 with GI distur-
case rate of 2.6/1,000). The case rates of cutaneous
bances, 3 with neurologic symptoms, and 1 with a
reactions for men and women were similar (37.8/
hypersensitivity skin reaction. Rare cutaneous reac-
1,000 and 37.2/1,000, respectively). These reactions
tions of urticaria, punctate erythematous rash, sebor-
were attributed to TAZ therapy because no similar
rhoeic dermatitis, acneiform eruptions, mobilliform
toxic reactions except acneiform lesions were de-
purpura lesions, photosensitivity, severe ichthyosis,
tected in the state‘s earlier extensive studies with SM
stomatitis, and alopecia have been reported.” Acute
and I N H in combination with PAS. Three cases of
rheumatic symptoms have also been observed fol-
Stevens-Johnson syndrome have been observed fol-
lowing drug administration.
lowing TAZ therapy.47 White4* reported one case of
toxic epidermal necrolysis (TEN) (Fig. 4). The patient
Cycloserine
was a 44-year-old woman who 6 days after discharge
Adverse reactions to CYS commonly include dose- from the hospital on I N H and TAZ returned with
related neurologic and psychiatric reactions. It has extensive skin bullae that had coalesced involving
been reported that 24% of the patients treated with the entire body except the face, hands, and feet. She
this agent develop neurotoxicity of sufficient severity had previously received 3 months of INH therapy
to warrant withdrawal of the medication^.^' Adverse and had noticed bullae only 5 days after TAZ was
cutaneous reactions are uncommon, and little mention initiated. She did not exhibit distinctive features of
of these other than being called ”skin rash” have Stevens-Johnson syndrome. A more likely diagnosis
. ~ date, one case of a
occurred in the l i t e r a t ~ r e To was considered to be TEN or possibly acute gener-
purplish scaly eruption has been reported, by Warney alized exfoliative dermatitis. At least three cases of
et TEN following administration of this agent have since
been reported in the l i t e r a t ~ r e . ~ ’ ~ ~ ~
Kanamycin, Capreomycin, and Viomycin
These drugs have had only minimal application for Miscellaneous Drugs
drug regimens in the treatment of TB. Hypersensitivity
A number of other drugs have been used for
reaction^^^,^^ were usually less severe and less frequent
treatment of TB, but because of significant side
and intense than with SM, yet damage to the eighth
effects and/or reduced efficacy, their use has been
cranial nerve has been irreversible in some cases.
restricted mainly t o experimental studies.
Severe urticaria, purpura, and eczema have been
reported following the use of VOM, and maculopap-
Arnikacin
ular rashes have been noted to occur in 6% of
patients using CAM.” AMK is a semisynthetic derivative of kanamycin A
that is reported to inhibit Mycobacteriurn tuberculosis
Thia ceta zone in v i m and in guinea pigs.53This drug was tested in
TAZ i s an interesting compound from the stand- 11 patients with TB; in four with multiply resistant
point of TB therapy. To date its use is mainly confined strains, there was no response as assessed by culture
2 84 INTERNATIONAL IOURNAL OF DERMATOLOGY June 1985 Vol. 24
and sputum smears. Side effects appear to be similar TABLE2. Challenge Dose5 for Detecting Cutaneous or
Generalized Hypersensitivity to Antituberculosis Drugs
to those ot other aminoglycosides along with cuta-
neous eruptions of exfoliative dermatitis and pruritis. Challenge Doses
Considering the expense of AMK over KNM and SM
and its inability to inhibit growth of all strains of M. Drug Day 1 Day 2
tuberculosis, there seems to be little use for this drug
lsoniazid 5 0 rng 300 rng
in the armamentarium for TB chemotherapy.
Rifampicin 75 mg 300 mg
Pyrarinamide 250 mg 1.0 g
Prothionarnide Ethionamide, prothinnamide 1 2 5 mg 375 mg
Cycloserine 125 mg 250 rng
This agent has found more use for the treatment Ethambutol 100 rng 500 mg
of leprosy (Mycobacterium leprae), yet it has i n the Para-aminosalicylic acid 1.0 g 5.0 g
past been used occasionally for TB treatment. PTA i s Thiacetazone 25 rng 50 mg
the n-propyf derivative of ETA. In a study by Tola Streptomycin or other
and T r e v ~ l a , ~13’ of 68 TI3 patients developed some aminoglycosides 125 mg 500 ma
type of side effect in less than 8 months of therapy Challenge doses of the drugs in the regimen should be given in
with this drug. Skin reactions, however, were not the sequence in which they are shown; the drugs near the bottom
observed. Most cutaneous reactions observed are of the list are the ones that are most likely to cause a reaction. If
similar to that of ETA, with an acneiform eruption the reaction is a severe one, smaller initial challenge doses should
noted on several occasions.’’,54 be given (approximately one tenth the dose shown for day 1).
From Girling.’
made to desensitize patients with severe exfoliative 26. Gange RW, Rhodes EL, Edwards CO, et al. Pemphigus induced
dermatitis even under steroidal coverage regimens.’ by rifampicin. Br J Dermatol. 1976;95:445-448.
27. Millar IW. Rifampicin-induced porphyria cutanea tarda. Br I
Dis Chest. 1980;74:405-408.
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