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Review

Adverse Cutaneous Reactions to


Antituberculosis Drugs

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.

Drug-related cutaneous reactions are among the


most common dermatoses. Through mechanisms that First-line Drugs
are not always clear, these undesirable effects may lsoniazid
appear despite great care to ensure proper adminis-
The incidence of adverse reactions to INH in more
tration. For the most part, skin eruptions are mild
and transitory; however, systemic manifestations of than 2,000 patients has been estimated to be 5.4%,
varying intensity are known to occur and sometimes with the most prominent reactions being cutaneous
may be serious or fatal. Some agents customarily eruptions (20/0), fever (1.2%), jaundice (0.5O/0), and
produce recognizable patterns, whereas others have peripheral neuritis ( O . ~ % O ) . ’ ~Reactions occur with
extremely varied manifestations, making the agent more frequency when dosages greater than 6 mg/kg
responsible difficult to identify. Baer and Levine’ are used and in alcoholism and renal disease. Hyper-
stated that 1-5% of all patients in general hospitals sensitivity reactions produce urticaria, angioneurotic
suffer undesirable effects from drugs, while Williams* edema,” and morbilliform eruptions, which may oc-
ascertained that 1 in 10 admissions in British geriatric ’
casionally progress to exfoliative dermatitis.’*,’ Other
hospitals are attributable t o adverse drug reactions. skin lesions noted include xerostomia, nonthrombo-
Antituberculosis drugs represent an interesting cytopenic purpura, striae cutis atrophica, pruritis, and
group of compounds from the standpoint of cuta- erythema.” Parish and W i t o ~ s k iobserved
’~ one case
neous drug reactions. It was determined in 1972 of an oral hypersensitivity to INH that included
1,070,548 patients worldwide had active t u b e r c u l ~ s i s . ~ burning of the mouth accompanied by erythema,
In the United States, the number of new cases in vesiculation, and ulceration of the palate. Acnetform
1981 was 27,373 (a case rate of 11.9/100,000 pop- eruptions have been particularly noted in younger
ulation), of which there had been no substantial patients with a previous history of acne vulgaris. In
decline for the previous 3 years.4 Considering the one study of seven patients with acneiform eruptions,
number of people who receive chemotherapy, sub- five (ages 32-48 years) were found to be slow acet-
stantial potential exists for adverse reactions t o these ylators of I N H and not to have a previous history of
agents to occur. acne vulgari~.’~ Figure 1 shows one of these patients
The 12 anti-TB drugs are listed in Table 1. O n e of (40 years old, slow acetylator) demonstrating an ad-
these compounds, TAZ, has not been used in the mixture of comedones and inflammatory papules.
United States and has been almost neglected in The patient had no previous history of alcoholism,
acne vulgaris, or phototoxic eruptions. Histologic
section demonstrated the early phase of INH-induced
Address for correspondence: Mack R. Holdiness, M.D., Ph.D., acne with open comedones and spiny follicular plus
Department of Pharmacology and Experimental Therapeutics, Lou-
isiana State University Medical Center, 1901 Perdido Street, New consisting of Dernodex folliculorurn organisms and
Orleans. LA 701 12. colonies of Corynebacterium acnes. Figure 2 repre-

280
No. 5 REACTIONS T O ANTI-TB DRUGS . Holdiness 28 1

TABLE1. Antituberculosis Drug,


~ ~~

Drug Comments
~

First-line Minimal or controllable side


lsoniazid ( I N H ) effects
Rifampicin (RIF)
Second line May produce undesirable or
Ethambutol (EMB) dangerous side effects in
Para aminosalicylic acid (PAS) some cases
Streptomycin (SM)
Pyrarinamide (PZA)
Third line More prone to produce side
tthionamide (ETA) reactions in certain cases
Cycloserine (CYS)
Kanamycin (KNM)
Capreomyon (CAM)
Viornycin (VOM)
Thiacetaronr (TAZ)
Miscellaneous drugs Experimental treatment of
Aniikac in (AMK) tuberculosis
FIG 2 Extensive acneiforrn eruption in response to isoniarrd
Prothionamide (PTA)
therapy All lesions have evolved into inflammatory papules Lesions
The classification of these agents as first , second , or third line ‘leared weeks Of peeling therapy (From Cohen et ’’
drugs is based upon popularity of use and increases in side effects
With permission)

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

men with genitourinary TB. Withdrawal of the med-


ication led to disappearance of the skin lesions within
3 weeks.15 One case each of pemphigus vulgarisZb
and porphyria cutanea tardaZ7have been reported to
be induced by RIF. In the latter case, RIF was
believed to have induced the liver enzyme aminole-
vulinic acid synthetase, which eventually led to blis-
tering and fragility of sun-exposed skin.18 RIF also
causes a tlu-like syndrome with shock, dysnepea,
To
anaphylaxis, and thrombocytopenia p ~ r p u r a . ' ~ ~ '
date, at least one case of Stevens-Johnson syndrome
related to RIF has been reported in an African man.
The drug was promptly discontinued, and the patient
improved with steroid adrnlnistration."'

Second-line Drugs

Etharnbutol

In a study by Pitt," of the 2,000 patients that


received 15 mg/kg EMB, less than 2% developed
adverse reactions of diminished visual acuity (0.8%),
cutaneous reactions (0.5%), and drug fever (0.3%).
Between 1968 and 1977, there were recorded 108 FIG 3 Lower portion of legs sharply demarcated dusky brown
skin reactions attributed to EMEL3'Hair loss accounted hyperpigmentations following pyrarinamide treatment. (From )or
gensen With permission )
for eight cases, while urticaria, erythema multiforme,
angioederna, hyperhidrosis, skin striae, bullous erup-
tions, and exfoliative dermatitis (one of two cases
was lethal) accounted for one to three cases each. scaling, lichenoid eosinophilia, lymphadenopathy,
Rash and pruritis accounted for 70% of the cutaneous mouth ulcers, purpura, and fever may accompany
side effects. Frentz et al.32reported one case of EMB- these eruptions. Exfoliative dermatitis occurs in ap-
induced lichenoid eruption and two cases of acute proximately 1% of individuals, and occasionally acute
gouty arthritis have also been noted.33 anaphylaxis may follow the administration of any
quantity of SM. Kushimoto and Aoki3" reported toxic
erythema with generalized follicular pustules, while
Para-aminosa/icy/icAcid
Hart3' observed SM-induced arthritis. To date, one
The incidence of untoward effects associated case of Stevens-Johnsonsyndrome has been reported
with PAS is about 10%. This drug usually produces in association with SM administration."
reactions approximately 4 weeks after the initiation
of therapy. Erythematous, maculopapular, urticarial, Pyrazinarnide*
pruritic, anaphylactic, exfoliative, nonthrombocyto-
penia purpuric, fixed-drug-like and lichenoid reactions The two most clinically important adverse reactions
are known to occur.".34 Lupus-like syndromes have t o PZA are hepatitis and arthralgia. About 15% of
also been observed.35 patients receiving 3 g/day will develop hepatic dis-
ease. Of these, 2-3% will have jaundice or death
Streptomycin due to hepatic necr~sis.'~Sensations of burning in
the skin and development of reddish-brown discol-
Of 515 TB patients treated with SM, 8.2% devel- oration on sun-exposed areas have been described."
oped adverse reactions: 50% of these involved the It has rarely been necessary to terminate PZA therapy
vestibular and auditory function of the eighth cranial due to arthralgia.' One case of pellagra has been
nerve. The remaining patients had undetermined
dermatitis (2%) and fever (1.4%)." Skin eruptions
have been reported in as many as 5% of patients * Minor and temporary increases in liver enzyme ronrmtrations
due to pyrarinamide do not imply serious toxicity. With modern
treated with this drug, including morbilliform, macu- dosage schedules, pyrazinamide i s not unacceptably hepatotoxic
lopapular, erythematous, and urticarial lesions. Pruritis, and is being used increasingly as a first-line drug.
No 5 REACTIONS T O ANTI-TB DRUGS . Holdinecs 283

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.’

Management of Adverse Reactions

The first step toward alleviating the symptoms of


cutaneous eruptions i s the removal of the offending
agent. Minor eruptions that cause little stress to the
patient may be treated symptomatically, such as
administration of an antihistamine or a nonsteroidal
antiinflammatory agent, without altering or interrupt-
ing the prescribed therapeutic regimen. For more
severe reactions, discontinuation of all treatment until
the adverse effects have subsided and identification
of the component responsible are indicated. This
may be done by challenging the patient daily to a
reduced dose of the drugs that are least suspected
of causing the eruptions so that administration of
these agents may be resumed without delay. Chal-
lenge doses of each anti-TB compound should be
given in the sequence listed in Table 2 until a reaction
is observed. Should none occur, the drug may be
continued as with the original therapeutic regimen.
It is important to strive for therapeutic coverage with
at least two agents to which the individual is not
hypersensitive so as to prevent the emergence of
acquired drug resistance. If the reaction is severe,
the challenge dose should be approximately one
tenth that of the dosage listed under day one. Patients
can be desensitized to these drugs either by (1)
giving a dose twice daily with steadily increasing
concentrations until full dosage is attained or (2)
adding oral steroids. If a reaction occurs during this
FIG.4. Two hours before death, with extensive lesions following
thiacetazone therapy for 6 days, the patient is remarkably lucid procedure, the concentration should be reduced and
and not in pain. (From White.& With permission.) gradually increased again. No attempts should be
No. 5 REACTIONS TO ANTI-TB DRUGS . lfoldinerc 285

made to desensitize patients with severe exfoliative 26. Gange RW, Rhodes EL, Edwards CO, et al. Pemphigus induced
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27. Millar IW. Rifampicin-induced porphyria cutanea tarda. Br I
Dis Chest. 1980;74:405-408.
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