Review
Adverse Cutaneous Reactions to
Antituberculosis Drugs
R. HOLDINESS,
MACK M.D., PH.D.
From the Department of Pharmacology and Experimental
Therapeutics, Louisiana State University Medical Center,
New Orleans Louisiana
Drug-related cutaneous reactions are among the
most common dermatoses. Through mechanisms that
are not always clear, these undesirable effects may
appear despite great care to ensure proper adminis-
tration. For the most part, skin eruptions are mild
and transitory; however, systemic manifestations of
varying intensity are known to occur and sometimes
may be serious or fatal. Some agents customarily
produce recognizable patterns, whereas others have
extremely varied manifestations, making the agent
responsible difficult to identify. Baer and Levine’
stated that 1-5% of all patients in general hospitals
suffer undesirable effects from drugs, while Williams*
ascertained that 1 in 10 admissions in British geriatric
hospitals are attributable t o adverse drug reactions.
Antituberculosis drugs represent an interesting
group of compounds from the standpoint of cuta-
neous drug reactions. It was determined in 1972
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
1981 was 27,373 (a case rate of 11.9/100,000 pop-
ulation), of which there had been no substantial
decline for the previous 3 years.4 Considering the
number of people who receive chemotherapy, sub-
stantial potential exists for adverse reactions t o these
agents to occur.
The 12 anti-TB drugs are listed in Table 1. O n e of
these compounds, TAZ, has not been used in the
United States and has been almost neglected in
Address for correspondence: Mack R. Holdiness, M.D., Ph.D.,
Department of Pharmacology and Experimental Therapeutics, Lou-
isiana State University Medical Center, 1901 Perdido Street, New
Orleans. LA 701 12.
280
American literature5; however, this drug has been
used extensively in Ethiopia, India, Pakistan,‘ East
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.
First-line Drugs
lsoniazid
The incidence of adverse reactions to INH in more
than 2,000 patients has been estimated to be 5.4%,
with the most prominent reactions being cutaneous
eruptions (20/0), fever (1.2%), jaundice (0.5O/0), and
peripheral neuritis ( O . ~ % O ) . ’ ~Reactions occur with
more frequency when dosages greater than 6 mg/kg
are used and in alcoholism and renal disease. Hyper-
sensitivity reactions produce urticaria, angioneurotic
edema,” and morbilliform eruptions, which may oc-
’
casionally progress to exfoliative dermatitis.’*,’ Other
skin lesions noted include xerostomia, nonthrombo-
cytopenic purpura, striae cutis atrophica, pruritis, and
erythema.” Parish and W i t o ~ s k iobserved
’~ one case
of an oral hypersensitivity to INH that included
vesiculation, and ulceration of the palate. Acnetform
eruptions have been particularly noted in younger
patients with a previous history of acne vulgaris. In
one study of seven patients with acneiform eruptions,
five (ages 32-48 years) were found to be slow acet-
ylators of I N H and not to have a previous history of
acne vulgari~.’~ Figure 1 shows one of these patients
(40 years old, slow acetylator) demonstrating an ad-
mixture of comedones and inflammatory papules.
The patient had no previous history of alcoholism,
acne vulgaris, or phototoxic eruptions. Histologic
section demonstrated the early phase of INH-induced
acne with open comedones and spiny follicular plus
consisting of Dernodex folliculorurn organisms and
colonies of Corynebacterium acnes. Figure 2 repre-
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
acetylator) with extensive acneiform lesions that
evolved into inflammatory papules. Although not
conclusively proved, these data are consistent with
the hypothesis that slow acetylators are predisposed
to this type of drug reaction due to their genotype.
A pellagra-like syndrome has been associated with
I N H therapy,l5.l6 probably due to the competitive
inhibition of nicotinic acid by structurally similar INH,
which leads to altered pyridoxine metabolism. Co-
administration of pyridoxine should prevent these
symptoms, although at least two reports exist in the
literature in which the syndrome was noted in patieiits
even though they were concomitantly receiving pyr-
idoxine h y d r ~ c h l o r i d e . ’ ~ ~INH-induced
” lupus ery-
thematosus (LE) syndromes have also been re-
This syndrome has mainly been noted to
occur with great frequency in slow acelylators of
INH. In one study, 10 of 14 patients with LE were
slow acetylators. In a second study, 17 of 25 patients
with idiopathic LE were slow acetylators.2’ This disease
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
skin reactions attributed to EMEL3'Hair loss accounted
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.
Rash and pruritis accounted for 70% of the cutaneous
side effects. Frentz et al.32reported one case of EMB-
induced lichenoid eruption and two cases of acute
gouty arthritis have also been noted.33
Para-aminosa/icy/icAcid
The incidence of untoward effects associated
with PAS is about 10%. This drug usually produces
reactions approximately 4 weeks after the initiation
of therapy. Erythematous, maculopapular, urticarial,
pruritic, anaphylactic, exfoliative, nonthrombocyto-
penia purpuric, fixed-drug-like and lichenoid reactions
are known to occur.".34 Lupus-like syndromes have
also been observed.35
Streptomycin
Of 515 TB patients treated with SM, 8.2% devel-
oped adverse reactions: 50% of these involved the
vestibular and auditory function of the eighth cranial
nerve. The remaining patients had undetermined
dermatitis (2%) and fever (1.4%)." Skin eruptions
have been reported in as many as 5% of patients
treated with this drug, including morbilliform, macu-
lopapular, erythematous, and urticarial lesions. Pruritis,
FIG 3 Lower portion of legs sharply demarcated dusky brown
hyperpigmentations following pyrarinamide treatment. (From )or
gensen With permission )
scaling, lichenoid eosinophilia, lymphadenopathy,
mouth ulcers, purpura, and fever may accompany
these eruptions. Exfoliative dermatitis occurs in ap-
proximately 1% of individuals, and occasionally acute
anaphylaxis may follow the administration of any
quantity of SM. Kushimoto and Aoki3" reported toxic
erythema with generalized follicular pustules, while
Hart3' observed SM-induced arthritis. To date, one
case of Stevens-Johnsonsyndrome has been reported
in association with SM administration."
Pyrazinarnide*
The two most clinically important adverse reactions
t o PZA are hepatitis and arthralgia. About 15% of
patients receiving 3 g/day will develop hepatic dis-
ease. Of these, 2-3% will have jaundice or death
due to hepatic necr~sis.'~Sensations of burning in
the skin and development of reddish-brown discol-
oration on sun-exposed areas have been described."
It has rarely been necessary to terminate PZA therapy
due to arthralgia.' One case of pellagra has been
* Minor and temporary increases in liver enzyme ronrmtrations
due to pyrarinamide do not imply serious toxicity. With modern
dosage schedules, pyrazinamide i s not unacceptably hepatotoxic
and is being used increasingly as a first-line drug.
No 5 REACTIONS T O ANTI-TB DRUGS
reported to be possibly due to PZA admini~tration.~”
Figure 3 shows the lower legs of this patient, dem-
onstrating the development of dusky brown hyper-
pigmentations following sunlight exposure. The pa-
tient also developed a butterfly-shaped erythema
over her face with slight anorexia and lethargy. Lab-
oratory investigations revealed normal levels of blood
nicotinic acid; this is to be expected when substrate
competition is the causative mechanism of the disease
contrary to pellagra caused by malnutrition4” (personal
communication with Dr. J. Jorgensen).
Third-line Drugs
E thionarn ide
The use of ETA is limited by its adverse effects,
most notably gastrointestinal irritation. A study by
Tala and TevoIa4’ of 68 patients who were given ETA
for less than 8 months revealed 10 with GI distur-
bances, 3 with neurologic symptoms, and 1 with a
hypersensitivity skin reaction. Rare cutaneous reac-
tions of urticaria, punctate erythematous rash, sebor-
rhoeic dermatitis, acneiform eruptions, mobilliform
purpura lesions, photosensitivity, severe ichthyosis,
stomatitis, and alopecia have been reported.” Acute
rheumatic symptoms have also been observed fol-
lowing drug administration.
Cycloserine
Adverse reactions to CYS commonly include dose-
related neurologic and psychiatric reactions. It has
been reported that 24% of the patients treated with
this agent develop neurotoxicity of sufficient severity
to warrant withdrawal of the medication^.^' Adverse
cutaneous reactions are uncommon, and little mention
of these other than being called ”skin rash” have
. ~ date, one case of a
occurred in the l i t e r a t ~ r e To
purplish scaly eruption has been reported, by Warney
et
Kanamycin, Capreomycin, and Viomycin
These drugs have had only minimal application for
drug regimens in the treatment of TB. Hypersensitivity
reaction^^^,^^ were usually less severe and less frequent
and intense than with SM, yet damage to the eighth
cranial nerve has been irreversible in some cases.
Severe urticaria, purpura, and eczema have been
reported following the use of VOM, and maculopap-
ular rashes have been noted to occur in 6% of
patients using CAM.”
Thia ceta zone
TAZ i s an interesting compound from the stand-
point of TB therapy. To date its use is mainly confined
. Holdinecs 283
to developing countries due to its toxic effects and
the fact that it is an extremely cheap drug to manu-
facture. Far more toxic reactions have been observed
since the original report by Levantine and Almeyda.”
In a recent study in Nigeria of TAZ in combination
with I N H or SM, toxic reactions were observed in
14% of a total of 1,212 patients4‘ Another study in
Brazil’ found 71 cases of drug-related cutaneous
reactions in 1,890 patients (a case rate of 37.6/1,000).
All skin eruptions occurred 2-92 days after initiation
of combined INH, SM, and TAZ therapy, and the
various eruptions were classified as mild (uncompli-
cated pruritis, acneiform eruption, mobilliform ery-
thema), moderate (extensive rnaculoerythematous
eruptions, urticaria, purpura), and severe (erythro-
derma, Stevens-Johnson syndrome, Lyell’s disease).
Of the 71 cases, 34 were mild, 19 were moderate,
and 18 were severe. Five deaths were recorded (a
case rate of 2.6/1,000). The case rates of cutaneous
reactions for men and women were similar (37.8/
1,000 and 37.2/1,000, respectively). These reactions
were attributed to TAZ therapy because no similar
toxic reactions except acneiform lesions were de-
tected in the state‘s earlier extensive studies with SM
and I N H in combination with PAS. Three cases of
Stevens-Johnson syndrome have been observed fol-
lowing TAZ therapy.47 White4* reported one case of
toxic epidermal necrolysis (TEN) (Fig. 4). The patient
was a 44-year-old woman who 6 days after discharge
from the hospital on I N H and TAZ returned with
extensive skin bullae that had coalesced involving
the entire body except the face, hands, and feet. She
had previously received 3 months of INH therapy
and had noticed bullae only 5 days after TAZ was
initiated. She did not exhibit distinctive features of
Stevens-Johnson syndrome. A more likely diagnosis
was considered to be TEN or possibly acute gener-
alized exfoliative dermatitis. At least three cases of
TEN following administration of this agent have since
been reported in the l i t e r a t ~ r e . ~ ’ ~ ~ ~
Miscellaneous Drugs
A number of other drugs have been used for
treatment of TB, but because of significant side
effects and/or reduced efficacy, their use has been
restricted mainly t o experimental studies.
Arnikacin
AMK is a semisynthetic derivative of kanamycin A
that is reported to inhibit Mycobacteriurn tuberculosis
in v i m and in guinea pigs.53This drug was tested in
11 patients with TB; in four with multiply resistant
strains, there was no response as assessed by culture
2 84 INTERNATIONAL IOURNAL OF DERMATOLOGY
and sputum smears. Side effects appear to be similar
to those ot other aminoglycosides along with cuta-
neous eruptions of exfoliative dermatitis and pruritis.
Considering the expense of AMK over KNM and SM
and its inability to inhibit growth of all strains of M.
tuberculosis, there seems to be little use for this drug
in the armamentarium for TB chemotherapy.
Prothionarnide
This agent has found more use for the treatment
of leprosy (Mycobacterium leprae), yet it has i n the
past been used occasionally for TB treatment. PTA i s
the n-propyf derivative of ETA. In a study by Tola
and T r e v ~ l a , ~13’ of 68 TI3 patients developed some
type of side effect in less than 8 months of therapy
with this drug. Skin reactions, however, were not
observed. Most cutaneous reactions observed are
similar to that of ETA, with an acneiform eruption
noted on several occasions.’’,54
FIG.4. Two hours before death, with extensive lesions following
thiacetazone therapy for 6 days, the patient is remarkably lucid
and not in pain. (From White.& With permission.)
June 1985 Vol. 24
TABLE2. Challenge Dose5 for Detecting Cutaneous or
Generalized Hypersensitivity to Antituberculosis Drugs
Challenge Doses
Drug Day 1 Day 2
lsoniazid 5 0 rng 300 rng
Rifampicin 75 mg 300 mg
Pyrarinamide 250 mg 1.0 g
Ethionamide, prothinnamide 1 2 5 mg 375 mg
Cycloserine 125 mg 250 rng
Ethambutol 100 rng 500 mg
Para-aminosalicylic acid 1.0 g 5.0 g
Thiacetazone 25 rng 50 mg
Streptomycin or other
aminoglycosides 125 mg 500 ma
Challenge doses of the drugs in the regimen should be given in
the sequence in which they are shown; the drugs near the bottom
of the list are the ones that are most likely to cause a reaction. If
the reaction is a severe one, smaller initial challenge doses should
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
procedure, the concentration should be reduced and
gradually increased again. No attempts should be
No. 5 REACTIONS TO ANTI-TB DRUGS
made to desensitize patients with severe exfoliative
dermatitis even under steroidal coverage regimens.’
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