Research letters
incidence of O25b-ST131 among antimicrobial-susceptible (as
defined by susceptibility to all of ciprofloxacin, co-trimoxazole
and gentamicin) isolates was low (2.9%, 5/175). PCR and se-
quencing showed that the only extended-spectrum b-lactamase
(ESBL)-producing O25b-ST131 isolate had blaCTX-M-14.
Our results showed that O25b-ST131 exhibited a wide range
of susceptibility patterns. Similar to previous studies,1,5 our
findings showed that O25b-ST131 isolates were often multi-
drug resistant and one was a CTX-M producer. However, the
only ESBL-producing O25b-ST131 isolate was found to have
blaCTX-M-14 instead of blaCTX-M-15.1,5 Among blood culture E. coli
isolates collected in 2007 08, our recent work showed that
O25b-ST131 accounted for 25.6% of the ESBL-producing iso-
lates.3 All ESBL-producing O25b-ST131 isolates had blaCTX-M-14
and none had blaCTX-M-15.3 As our previous studies revealed,
the dissemination of blaCTX-M-14 in O25b-ST131 isolates was
associated with the acquisition of an epidemic pHK01 plasmid
with FII replicon.3 In conclusion, this study showed that the
O25b-ST131 clonal group is widely distributed among E. coli iso-
lates causing community-acquired UTI in the region. The finding
highlights the importance of clonal expansion in dissemination of
antimicrobial resistance involving first-line drugs commonly used
for treatment of UTIs.
Funding
This study was supported by the Research Fund for the Control of Infec-
tious Diseases (RFCID) of the Health and Food Bureau of the Hong Kong
SAR government.
Transparency declarations
None to declare.
References
1 Rogers BA, Sidjabat HE, Paterson DL. Escherichia coli O25b-ST131: a
pandemic, multiresistant, community-associated strain. J Antimicrob
Chemother 2011; 66: 1 14.
2 Zong Z, Yu R. blaCTX-M-carrying Escherichia coli of the O25b ST131 clonal
group have emerged in China. Diagn Microbiol Infect Dis 2011; 69:
22831.
3 Ho PL, Yeung MK, Lo WU et al. Predominance of pHK01-like incompatibility
group FII plasmids encoding CTX-M-14 among extended-spectrum
b-lactamase-producing Escherichia coli in Hong Kong, 1996 2008.
Diagn Microbiol Infect Dis 2012; 73: 1826.
4 Ho PL, Yip KS, Chow KH et al. Antimicrobial resistance among
uropathogens that cause acute uncomplicated cystitis in women in
Hong Kong: a prospective multicenter study in 2006 to 2008. Diagn
Microbiol Infect Dis 2010; 66: 8793.
5 Clermont O, Lavollay M, Vimont S et al. The CTX-M-15-producing
Escherichia coli diffusing clone belongs to a highly virulent B2
phylogenetic subgroup. J Antimicrob Chemother 2008; 61: 1024 8.
6 Clermont O, Dhanji H, Upton M et al. Rapid detection of the
O25b-ST131 clone of Escherichia coli encompassing the CTX-M-15-
producing strains. J Antimicrob Chemother 2009; 64: 2747.
JAC
J Antimicrob Chemother 2012
doi:10.1093/jac/dks225
Advance Access publication 11 June 2012
Lichenoid drug reaction to
antituberculosis drugs treated through
with topical steroids and phototherapy
Rannakoe J. Lehloenya1,2*, Gail Todd1,
Lesiba Mogotlane3, Nomphelo Gantsho1, Carol Hlela1,4
and Keertan Dheda2,4
1
Division of Dermatology, Department of Medicine, University of
Cape Town, South Africa; 2Lung Infection and Immunity Unit,
Division of Pulmonology, Department of Medicine & UCT Lung
Institute, University of Cape Town, South Africa; 3Pathcare
Laboratories, Cape Town, South Africa; 4Institute of Infectious
Diseases and Molecular Medicine, University of Cape Town,
South Africa
*Corresponding author. Dermatology Ward G23, New Main Building,
Groote Schuur Hospital, Anzio Road, Observatory, 7925 South Africa.
Tel: +27-214045269; Fax: +27-214478232;
E-mail: rannakoe.lehloenya@uct.ac.za
Keywords: tuberculosis, TB, adverse reactions, AIDS
Sir,
Tuberculosis-associated adverse drug reactions (ADRs) result in
an interruption and change of treatment, both impacting on
treatment failure, the development of drug resistance, relapse
and the transmission of disease.1 The threat of transmission
makes prompt resumption of therapy necessary, but the
limited number of effective antituberculosis drugs complicates
management.
The spectrum of severe tuberculosis-associated cutaneous
ADRs is wide and includes Stevens Johnson syndrome, drug
hypersensitivity syndrome and lichenoid drug reactions (LDRs).2
In all, with the exception of LDRs, acute clinical or laboratory
markers enable early detection and withdrawal of the offending
drug following drug rechallenge.3
We present a case of severe LDR related to antituberculosis
drugs in which the offending drug could not be definitively iden-
tified and therapy was continued successfully under the cover of
topical steroids and phototherapy.
A 39-year-old HIV-infected man presented with erythroderma
3 months after starting isoniazid, rifampicin, pyrazinamide
and ethambutol for pulmonary tuberculosis and co-trimoxazole
for Pneumocystis jiroveci prophylaxis. He had a CD4 count of
8 cells/mm3 and was taking efavirenz, lamivudine and stavudine,
all of which were started after the onset of the rash. A skin biopsy
showed a lichenoid reaction with eosinophils and apoptotic
keratinocytes compatible with LDR. Antituberculosis drugs and
co-trimoxazole were stopped and he was started on topical
clobetasol (DovateTM ) daily. The rash settled with residual pig-
mentation and ofloxacin, streptomycin and ethionamide were
initiated.1 Rifampicin was then reintroduced with escalating
2535
Research letters
(a) (b)
Figure 1. (a and b) Lichenoid drug reaction showing depigmentation, hyperpigmentation and fissuring. (c) Clinically improved skin 1 week after
completing antituberculosis therapy.
doses over 4 days without a clinically evident reaction. Etham-
butol, pyrazinamide and isoniazid were not reintroduced on the
assumption that they were the likeliest offenders. He was dis-
charged from hospital on the four antituberculosis drugs.
Six weeks later he presented again with a 3 week history of
the same rash. In the meantime his sputum reverted to culture-
negative, and his tuberculosis symptoms and radiological
features had improved. We thought rifampicin was the likeliest
offender, but decided not to replace it with another second-line
drug or rechallenge with the three first-line drugs initially
omitted. This was informed by the patients unwillingness to
restart the rechallenge process, the clinical improvement and
the delay in clinical manifestation of LDR, possibly due to
topical steroids. We continued treatment under cover of clobeta-
sol. The rash improved and he was discharged from hospital.
He presented again 3 weeks later with worsening hyperpig-
mentation, depigmentation and diffuse alopecia, despite
topical steroids. We introduced thrice weekly bath psoralen and
ultraviolet A (PUVA). His skin gradually improved; however,
1 month later he developed photo-distributed rash with painful
fissures, which we attributed to excessive sun exposure (see
Figure 1). PUVA was suspended for 1 week and he was advised
to minimize sun exposure. Sunscreen was prescribed, and he
was advised to wear a hat and gloves on the day he received
psoralen, a potent photosensitizer. He completed 12 months of
treatment, and continued steroids and PUVA for 3 months there-
after. His skin has clinically improved with only residual hyperpig-
mentation and leucoderma (see Figure 1).
LDR presents as purple itchy papules becoming confluent and
hyperpigmented with continuing exposure to the offending drug.
The interval between initiating the drug and the rash ranges from
days to years, with most cases occurring within months. On
withdrawing the drug, the lesions resolve with persistent hyper-
pigmentation, often lasting for many years.4
The lack of acute markers, insidious onset of the rash, and
varying intervals between drug initiation and a clinically detect-
able rash make it difficult to establish a temporal relationship
with the drug and ascribe causality in LDR. This is more so in
patients receiving multiple drugs. The limited number of effective
antituberculosis drugs, the cessation of which is associated with
a higher mortality, increases risk of drug resistance, longer dur-
ation of therapy and public health concerns, make it necessary
2536
(c)
to balance the interruption of therapy against treating through
the ADRs.1,5
PUVA is used to treat a wide variety of inflammatory derma-
tological conditions, such as scleroderma, lichen planus, psoria-
sis, vitiligo, cutaneous T cell lymphoma and atopic dermatitis.
It is also effective for pruritus associated with systemic
disease. Psoralen is administered orally or topically by soaking
in bathwater, followed by irradiation.
The first-line therapy generally used for LDRs is high-potency
topical steroids, although there are no clinical trials supporting
their use. There are better data supporting the use of acitretin,
systemic steroids and other immunosuppressants.6 However,
considering our patients marked immunosuppression and con-
current tuberculosis, we decided to use only topical steroids.
This case illustrates practical dilemmas in managing
tuberculosis-associated ADRs. Should suboptimal treatment be
used or should a potentially life-threatening therapy be contin-
ued despite serious side effects? We decided to continue treat-
ment and manage the side effects, as the alternative would
likely result in a poorer outcome. Phototherapy, in combination
with topical steroids, is an option in the management of LDRs
when the offending drug cannot be identified.
Written permission was given by the patient to publish the
case and images.
Funding
There was no funding obtained for this case study. The data were
obtained during the course of routine care at Groote Schuur Hospital,
Cape Town.
R. J. L. is supported by the Discovery Foundation and the Dermato-
logical Society of South Africa and is a recipient of the Carnegie Corpor-
ation Infectious Disease award. Part of the training for R. J. L. was
provided by the South African Tuberculosis and AIDS Training (SATBAT)
programme of the NIH/Fogarty International Centre (1U2RTW007370/
3). C. H. is supported by an NIH/Fogarty International Research Clinical
Fellowship. K. D. is supported by the South African National Research
Foundation (SARChI), the South African Medical Research Council (EU
FP7) and the European and Developing Countries Clinical Trials Partner-
ship (EDCTP).
Research letters
Transparency declarations
None to declare.
References
1 Lehloenya RJ, Dheda K. Cutaneous adverse drug reactions to
anti-tuberculous drugs: state of the art and into the future. Expert Rev
Anti Infect Ther 2012; 10: 475 86.
2 Lehloenya RJ, Todd G, Badri M et al. Outcomes of reintroducing
anti-tuberculosis drugs following cutaneous adverse drug reactions. Int
J Tuberc Lung Dis 2011; 15: 1649 57.
3 Bircher AJ, Scherer K. Delayed cutaneous manifestations of drug
hypersensitivity. Med Clin North Am 2010; 94: 71125, x.
4 Ellgehausen P, Elsner P, Burg G. Drug-induced lichen planus.
Clin Dermatol 1998; 16: 32532.
5 Nahid P, Jarlsberg LG, Rudoy I et al. Factors associated with mortality in
patients with drug-susceptible pulmonary tuberculosis. BMC Infect Dis
2011; 11: 1.
6 Asch S, Goldenberg G. Systemic treatment of cutaneous lichen planus:
an update. Cutis 2011; 87: 129 34.
J Antimicrob Chemother 2012
doi:10.1093/jac/dks217
Advance Access publication 11 June 2012
Teicoplanin therapy leading to a
significant decrease in viral load in a
patient with chronic hepatitis C
Andreas Maieron1 and Heidrun Kerschner2*
1
Gastroenterology and Hepatology, Elisabethinen Hospital,
Fadingerstrasse 1, 4020 Linz, Austria; 2Institute for Hygiene,
Microbiology and Tropical Medicine, Elisabethinen Hospital,
Fadingerstrasse 1, 4020 Linz, Austria
*Corresponding author. Tel: +43-732-7676-3689; Fax: +43-732-7676-
3686; E-mail: heidrun.kerschner@elisabethinen.or.at
Keywords: HCV, teicoplanin, therapy, viral load, glycopeptides
Sir,
We read with interest the paper by Obeid et al.,1 Inhibition of
hepatitis C virus replication by semi-synthetic derivatives of gly-
copeptide antibiotics. It provided us with a possible explanation
for a clinical observation that we made.
We would like to report an elderly patient with chronic hepa-
titis C. The patients alanine aminotransferase levels were con-
sistently 120 U/L and a Fibroscan showed liver stiffness of
43.5 kPa correlating with stage IV fibrosis in 2010. The patient
had completed a total of three antiviral treatment cycles
with pegylated interferon and weight-based ribavirin. The last
course of therapy had been maintained for 72 weeks and
was finished in April 2010. Although the patient experienced
JAC
on-treatment response, relapse occurred very shortly after the
end of each therapy.
In April 2010, the patient received a right hip joint replace-
ment in another hospital, which was complicated by delayed
wound healing. On 31 May 2010, the patient fell on their hip
and had to have repeat surgery. During the following days a
fever developed and on 4 June two blood cultures were positive
for Staphylococcus aureus. The surgical site was presumed the
focus of infection and an antimicrobial therapy with ampicillin/
sulbactam was initiated. The patient was then transferred to
the gastroenterology ward of our hospital on 28 June 2010. In
consultation with infectious diseases specialists and orthopaedic
surgeons, we decided to switch the antimicrobial therapy
to long-term teicoplanin starting on 7 July. We administered
1600 mg of teicoplanin intravenously two to three times a
week for a total of 10 weeks (trough level 9.2 19.9 mg/L). Sur-
prisingly, 12 days after the initiation of teicoplanin treatment,
normal serum transaminase levels were measured for the first
time in 30 years. Hepatitis C viral load measurement on 13
August showed a significant decrease in the patients RNA load
to 2.0 log10 IU/mL (previous measurement on 28 June:
6.9 log10 IU/mL). Subsequent measurements yielded RNA
loads of ,15 IU/mL on 27 August and 2.9 log10 IU/mL on 17 Sep-
tember, which was the last day of teicoplanin therapy (Figure 1).
Transaminase levels remained normal until 1 October, but have
been elevated since. Also, the patients hepatitis C RNA levels
returned to the usual baseline levels of 6.0 log10 IU/mL.
There is some evidence that glycopeptides and their deriva-
tives show antiviral effects against retroviruses and corona-
viruses,2,3 but Obeid et al.1 were the first to report activity of
teicoplanin derivatives against hepatitis C virus replicons in an
in vitro model. The mechanism of action of these compounds
and the exact molecular substructures responsible for inhibition
of viral replication have not yet been elucidated. However, the
authors speculate that the peptide scaffold common to all
these substances might play a major role in their antiviral
activity.
Our patient showed significant decreases in the hepatitis C
viral load and transaminase levels during teicoplanin therapy.
Teicoplanin has been shown to enter human cells4 and therefore
a post-entry interaction with the hepatitis C virus replication
cycle, as proposed by Obeid et al.1 for their compound
LCTA-949, may be a possible explanation for the observed
effect. Another conceivable mechanism might be interference
of teicoplanin with host cell factors such as lipid metabolism
and membrane organization, which are both important for hepa-
titis C virus replication.5
It has been suggested that heterologous viral infections may
trigger hepatitis C virus-specific T cell responses;6,7 however,
hepatitis B virus and HIV infection were excluded in our
patient. Furthermore, our patient did not show any clinical
signs of influenza and there was no influenza activity in Austria
at that time. In the absence of any other explanation, we specu-
late that teicoplanin interfered with hepatitis C virus replication
and led to the observed decrease in the viral load.
Unfortunately, our patient was not available for a trial of
repeat exposure to teicoplanin, because the patient is currently
undergoing treatment with triple antiviral therapy. To the best
of our knowledge this is the first description of a possible effect
of teicoplanin on in vivo hepatitis C virus replication.
2537