Case Report

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A rare case of toxigenic diphtheria tonsillitis resistant to penicillin

causing sepsis and death
Peter Floros1, Dakshika A. Gunaratne2, Andrew Chang3,4, William B. Coman3,4
1
Department of Otolaryngology, Head and Neck Surgery, St Vincent’s Hospital, Sydney, Australia; 2Department of Otolaryngology, Head and Neck
Surgery, St George Hospital, Sydney, Australia; 3Department of Otolaryngology, Head and Neck Surgery, Mater Hospital, Brisbane, Australia;
4
Department of Otolaryngology, Head and Neck Surgery, The Princess Alexandra Hospital, Brisbane, Australia
Correspondence to: Dr. Peter Floros. St Vincent’s Hospital, 390 Victoria Street, Darlinghurst, NSW 2010, Australia. Email: peter_floros@hotmail.com.

Abstract: Diphtheria is a rare, contagious and potentially life threatening acute bacterial infection caused
by toxigenic and non-toxigenic strains of Corynebacterium diphtheriae. Australian public health immunization
initiatives have resulted in near complete eradication. An unimmunized 22-year-old female presented
to the Emergency Department of the Princess Alexandra Hospital with a 6-day history of a sore throat
despite previous oral and intravenous antibiotic therapy. Examination and investigation revealed diffuse
pseudomembranous coating of her upper aerodigestive tract and tracheobronchial tree. Biopsy confirmed
Corynebacterium diphtheriae and sensitivity testing demonstrated penicillin-resistance. Unfortunately, she
progressively deteriorated despite maximal antimicrobial therapy and succumbed to the infection on day
six of admission. This is the first documented Australian death from toxigenic Corynebacterium diphtheriae
since 1992 and the first reported case of penicillin-resistance. Immunization is fundamental in preventing
diphtheria-related morbidity and mortality. Clinicians must now be wary of emerging penicillin-resistance.

Keywords: Diphtheria; tonsillitis; penicillin- resistance

Received: 24 January 2018; Accepted: 22 October 2018; Published: 07 November 2018.

doi: 10.21037/ajo.2018.10.01
View this article at: http://dx.doi.org/10.21037/ajo.2018.10.01

Introduction of childhood immunization reducing the clinical incidence

Diphtheria is a rare, contagious and potentially life
threatening acute bacterial infection caused by toxigenic
and non-toxigenic strains of Corynebacterium diphtheriae (1).
Previously a source of significant morbidity and mortality
in the Australian population, the implementation of public
health initiatives including greater community awareness
and most notably, active immunization programs lead
to a marked decline in incidence, and near complete
eradication by the 1960s (2). A minority of cases continue
to be reported on yearly basis, restricted to unimmunized
individuals travelling to, or having contact with travelers
from countries where diphtheria remains endemic (3), and
in subpopulations in the Northern Territory (particularly
indigenous Australians), where non-toxigenic strains remain
endemic (4). Additionally, there has been an emerging
trend of adult infections postulated to be the consequence
of, and circulation of the toxigenic diphtheria strain,
preventing the opportunity to acquire natural immunity
or boost vaccine induced immunity (5). On account of the
aforementioned public health initiatives and wide access
to penicillin-based therapy, diphtheria-related mortality
in Australia is exceedingly rare with the last reported
occurrence in 1992 (5). Herein, we describe the first
subsequent death from toxigenic Corynebacterium diphtheriae
and first reported case of penicillin-resistance.
Case presentation
A previously healthy, unimmunized, non-indigenous
2 2 - y e a r- o l d f e m a l e p r e s e n t e d t o t h e E m e r g e n c y
Department of Princess Alexandra Hospital (Brisbane,
Australia) with a 6-day history of progressive odynophagia,
dysphagia and reduced oral intake despite analgesia and

© Australian Journal of Otolaryngology. All rights reserved. www.TheAJO.com Aust J Otolaryngol 2018;1:29
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Figure 1 Post mortem section of proximal trachea and infraglottic
region showing classical pseudomembranous respiratory epithelium
in Corynebacterium diphtheriae infection.
antibiotics (penicillin). She had been reviewed twice
previously throughout the course of her illness and had
received intravenous benzylpenicillin and dexamethasone
for acute tonsillitis (in addition to her outpatient oral
therapy). Serological testing for Epstein-Barr virus was
negative. On examination, apart from a mild tachycardia
(108 beats per minute), her observations were within
normal parameters. She was dysphonic, but conversing in
full sentences, not stridulous and swallowing her saliva.
Oral examination revealed grade 2+ erythematous tonsils
with a pseudomembranous coating. Flexible nasendoscopy
demonstrated extension of the pseudomembrane to
the oro- and hypopharynx, supraglottis and vocal cords
bilaterally. She was admitted for intravenous antibiotic
(benzylpenicillin and metronidazole) and dexamethasone
therapy.
The following day, the patient deteriorated with
increased work of breathing, stridor and worsening hypoxia
(SaO2 88% on 10 L of oxygen) necessitating emergency
intubation and transfer to the intensive care unit.
Intravenous therapy was continued as previous. On the third
day of admission, her ventilator requirements had increased
and bilateral lower lobe pulmonary consolidation was
noted. Urgent bronchoscopy revealed a pseudomembranous
coating of the lower respiratory tract extending into
subsegmental bronchi (Figure 1). Tissue biopsies taken from
the pseudomembranous oropharynx on admission cultured
positive for Corynebacterium diphtheriae, however sensitivities
were pending (Figure 2). Following test dosing, diphtheria
antitoxin was administered. Her condition continued to
worsen on the fourth day with problematic oxygenation
secondary to pseudomembrane sloughing, endotracheal tube
© Australian Journal of Otolaryngology. All rights reserved.
Australian Journal of Otolaryngology, 2018
Figure 2 Histological specimen. The trachea is highlighted by
the tracheal rings seen in cross section. There is an overlying thick
purulent inflammatory membrane (to the left of the rings) which
corresponds to the pseudomembrane seen in autopsy specimen.
and bronchial plugging and worsening sepsis manifesting
as acute renal and hepatic failure and increasing inotropic
requirements. Ticarcillin was commenced empirically
following consultation with infectious diseases. On days 5
and 6, end organ failure worsened and she developed toxin-
induced cardiomyopathy and nephropathy. At this time, it
was discovered that this strain of C. diphtheriae was resistant
to penicillin. Meropenem and lincomycin were commenced,
however despite maximal efforts, her condition continued
to deteriorate, and she passed away shortly thereafter of
acute cardiac failure secondary to complete heart block
and refractory ventricular arrhythmias. Autopsy confirmed
significant myocardial dystrophic, necrotic and sclerotic
alterations. Additional relevant autopsy findings included
disseminated mucosal ulceration of the pharynx, larynx,
trachea and main bronchi with pseudomembranous coating.
Mucosal erythema and satellite coating of smaller bronchi
was also noted in association with pulmonary haemorrhage
and bronchial plugging with fibrinopurulent exudate.
Discussion
Corynebacterium diphtheriae is gram positive, non-
motile, unencapsulated bacillus transmitted via direct
contact or respiratory droplets (1,6). Toxin production
is dependent on lysogenic integration of one of a family
of corynebacteriophages carrying the structural gene for
diphtheria toxin (7). Lysogenic conversion from non-
toxigenic to toxigenic strain can occur in situ or in vitro (7).
Toxigenic strains are responsible for most pharyngeal,
respiratory, cardiac, neurological and systemic sequelae,
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Australian Journal of Otolaryngology, 2018
whilst non-toxigenic strains manifest predominantly as
cutaneous infections (1,6). However, a recent increase in
invasive non-toxigenic infections suggests that C. diphtheriae
may possess additional virulence factors other than toxin-
linked molecular mechanisms (8).
Early clinical recognition is paramount to successful
management. As highlighted in this case, pharyngeal
diphtheria presents with findings of pharyngitis, fever,
cervical lymphadenitis (bull-neck diphtheria) and airway
obstruction secondary to gray-green pseudomembrane
formation (fibrin, bacteria and inflammatory cells) (7).
Pseudomembrane coating may be difficult to distinguish
from the more common exudative plaques associated with
bacterial and viral tonsillitis (e.g., Epstein-Barr virus).
Cutaneous diphtheritic lesions are usually covered by a gray-
brown pseudomembrane (7). Disease progression signifies
toxin penetrance into myocardium or peripheral neural
tissue, at which stage the effects are rarely reversible (7).
Management of acute toxigenic pharyngeal diphtheria
entails isolation and droplet precaution interactions, health
department notification, diphtheria antitoxin administration,
penicillin-based antimicrobial therapy and contact tracing.
Prompt passive immunization with diphtheria antitoxin
is most effective in reducing mortality which can reach
20–30% (7,9). Unfortunately, in our case, the disease had
significantly progressed by the time of administration and
toxin-mediated systemic effects could not be reversed or
suppressed. Penicillin is the mainstay of therapeutic and
prophylactic treatment. Resistance, as demonstrated in our
case is rare and was unexpected, and this in combination
with the patient’s lack of underlying immunity lead to her
ultimately succumbing to the infection. Although penicillin-
resistance has been reported in non-toxigenic strains of C.
diphtheriae previously (10,11), to the best of our knowledge,
this is the first reported case of penicillin-resistant toxigenic
C. diphtheriae.
In recent times, objection to immunization and parental
refusal to adhere to recommended health authority
guidelines has come to the fore in the Australian media and
public. Although recent analysis has only demonstrated
a small increase in registered or unregistered vaccination
objection (to 3.3%) (12), the issue has been of sufficient
significance so as to prompt multiple federal and state
government initiatives (13). However, these enterprises are
restricted to the pediatric population and consequently, vast
numbers of adults remain under-vaccinated (14). This case
demonstrates the importance of childhood and regular adult
booster immunization against diphtheria, which in our case,
© Australian Journal of Otolaryngology. All rights reserved.
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may have prevented the development of, or limited the
extent of infection. Additionally, the importance of routine
questioning of immunization status and consideration of
diphtheria amongst the differential diagnoses is highlighted.
However, a complete reliance on immunization history is
thwart with danger as immune titers to Corynebacterium
diphtheriae toxin may be suboptimal in previously
immunized individuals (15). Furthermore, with the benefit
of hindsight, additional interventions to be considered
in such atypical and refractory cases of tonsillitis include
obtainment of pharyngeal swabs earlier in the disease
course (in the context of multiple emergency department
representations and negative serology for Epstein-Barr
virus), and empiric treatment with broader spectrum
antimicrobial agents through consultation with infectious
diseases.
Conclusions
Immunization is fundamental in preventing diphtheria-
related morbidity and mortality. Clinicians must be wary
of emerging penicillin-resistance and prompt antibiotic
escalation considered if clinical deterioration occurs and
specimen sensitivities are unavailable.
Acknowledgements
None.
Footnote
Conflicts of Interest: The authors have no conflicts of interest
to declare.
Informed Consent: The patient died within 6 days of hospital
admission, and the family/next of kin of the patient were
no longer contactable. Institutional human research ethics
committee approval was obtained for this study (HREC/11/
QPAH/274).
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doi: 10.21037/ajo.2018.10.01
Cite this article as: Floros P, Gunaratne DA, Chang A, Coman
WB. A rare case of toxigenic diphtheria tonsillitis resistant
to penicillin causing sepsis and death. Aust J Otolaryngol
2018;1:29.
© Australian Journal of Otolaryngology. All rights reserved.
Australian Journal of Otolaryngology, 2018
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