LEADING ARTICLE Drug Safety 1997 Dec; 17 (6): 369-373

0114-5916/97/0012-0369/S02.50/0

© Adis International Umited. All rights reserved.

Nonsteroidal Anti-Inflammatory Drugs

and Necrotising Fasciitis
An Update
E. Paul Holder,1,2,3 Pennie Thomas Moore 1,2 and Barry A. Browne 1,2,3
1 Department of Pharmacy, Scott and White Memorial Hospital, Temple, Texas, USA
2 College of Pharmacy, The University of Texas at Austin, Texas, USA
3 College of Medicine, Texas A&M University Health Science Center, Temple, Texas, USA

Summary Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen

and others are the treatment of choice for mild to moderate pain. Because of the
relative safety and efficacy of NSAIDs, many of the agents are now available in
the US and in other parts of the world without a physician prescription. While
these drugs are relatively well tolerated, adverse effects resulting from their use
can occur. One such adverse effect recently linked to NSAID use is necrotising
fasciitis. Reports of necrotising fasciitis possibly associated with NSAID use have
been published in both the medical and lay literature. Several hypotheses regard-
ing a possible association between NSAIDs and the development of necrotising
fasciitis have appeared in the literature. One hypothesis is a simple masking of
the signs and symptoms of an existing infection, leading to a delay in diagnosis.
Some authors have speculated that in certain skin and soft-tissue infections, par-
ticularly those caused by group A ~-haemolytic streptococci, this delay in diag-
nosis may have allowed a simple infection to progress to necrotising fasciitis.
Other postulated mechanisms of NSAID involvement in the development of
necrotising fasciitis include an impairment of natural host defense mechanisms.
A review of the medical literature for reports of possible NSAID-associated
necrotising fasciitis revealed that the events were rare, but clinically significant.
From the available evidence, a causal relationship between NSAIDs and necrotis-
ing fasciitis cannot be established.

Recent reports of necrotising fasciitis develop-
ing in patients with bacterial infections who re-
ceived concurrent therapy with nonsteroidal anti-
inflammatory drugs (NSAIDs) have prompted
considerable speculation about a possible associa-
tion between NSAID use and the development of
nec~otising fasciitis. Necrotising fasciitis is an un-
common, potentially fatal soft tissue infection that
demands early recognition for effective treat-
ment.£ll Generally, within 24 hours of the appear-
ance of the initial lesion, areas become oedemat-
ous, erythematous, warm and tender.[ll Untreated,
the condition progresses rapidly, with infection
spreading to soft tissue or viscera.
Early diagnosis and aggressive treatment are
required to reduce or prevent the morbidity and
mortality associated with necrotising fasciitis. Pre-
disposing conditions include diabetes mellitus,
370
malnutrition, obesity, advancing age, atherosclero-
sis, trauma, and operative proceduresP-6] Support-
ive treatment consists of the administration of
intravenous fluids, high doses of appropriate sys-
temic antibacterials, and, when necessary, resusci-
tative measures and blood transfusions. Tissue de-
bridement is often the initial procedure of choice
and can have a major impact on the outcome of this
potentially fatal disease.[7]
Group A ~-haemolytic streptococci (GAS) and
staphylococci have been identified in as many as
88% of reported cases of necrotising fasciitisP] In
the remaining cases, Gram-negative organisms
were the most commonly reported infecting organ-
isms. Pseudomonas aeruginosa and a combination
of gram-positive and other Gram-negative organ-
isms have also been isolated from affected sites of
necrotising fasciitis. In a report of 11 cases, haemo-
lytic streptococci were found in 50% of cases and
the remainder involved either staphylococci or P.
aeruginosa.[8] In some instances, specific bacterial
organisms have been correlated with clinical situ-
ations, but data are limited. For example, Brook
and Frazier[9] reported a foul odour with Bacteroi-
des spp.; gas and crepitation with Enterobac-
teriaceae and Clostridium species; and oedema
with Clostridium species, Staphylococcus aureus
and group A streptococci.
Although initially described as a 'hospital gan-
grene' by the Confederate Army surgeon Joseph
Jones, many descriptive terms have been used in
the literature.[8] Terms used to describe necrotising
fasciitis were 'acute infective gangrene', 'necrotis-
ing erysipelas', 'haemolytic streptococcus gan-
grene', 'suppurative fasciitis' and 'flesh-eating
bacteria' .[1,8] In 1952, Wilson was first to accu-
rately describe necrotising fasciitis. Since Wilson's
description, the term 'necrotising fasciitis' has
been preferred to other descriptive terms,llO] Be-
cause of the serious nature of this condition and the
need for early diagnosis, the potential role of
NSAIDs in the development of necrotising fasciitis
in patients with infectious processes deserves ex-
ploration.
© Adis International Limited. All rights reserved.
Holder et al.
1. Evidence for a Link
14 cases of necrotising fasciitis in children with
primary varicella infections between December
1993 and May 1995, in the Seattle, Washington, US
area were retrospectively reviewed by Brogan and
colleagues. [II] Patient demographic information,
duration of varicella infection, presenting second-
ary symptoms, location of fasciitis and outpatient
therapies were discussed along with a review of
each patients hospitalisation. All 14 children un-
derwent surgical exploration and debridement.
Following surgery, all patients received aggressive
parenteral antibacterial therapy (combination ther-
apy including clindamycin and penicillin was ulti-
mately used in each case) and intensive care. Gram-
stained smears and cultures taken from the site of
infection were positive for GAS in all the children;
2 patients also had positive GAS blood cultures.
Eight patients received adjunctive hyperbaric oxy-
gen (HBO) therapy for as many as 6 treatments,
with subjective improvement noted in 6 of the 8
patients. Not all the patients were treated with
NSAIDs, but 5 of the children received ibuprofen
or paracetamol (acetaminophen) prior to present-
ing with GAS-associated necrotising fasciitis. l 11,12]
The NSAID-treated patients had no documented
necrotising fasciitis prior to ibuprofenlparacetamol
use. All 14 patients received appropriate care and
were well when discharged. Brogan and col-
leagues l II] proposed that the varicella lesions
might have served as portals of entry for GAS re-
siding on the skin. Although, other possible causes
for necrotising fasciitis could not be excluded, the
relationship between the initiation of NSAID ther-
apy and the deterioration of the patients' conditions
raised the possibility that a link between NSAIDs
and necrotising fasciitis might exist. Brogan and
colleagues[ II] speculated that a possible associa-
tion might be caused by the ability of NSAIDs to
mask the signs and symptoms of an existing infec-
tion.
Pillans and O'Connor[13] reported 6 cases of
necrotising fasciitis and/or severe tissue necrosis in
adults after administration of intramuscular diclo-
fenac. Necrotising fasciitis was described in half of
Drug Safety 1997 Dec; 17 (6)