lAC
Journal of Antimicrobial Chemotherapy (1997) 39, 371-381
Risk factors for adverse cutaneous reactions associated with
intravenous vancomycin
Tony M. Korman*, John D. Turnidge and M. Lindsay Grayson
Department of Infectious Diseases and Microbiology, Monash Medical Centre, Clayton, VIC 3168, Australia
We retrospectively studied adverse cutaneous reactions associated with intravenous
vancomycin therapy over a 14-month period when two different brands of vancomycin were
used. Of 224 adults, 12 (5.4%) had infusion-related reactions; ten of 174 patients who
received more than one day of vancomycin (5.7%) had delayed cutaneous reactions. Age
less than 40 years was a risk factor for both infusion-related and delayed reactions by both
univariate and multivariate analysis. Duration of therapy greater than 7 days was a risk factor
for delayed reactions. There was a significant increase in adverse cutaneous reactions
associated with the use of a particular batch of vancomycin, although analytical testing of
this batch failed to identify any difference from other batches associated with routine rates
of adverse reactions. Awareness of vancomycin-associated infusion-related and delayed
cutaneous reactions is necessary, and the risk factors associated with these reactions may
have important clinical implications.
Introduction
Over the past decade, f1-lactam-resistant Gram-positive
organisms have emerged as significant nosocomial
pathogens and vancomycin usage has increased considerably. The widespread use of vancomycin may result in
increased morbidity from adverse drug reactions. 1
Adverse cutaneous reactions are the most common
reason for the cessation of vancomycin therapy.2 Infusionrelated 'red man syndrome' occurs in 80-90% of healthy
volunteers 3- 5 but rates in patients vary from 0% to
50%.6--8 The incidence of non-infusion-related cutaneous
reactions is not well established. Patient factors predisposing for adverse cutaneous reactions have not been
identified in clinical studies. Patients with reactions to one
brand of vancomycin may tolerate other brands without
complications; however, few studies have compared the
incidence of reactions with different brands.
During early 1994 an apparent increase in the incidence
of vancomycin-associated cutaneous reactions was observed
at our institution. Subsequently, we discovered that there
had been a recent change in the brand of vancomycin used.
This prompted us to undertake a retrospective study to
investigate whether the incidence of reactions had actually
increased after the change in the brand of vancomycin.
Other objectives were to characterize the clinical features
and identify potential risk factors for adverse cutaneous
reactions associated with vancomycin therapy.
Patients and methods
Patient selection
Monash Medical Centre is a 747-bed acute community and
tertiary referral centre in Melbourne, Australia. Patients
over 16 years of age who had received iv vancomycin
during a 14-month period from June 1993 to July 1994 were
identified by review of in-patient pharmacy medication
profiles. Patients who had received vancomycin in the
intensive care unit or operating theatre were excluded
from the analysis because adverse cutaneous reactions, in
particular infusion-related reactions, may be difficult to
recognize in these patients. 6
Definitions
The duration of a course was defined as the number of
days between the administration of the first and last doses
of vancomycin (inclusive). When not administered daily
(e.g. in patients with renal impairment), the duration
*Tel: +61-3-9550-4564; Fax: +61-3-9550-4533.
371
T. M. Korman et al.
included days when detectable serum vancomycin levels
would have been maintained.
Adverse cutaneous reactions were defined as either
infusion-related or delayed. An infusion-related reaction
was defined as the development of symptoms or signs
(e.g. pruritus, erythema) during iv infusion of vancomycin. A delayed reaction was defined as the development of a skin rash during a course of vancomycin
therapy, not temporally related to iv infusion. Only
patients who received more than one day of vancomycin
were included in the analysis of delayed reactions. Since
thrombophlebitis would be difficult to identify accurately
in a retrospective study, it was not recorded.
In order to assess the likelihood that the adverse
reactions were caused by vancomycin, each was allocated
a causality rating using the following standard published
criteria: 9 (i) Certain: confirmed by rechallenge; and/or
confirmed by laboratory data; and/or reaction onset
immediately followed drug administration (within 5 min
if injection was the method of administration); (ii) Probable: temporal or spatial (e.g. skin) correlation with
administration; and/or recovery on withdrawal of drug if
no other drug is withdrawn and no therapy given; and/or
uncommon clinical phenomenon associated with the
administration of drug in the absence of other factors; (iii)
Possible: a possible alternative explanation exists; and/or
more than one drug is suspected; and/or data are incomplete and/or recovery follows withdrawal of more than
one drug; and/or time relationship is not clear; and/or
outcome of the reaction is not recorded; and/or recovery
follows therapy in addition to withdrawal of drug; (iv)
Causality unclear: this classification is accorded where a
clinical event may well be explained as arising from
factors related to underlying disease, or other non-drug
aetiology. Only suspected adverse reactions allocated the
rating of certain, probable or possible were included in
the analysis of vancomycin-associated adverse reactions.
Patients and courses
The clinical records of patients receiving a course of vancomycin were reviewed and the following data were
obtained: age, sex, weight, underlying disease(s), concomitant drug therapy, previous history of drug allergy
and duration of therapy. The initial dose of vancomycin
administered was calculated as mg/kg/dose, and the
subsequent dose calculated as mg/kg/day. The actual
duration of vancomycin infusions was not routinely documented in patient records; however, hospital guidelines
dictate that a 1 g dose of vancomycin is given as an infusion in at least 500 mL of fluid over 1 h.
Adverse drug reactions
Suspected adverse drug reaction reports generated by
nursing, pharmacy or medical staff caring for the patients
were examined. In addition, patient charts were reviewed
for any adverse reactions documented during vancomycin
courses. The following details of the suspected adverse
cutaneous reactions were collected: day of onset during
vancomycin therapy, clinical features (including description of skin rash, pruritus, fever attributed to vancomycin), associated eosinophilia (increase in the
absolute eosinophil count to > 0.44 X 109/L), the treatment required (if any) and the outcome of the reaction.
Details of any attempts at rechallenge and further management were recorded.
Serum vancomycin concentrations
Serum vancomycin concentrations determined by enzyme
multiplied immunoassay technique (EMIT) were
recorded. The mean peak and trough levels measured
during each course were calculated. If the trough level
measured less than the sensitivity of the assay «5 mg/L),
an arbitrary level of 4 mg/L was used for calculations. If
the peak level measured >80 mg/L an arbitrary level of
81 mg/L was used for calculations.
Vancomycin brands and analytical testing of
batches
Pharmacy records were used to ascertain the brand and
batch of vancomycin used for each course. The brands of
vancomycin used included: Vancocin CP (Eli Lilly, West
Ryde, New South Wales, Australia), Vancoled (Lederle
Laboratories, Baulkham Hills, New South Wales,
Australia) and vancomycin hydrochloride (Faulding
Pharmaceuticals/David Bull Laboratories, Mulgrave
North, Victoria, Australia), hitherto referred to as DEL
vancomycin. Product specifications for minimum vancomycin B content were 95% for the chromatographically
purified Vancocin CP, and 88% for both Vancoled and
DBL vancomycin.
Analytical testing of DBL vancomycin batches was performed by the manufacturer in response to adverse drug
reaction reports forwarded to the company by our institution. The vancomycin B content and impurity profiles
of batches of raw material and finished product were
analysed by HPLC.
Statistical analysis
Data were evaluated by Student's t-test, X2 test or Fisher's
exact test where appropriate. P < 0.05 was considered significant. Significant univariate risk factors for adverse
reactions were analysed by stepwise multiple logistic
regression using a computed model (TRUE EPIST AT
Version 5, Epistat services, Richardson, TX, USA, 1994).
Data are presented as mean:±: standard deviation.
372
Vancomycin-associated cutaneous reactions
Results
Patients and courses
During the study period 269 patients commenced a course
of vancomycin, of whom the records of 267 patients
(99.3 %) were available for analysis. Of these 267 patients,
43 who had received vancomycin in the intensive care unit
(n = 41) or the operating room (n = 2) were excluded.
For the 224 patients analysed, mean age was 56.0 ± 19.0
years (range 16-90; 110 males and 114 females), and duration of vancomycin therapy was 7.5 ± 9.3 days.
further infusion~related adverse reactions, but developed
an erythematous maculopapular rash, pruritus, fever and
eosinophilia on day 23 of vancomycin therapy. The reaction resolved after stopping vancomycin (along with
ceftriaxone and doxycycline) after 42 days. Patient 12
had no further infusion-related adverse reactions but
developed a widespread bullous eruption, fever and
eosinophilia on day 28 of vancomycin therapy. The eruption subsided after ceasing vancomycin, and a course of
ftucloxacillin was tolerated without complications.
Delayed cutaneous reactions
Adverse cutaneous reactions
Twelve of the 224 patients (5.4%) had infusion-related
reactions; ten patients out of 174 (5.7%) who received
more than 1 day of vancomycin had delayed cutaneous
reactions, including two patients who had both infusionrelated and delayed reactions. Thus, a total of 20 of the
224 patients (8.9%) had a vancomycin-associated adverse
cutaneous reaction. Details of the patients with
vancomycin-associated adverse cutaneous reactions are
shown in Table 1.
Infusion-related cutaneous reactions
Thirteen patients with infusion-related adverse reactions
were identified. One reaction was excluded as the patient
developed pruritus and erythema when her third dose of
vancomycin was inadvertently administered over 10 min,
but she tolerated previous and subsequent doses administered over at least 60 min. Therefore, 12 of the 224 (5.4 % )
patients were defined as having infusion-related reactions.
All 12 patients complained of pruritus, and ten had
accompanying skin erythema. Patient 5 had a past history
of a vancomycin infusion-related reaction and developed a
nonpruritic erythematous maculopapular skin rash which
resolved 2 days after a single vancomycin infusion. In the
other 11 patients, the signs and symptoms abated soon
after ceasing the infusion. Four patients were treated with
Hrreceptor antagonists. By definition, all the infusionrelated reactions were accorded the causality rating
'certain'. Four patients in this group received no further
doses of vancomycin. Five patients tolerated continued
vancomycin therapy at infusion rates of 500-1000 mg/h
without further reactions. The other three patients developed adverse cutaneous reactions after receiving further
vancomycin. Patient 2 had an infusion-related reaction
associated with DBL vancomycin, was rechallenged with
Vancoled, and developed pruritus and erythema after
5 mins of vancomycin infusion (rate of 500 mg/h). She
tolerated an 8-week course of iv teicoplanin without an
adverse cutaneous reaction. Two patients who continued
prolonged courses with DBL vancomycin despite having
an infusion-related adverse reaction developed delayed
reactions. Patient 11 tolerated vancomycin without
Thirteen patients with delayed cutaneous reactions were
identified. Three reactions related to underlying disease
or other non-drug aetiology, i.e. 'causality unclear', were
excluded from further analysis. Therefore, ten patients
had delayed reactions or 5.7% of the 174 who received
vancomycin for more than 1 day. Nine of 74 patients
(12.2%) who received vancomycin for >7 days and eight
of 32 patients (25%) treated for ;;.14 days experienced
delayed reactions.
The mean onset of the delayed reactions was 20.1 ±
8.8 days (range: 6-31 days) after the commencement of
vancomycin therapy. Cutaneous manifestations of the
delayed reactions included: erythematous skin rashes (n
= 8), exfoliative dermatitis (n = 1), bullous eruption (n =
1), facial oedema (n = 1) and pruritus (n = 5). Fever
attributed to vancomycin was noted in eight patients, one
of whom also had rigors, myalgias and a dry cough. One
patient developed acute renal failure concurrently. Six of
ten patients (60%) had associated eosinophilia.
Delayed reactions resolved in seven patients after
ceasing vancomycin alone. Two of these reactions were
confirmed on rechallenge with vancomycin (see below)
and hence they were allocated the causality rating
'certain'. The other five reactions resolved after the withdrawal of vancomycin alone, but were not confirmed by
rechallenge and hence were allocated the causality rating
'probable'. In three patients, the adverse reaction was
considered 'possible' as a resolution followed the cessation of vancomycin and at least one other drug. Four
patients received specific therapy for the adverse reactions: two received Hrreceptor antagonists alone and two
required Hrreceptor antagonists and treatment with
systemic corticosteroids for 1-3 days.
Three patients with delayed adverse cutaneous reactions associated with DBL vancomycin were rechallenged
with vancomycin. Two patients had recrudescence of
pruritic, erythematous skin rashes promptly after rechallenge with DBL vancomycin (patient 19) or Vancocin CP
(patient 15). The third patient (patient 20) had a reaction
with DBL vancomycin but tolerated a 42-day course of
Vancoled without a skin rash before developing
eosinophilia which resolved only after cessation of
Vancoled.
373
~
Pen
no
acute
myeloid
leukaemia
none
F
63
33
5
6
none
reflux
nephropathy
thalassaemia
intermedia
M
F
60
20
33
9
10
11
F
none
F
16
8
F
26
7
no
no
no
no
Van
no
Crohn's
disease
gastric
carcinoma
M
67
4
M
no
none
M
20
3
no
none
F
23
Pen
none
F
2
Past
drug
allergy
Underlying
Sex disease(s)
20
Age
(years)
1
Patient
no.
ceftriaxone,
doxycycline,
ranitidine,
warfarin
ampicillin,
warfarin,
gentamicin
none
gentamicin,
phenytoin,
ranitidine
none
medroxyprogesterone,
oestrogen
allopurinol
hydrocortisone
none
metronidazole,
gentamicin
warfarin
Concomitant
medications
DBL
(324)
DBL
(324)
DBL
(324)
DBL
(324)
DBL
(324)
IR
DBL
(324)
DBL
(324)
VLD
DBL
(324)
DR
IR
IR
IR
IR
IR
IR
IR
IR
IR
IR
Type
of
reaction
VLD
pyelonephritis DBL
(324)
endocarditis
DBL
(324)
septic
arthritis
prophylaxis
prophylaxis
prophylaxis
VPshunt
infection
VC-related
septicaemia
VC-related
septicaemia
endocarditis
endometritis
Indication
for
Brand
vancomycin (batch)
23
1
1
1
1
1
1
1
1
1
1
1
Day
of
onset
rash,
pruritis,
fever,
eosinophilia
erythema,
pruritis
pruritis
erythema,
pruritis
erythema,
pruritis
erythema
erythema,
pruritis
erythema,
pruritis
erythema,
pruritis
erythema,
pruritis
erythema,
pruritis
erythema,
rash
Features
of
reaction
no
Vanc,d
Vanc
none
none
no
yes (no IR,
but later DR)
no
Vanc
Van
yes (no IR
or DR)
yes (no IR)
none
yes (no IR)
yes (no IR
or DR)
no
none
none
no
Vanc
possible
certain
certain
certain
certain
certain
certain
certain
certain
certain
certain
yes (IR)b
Van
Causality
rating"
certain
Rechallenge
(outcome)
yes (IR)
none
Medications
ceased
Table I. Patient details and features of vancomycin-associated cutaneous adverse reactions
:--0
~
~
!
....
~
..=a
~
.3:
tDI!
-.JI
("j.)
M
54
75
22
26
13
14
15
16
F
70
42
30
18
19
20
no
no
none
chronic
renal failure
diabetes
mellitus
none
none
none
no
no
no
Pen
no
haemono
dialysis
epidermolysis no
buHosa
hypersensitivity
pneumonitis
thalassaemia
major
ticarcillinl
davulanate,
frusemide,
ranitidine
imipeneml
cilastin,
dothiepin
ranitidine
imipeneml
cilastin
none
ceftriaxone
none
bumetanide
hydrocortisone,
digoxin
ceftriaxone,
desferrioxamine
osteomyelitis
osteomyelitis
osteomyelitis
endocarditis
osteomyelitis
VC-related
septicaemia
VC-related
septicaemia
osteomyelitis
osteomyelitis
DR
DR
DR
DR
DR
DR
DR
DR
. _ - - _...
(324)
DBL
(324)
DBL
VLD
(324)
DBL
(324)
DBL
(324)
DBL
VLD
(324)
DBL
10
13
25
29
23
13
6
31
rash,
fever
rash,
pruritis,
fever
Van
Van d
bullous
none
eruption,
fever,
eosinophilia
Van
rash,
fever,
acute renal
failure
exfoliative
Van,
bumetanide
dermatitis
rash,
Van
fever,
eosinophilia
Vanc,d
rash,
pruritis,
fever, rigors,
myalgia, cough
eosinophilia
Vanc,d
rash,
pruritis, facial,
oedema,
eosinophilia
rash,
Van,
pruritis,
ticarcillinl
eosinophilia davulanate C
28
DR
VLD
none
pruritis
1
IR
VLD
orDRe )
yes (no IR
yes OR)
no
no
yes OR)
no
no
no
probable
certain
possible
probable
certain
probable
possible
probable
yes (no IR,
certain
but later DR)
no
probable
DEL, DEL vancomycin; DR, delayed cutaneous reaction; JR, infusion-related reaction; Pen, penicillin; Van, vancomycin; VC, vascular catheter; VLD, Vancoled; VP, ventriculo-peritoneal.
a See 'Patients and methods' for definitions (infusion-related reactions are classified as 'certain').
b Tolerated 8 weeks of teicoplanin without infusion-related reactions.
c Patient received promethazine treatment.
d Patient received corticosteroid (oral prednisolone or iv hydrocortisone) treatment.
e Developed eosinophilia which resolved after cessation of vancomycin.
F
F
17
17
M
F
F
F
M
25
12
~
1!r
:I
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=
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T. M. Korman et al.
The figure demonstrates the number of patients commencing vancomycin and the occurrence of adverse cutaneous reactions per month. From June to December 1993
Vancoled was used predominantly, and from January to
July 1994 patients received DBL vancomycin. During
January-May 1994, DBL vancomycin batch 324 was used,
and there was a significant increase in both infusionrelated (P = 0.004) and delayed (P = 0.037) reactions
when compared with the remainder of the study period
when other vancomycin batches were used (see Table II).
No reactions were noted during June-July 1994, when
other batches of DBL vancomycin were used.
During the period of increased incidence of adverse
drug reactions associated with DBL vancomycin batch
324, pharmacy staff noted brown discoloration of several
vials of vancomycin powder. The manufacturer attributed
this to oxygenation resulting from cracks in the vials.
Analysis of all batches and raw material were within
product specification for vancomycin B content and
related impurities. Comparison of the HPLC impurity
profiles of batch 324 with other batches revealed no
differences. However, following these investigations the
manufacturer has decided to produce only chromatographically purified vancomycin (93% vancomycin B).
Risk factors for adverse cutaneous reactions
Table II shows the risk factors for infusion-related and
delayed cutaneous reactions. Univariate analysis revealed
that age less than 40 years was a significant risk factor for
both infusion-related (P < 0.001) and delayed cutaneous
reactions (P = 0.001). Duration of therapy greater than 7
days (P = 0.002) was a significant risk factor for delayed
reactions. The brand of vancomycin used was not a significant risk factor for infusion-related (P = 0.077) or
delayed cutaneous reactions (P = 0.332). However, the
use of vancomycin batch 324 was a significant risk factor
for both infusion-related (P = 0.004) and delayed reactions (P = 0.037).
Significant risk factors for vancomycin-associated cutaneous reactions in the multivariate analysis are shown in
Table III. Age less than 40 (P < 0.001) and the use of vancomycin batch 324 (P = 0.012) were independent predictors for infusion-related reactions. Age less than 40 (P =
Vancomycin
Vancoled
50
40
.s0:
0
S
....
<1)
V>
0..
0:
.S
u
.~
S
0
~
30
'"
g
~:l
:l
u
§
>
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u
0:
u
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20
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0..
u
€
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0
Z
<1)
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0
Z
Month 1993--1994
Figure. Patients commencing vancomycin per month, brands and batches used, and vancomycin-associated cutaneous reactions .
• , infusion-related reactions,
delayed reactions; . , patients commencing vancomycin.
376
Vancomycin-associated cutaneous reactions
Table II. Risk factors for patients with vancomycin-associated cutaneous reactions
Infusion-related reactions
Age (years)
mean ± S.D.
<40 years
Sex (male/female)
Weight (kg) mean ± S.D.
Initial vancomycin dose
(mg/kgldose), mean ± S.D.
Duration of vancomycin course
(days), mean ± S.D.
>7 days
Underlying diseases
diabetes mellitus
malignancy (non-cutaneous)
neutropenia
end-stage renal failure or
dialysis
Previous drug allergy
fi-Iactam
vancomycin
Concomitant medications
HI-receptor antagonist
Hz-receptor antagonist
corticosteroid (systemic)
calcium antagonist
Vancomycin brand
DBL vancomycin
vancoled
Vancomycin batch
DBL vancomycin batch 324
all other batches
reactionsb
(n = 12)
no reactions
(n = 212)
33.8 ± 18.5
9
4/8
64.5 ± 15.4
15.4 ± 3.8
Delayed reactionsa
Pvalue
reactionsb
(n = 10)
no reactions
(n = 164)
Pvalue
57.3 ± 18.2
42
106/106
70.2 ± 15.1
<0.001
<0.001
NS
NS
39.3 ± 20.1
6
3/7
69.5 ± 15.1
59.1 ± 18.5
29
75/89
69.8 ± 14.9
0.013
0.001
NS
NS
14.2 ± 4.3
NS
15.2 ± 5.2
14.1 ± 4.5
NS
23.6 ± 11.0
9
8.8 ± 8.8
65
0.002
0.002
0
2
0
39
41
21
NS
NS
NS
1
0
0
27
33
21
NS
NS
NS
0
41
NS
1
11
NS
2
1
38
1
NS
NS
2
0
36
0
NS
NS
0
2
1
0
3
66
34
27
NS
NS
NS
NS
0
3
1
1
1
47
22
12
NS
NS
NS
NS
9
3
100
112
}0.077
7
3
83
81
}0.332
9
3
69
143
}0.004
7
3
56
108
}0.037
DBL, David Bull Laboratories; NS, not significant.
a Only patients receiving vancomycin for >1 day (n = 174) included in analysis of delayed reactions.
b Two patients had infusion-related reactions followed by delayed reactions and are therefore included in both analyses.
0.014) and duration of therapy greater than 7 days (P =
0.026) were independent predictors for delayed reactions.
The use of DBL vancomycin batch 324 was not a significant risk factor in the multivariate analysis of delayed
reactions (P > 0.1).
There were no differences in characteristics of patients
receiving different brands or patients receiving different
batches of vancomycin, except that significantly more
patients who received Vancoled had end-stage renal
failure (ESRF) or dialysis (32 of 115) compared with
those receiving DBL vancomycin (eight of 109). When all
patients with ESRF or dialysis were excluded from the
analysis, the same risk factors remained significant.
Factors which had no significant effect on the incidence
of infusion-related or delayed reactions included sex,
weight, initial or subsequent vancomycin dose, diabetes
mellitus, malignancy, neutropenia, ESRF or dialysis, previous penicillin or vancomycin allergy, and concomitant
administration of Hr or Hz-receptor antagonists, corticosteroids or calcium antagonists. There was no apparent
correlation between peak or trough serum vancomycin
concentrations and reactions although they were not
measured for most patients with infusion-related reactions.
Discussion
Vancomycin-infusion-related adverse reactions are commonly known as the 'red man syndrome'. Polk suggested
377
T. M. Korman et al.
Table III. Multivariate risk factors for vancomycin-associated cutaneous reactions
OR
95% CI
Pvalue
Infusion-related reactions
age <40 years
vancomycin DBL batch 324
Delayed reactionsa
age <40 years
duration> 7 days
11.8
6.0
3.0-46.8
1.5-24.0
<0.001
0.012
5.6
11.1
1.4-22.0
1.4-91.2
0.014
0.026
DBL, David Bull Laboratories; OR, Odds Ratio.
Only patients receiving vancomycin for> 1 day (n
=
a
the terminology 'glycopeptide-induced anaphylactoid
reaction' as the major underlying mechanism is the nonimmunological release of histamine,lO although some
reactions may be mediated by other factors.11 The clinical
features include pruritus, erythematous skin rash and
hypotension. Reactions are most common and severe
with the first dose of vancomycin. 3,6
Other vancomycin-associated adverse cutaneous reactions reported include cutaneous vasculitis,12 exfoliative
dermatitis,13,14 toxic epidermal necrolysis,15 six cases of
erythema multiforme/Stevens-Johnson syndrome,16 and
ten cases of linear IgA bullous dermatosisY-22
The overall incidence of adverse cutaneous reactions
associated with vancomycin therapy ranges from 3% to
6%.23,24 In one prospective study, maculopapular skin
rashes attributed to vancomycin developed in three of 54
patients (6%) and constituted the most common indication for cessation of therapy?
Estimates of the incidence of 'red man syndrome' vary
widely in studies reflecting differences in the rate and concentration of vancomycin infusion, study design (e.g. definitions of reactions, intensity of monitoring), selection of
subjects (e.g. whether subjects are healthy volunteers or ill
patients) and concomitant medications. The incidence in
healthy volunteers who are closely monitored while receiving
a 1 g infusion over 1 his 80-90%.3-5 Polk suggested that ill
patients receiving vancomycin may be at a lower risk, possibly related to modified histamine release which may
accompany infection, malignancy or renal failure. to Antihistamine pretreatment25 prevents 'red man syndrome',
and concurrent use of corticosteroids and histaminereleasing drugs (e.g. opioids and neuromuscular blockers)
may also protect against infusion-related reactions. lo
Clinical studies have reported the incidence of
vancomycin-related 'red man syndrome' from between
zero and 50%.6-8,26 In the prospective double-blind study
by Wallace et al. the rate of first-dose 'red man syndrome'
was 47%6 as opposed to the low incidence (3.4%)
reported by O'Sullivan et al. 3 Both studies excluded
patients who had received antihistamines. The reasons for
the discrepancy between the two studies are debatable. 8,27
174) included in analysis of delayed reactions.
The risk factors for both infusion-related and delayed
adverse cutaneous reactions are not well-established.
'Red man syndrome' appears to occur with approximately
equal frequency in men and women. 28 Higher doses and
more rapid rates of infusion increase the risk in healthy
volunteers. 29 Concomitant nifedipine may be associated
with an increased risk.3o Data regarding delayed cutaneous reactions are less clear. Of 16 severe cases reported
by Forrence & Goldman,15 six patients had fever and two
had eosinophilia. The mean age was 53.6 years (range
19-79) with no gender predominance. The reactions
occurred 2-31 days (mean 13 days) after the initiation of
therapy. Ten patients had renal impairment, two with
ESRF receiving dialysis. There are other reports of
prolonged hypersensitivity reactions (skin rash, fever
and eosinophilia) in patients receiving haemodialysis
attributed to delayed vancomycin elimination. 31 ,32
In our study, 12 of 222 (5.4%) patients had infusionrelated reactions and ten of 174 patients (5.7%) who
received more than one day of vancomycin developed
delayed reactions. Of the ten patients with delayed reactions, one patient developed an exfoliative dermatitis,
another a bullous eruption and six had associated
eosinophilia. Delayed reactions occurred 6-31 days (mean
20.1 ± 8.8 days) after commencing therapy. Two patients
with delayed reactions had renal impairment. One was
receiving haemodialysis, and another developed acute
renal failure concurrently.
Multivariate analysis of our data suggested that age less
than 40 years was a significant risk factor for infusionrelated reactions. Studies investigating 'red man syndrome' have used healthy volunteers with a mean age of
less than 30 years. The high incidence in these studies
could be related to the young age of the subjects, not only
the absence of illness. Age less than 40 years and duration
of therapy greater than 7 days were independent predictors for the development of delayed reactions.
Differentiation between infusion-related anaphylactoid
reactions and IgE-mediated allergic reactions may be
difficult. 33 Of the 12 patients in our study with infusionrelated reactions, one had a previous infusion-related
378
Vancomycin-associated cutaneous reactions
reaction. Three patients developed adverse cutaneous
reactions after receiving further vancomycin. One patient
was rechallenged with a different brand of vancomycin
and again had an infusion-related reaction, but tolerated
a course of teicoplanin. Two other patients had mild
infusion-related reactions, and tolerated further courses
of vancomycin without infusion-related reactions, but
developed delayed cutaneous reactions with eosinophilia.
Rechallenge with vancomycin or teicoplanin following
vancomycin-associated delayed reactions is not well documented in the literature. Markowitz et al. 34 reported that
three patients in whom vancomycin therapy was discontinued due to rashes had reappearance of the rash when
'slowly rechallenged' 24 h later. Of three patients with
delayed reactions rechallenged with vancomycin in our
study, two had further reactions, and another developed
eosinophilia without a skin rash which resolved only after
the cessation of vancomycin.
Following vancomycin-associated reactions, care is
needed when considering further administration of glycopeptide antibiotics. Infusion-related reactions with
teicoplanin are rare,5,7,35 although there are concerns
regarding possible allergic cross-reactivity with vancomycin?6-39 For example, many patients are able to
tolerate teicoplanin after vancomycin-associated reactions,40--42 but occasionally patients with true IgE-mediated allergic reactions may also have adverse reactions
with teicoplanin. 43 Desensitization of patients with vancomycin hypersensitivity may be successful4~6 and useful in
some cases.
Early preparations of vancomycin, often called 'Mississippi mud', contained many impurities which potentially
contributed to the frequency of adverse effects. 47 The toxicity associated with vancomycin therapy has diminished
along with improved purification procedures. However,
adverse reactions still occur, even with chromatographically purified vancomycin. 48 Studies using currently available vancomycin formulations with varying purities have
demonstrated similar rates of 'red man syndrome' in
healthy volunteers. 10 Polk postulates that vancomycin
itself, and not "impurities", are responsible for 'red man
syndrome,.lD However, some patients might be allergic to a
minor component of vancomycin from one manufacturer
which may not be present in another batch or another
manufacturer's product. There are reports of patients
with reactions to a particular brand of vancomycin who
tolerate a different brand with increased purity without
complications,49,5o although one study found no significant
differences in rates of adverse reactions between different
vancomycin brands. 51 This was also the case in our study.
However, there was a significant increase in both infusion-related and delayed reactions during a period in
which a particular vancomycin batch was used predominantly. HPLC has been used to measure the chemical
purity of vancomycin-containing products,52 although
testing of this vancomycin batch by the manufacturer
failed to identify any differences from other batches associated with routine rates of reactions.
In summary, the incidence of clinically significant infusion-related cutaneous reactions in our patient popUlation
was low (5%). Younger age was a significant risk factor,
which could explain the higher incidence of these reactions in previous studies of healthy volunteers. Delayed
cutaneous reactions developed in 6% of patients, with the
significant risk factors of younger age and longer duration
of therapy. In addition, our study demonstrates that the
incidence of adverse cutaneous reactions may vary significantly depending on the batch of vancomycin administered, but that the cause for this may not be easily
identifiable. Awareness of vancomycin-associated, infusion-related delayed cutaneous reactions is necessary, and
the factors associated with their higher incidence may
have important clinical implications.
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Received 16 April 1996; returned 27 June 1996; revised 2 August
1996; accepted 12 September 1996
381