A m é lia G o re te A fo n s o d a C o s ta R e is , S a n d ra J o s e fin a F e rra z E lle ro G ris i,
A dverse effects of vancom ycin in children:
a review of 22 cases
Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
Department of Pediatrics, University of São Paulo - São Paulo, Brazil
V a n c o m y c in h a s b e e n fre q u e n tly re c o m m e n d e d fo r th e tre a tm e n t o f m u lti-re s is ta n t in fe c tio n s .T w e n ty -tw o c h ild re n u n d e rg o in g v a n c o m y c in tre a tm e n t w e re o b s e rv e d . N in e a d v e rs e e ffe c ts w e re re g is te re d in 6 c h ild re n : e o s in o p h ilia in 5 c a s e s , s k in ra s h in 2 c a s e s , a n d a n in c re a s e in p la s m a c re a tin in e in 2 c a s e s . A li a d v e rs e e ffe c ts re m itte d w ith w ith d ra w a l o f th e d ru g .
U N IT E R M S ~ V a n c o m y c in . A d v e rs e e ffe c ts . C h ild re n . A n tib io tic s .
V
a n c o m y c in1 9 5 6 a n d in tro d u c e d in to m e d ic a I p ra c tic e in 1 9 5 8 ,is a p o ly p e p tid e a n tib io tic iso la te d in fo r tre a tin g in fe c tio n s c a u se d b y p e n ic illin-re sista n t sta p h y lo c o c c i.1 It h a s m a n y m e c h a n ism s o f a c tio n ,
th e b e st k n o w n a n d p ro b a b ly m o st im p o rta n t b e in g th e
in h ib itio n o f c e ll w a ll sy n th e sis in b a c te ria .2 In a d d itio n
to b e in g e x tre m e ly e ffe c tiv e a g a in st G ra m -p o sitiv e b a c te ria ,3 -5tw o fe a tu re s o f v a n c o m y c in a re o f g re a t in te re st
in m e d ic a I p ra c tic e : th e lo w le v e I o f b a c te ria l re sista n c e
to th e a n tib io tic , a n d th e n e g lig ib le -in c id e n c e o f c ro ss
re a c tio n s w ith o th e r a n tib io tic s.
In itia l p re p a ra tio n s o f v a n c o m y c in c o n ta in e d m a n y
im p u ritie s fre q u e n tly a sso c ia te d w ith a d v e rse e ffe c ts.
T o d a y , w ith d ru g p u rific a tio n , th e n u m b e r o f p a tie n ts w h o
e x p e rie n c e to x ic e ffe c ts is v e ry sm a ll. F u rth e rm o re , w e
ll-c o n tro lle d d ru g a d m in istra tio n , a c c o rd in g to te c h n ic a l
A d d re s s fo r c o rre s p o n d e n c e :
A m é lia G o re te A . C . R e is
R u a A lv e s G u im a rã e s 6 2 3 , a p to 1 4 2 , J a rd im A m tftrie a S ã o P a u lo /S P - B ra s il- C E P 0 5 4 1 0 -0 0 1
S ã o P a u lo M e d ic a i J o u rn a l/R P M 1 1 5 (3 ): 1 4 5 2 -1 4 5 5 , 1 9 9 7
sta n d a rd s, h a s a lso c o n trib u te d to a re d u c tio n in th e
in c id e n c e o f a d v e rse e ffe c ts.
A fte r in tra v e n o u s a d m in istra tio n , v a n c o m y c in is
d istrib u te d in to v a rio u s b o d y flu id s. M a n y fa c to rs
in flu e n c e th e d ru g 's p h a rm a c o d y n a m ic s, in c lu d in g a g e .
T o ta l b o d y c le a ra n c e o f v a n c o m y c in in c re a se s w ith a g e .
D u e to th e c o m p le x p h a rm a c o k in e tic s o f th e d ru g , th e
m o n ito rin g o f th e a n tib io tic c o n c e n tra tio n in p la sm a is
re c o m m e n d e d to a ssu re su c c e ssfu l th e ra p y .6 -9
T h e m a in a d v e rse e ffe c ts a sso c ia te d w ith v a n c o m y c in a re :1 0 -1 2
• H ista m in e -lik e re a c tio n , c o m m o n ly se e n a s
flu sh in g a n d a m a c u lo -p a p u la r ra sh o f th e fa c e ,
n e c k , u p p e r th o ra x , b a c k a n d a rm s. T h e re a c tio n
m a y a ffe c t th e e n tire b o d y su rfa c e a n d b e
a c c o m p a n ie d b y itc h in g , p a re sth e sia , d iz z in e ss,
fe v e r, c h e st p a in a n d e d e m a o f th e fa c e , lip s,
a n d e y e lid s. M o re se v e re sy m p to m s su c h a s
ta c h y c a rd ia o r b ra d y c a rd ia a n d , m o re ra re ly ,
sy ste m ic a rte ria l h y p o te n sio n o r sh o c k , m a y b e o b se rv e d ;13
• N e p h ro to x ic ity h a s b e e n a sso c ia te d w ith
v a n c o m y c in sin c ~ th e b e g in n in g o f its u se .
A n a ly sis o f th e se stu d ie s a re d iffic u lt h o w e v e r,
R E IS , A .G .A .C .; G R IS I, S .J .F .E . - A d v e rs e e ffe c ts o f v a n c o m y c in in c h ild re n :
. 1453
A d v e rs e E ffe c ts
e o s in o p h ilia
e o s in o p h ilia , s k in ra s h s k in ra s h
in c re a s e in s e ru m c re a tin in e e o s in o p h ilia
e o s in o p h ilia e o s in o p h ilia
in c re a s e in s e ru m c re a tin in e 0 8 .1
1 5 .0
05.6
S e ru m c o n c e n tra tio n s
L o w (m c g /m l)
25.6 16.7 04.0
T he drug w as prepared for intravenous adm inistration at a concentration of 5 m g/m l. T he dosage used w as 15 m g/kg/dose over a 60-m inute period, every 6 hours.
M easurem ents of plasm a concentration of vancom ycin w ere taken at m axim al and m inim al concentration leveIs of the phase of equilibrium , that is, after the second day of therapy. Plasm a concentration w as determ ined by poIarized im m unofluorescence on T D x equipm ent. A s plasm a concentrations presented great individual variation, leveIs of 30 to 40 m cg/m l at m axim al, and below 10 m cg/m I at m inim al w ere considered adequate.9 O ptim um plasm a leveIs w ere observed in only eight children.
H em ogram , urea and creatinine concentration, serum transam inase leveIs and urinanalysis w ere perform ed at the beginning of therapy and w eekly during treatm ent in order to m onitor adverse effects. O totoxicity w as not evaluated. C oncom itant therapy w ith a cephalosporin or am inoglycoside w as necessary in 14 cases.
N ine adverse effects observed in six children are described in the T able. C hanges in plasm a urea and creatinine leveIs upon introduction of vancom ycin therapy did not occur.
T he follow ing adverse effects w ere observed: tw o cases of skin rash (9.1 percent), five episodes of eosinophilia (22.7 percent), and tw o cases of increase in serum creatinine concentration (9.1 percent).
Skin rashes w ere observed during drug infusion, and after the second w eek of treatm ent. E osinophilia w as defined as the num ber of eosinophils above 500 cells/ m l, and w as observed after the second w eek of treatm ent in five cases. R em ission occurred after the end of treatm ent. C hanges in plasm a creatinine w ere observed during the second and third w eeks of treatm ent. T w ofold or greater increases w ere considered significant. B oth cases w ith an increase in plasm a creatinine concentration
29.9
2 3 .1 3 7 .7
3 0 .9
54.6
S e ru m c o n c e n tra tio n s
P e a k (m c g /m l)
50.4
T a b le
A d v e rs e e ffe c ts a n d s e ru m c o n c e n tra tio n s o f v a n c o m y c in
•
•
•
•
•
because m any concom itant factors that m ay im pair renal function in vancom ycin treatm ent are also present in these studies; 14,15
O totoxicity has been difficult to evaluate, as m ost patients are not subm itted to audiom etric tests during treatm ent. Im pairm ent of the auditory nerve, considered the m ost severe adverse effect, m ay lead to perm anent hearing IO SS;16,17 T hrom bophlebitis w as frequent w ith initial preparations of vancom ycin, occurring in up to 50 percent of cases. T he incidence fell to betw een 6-13 percent after the purification process; 18
T oday, fever and chills are rare adverse effects; they w ere m ore com m only observed w ith initial preparations of the antibiotic; 10,19
H em otoxicity, m ainly represented by neu tropenia and eosinophilia, has been described m ore frequently, and does not seem to be related to dosage or plasm a concentration of the drug. B lood count returns to norm al values upon w ithdraw al of the drug;20 A lthough increase in serum bilirubin has been associated to the use of vancom ycin, there is no clear proof of hepatoxicity; 10
A rterial hypertension has been described recently, aIthough hypotension is the cardiovascular effect m ost frequently observed.
T he C hildren ~s Institute of the H ospital das C linicas of the U niversity of São Paulo, a m ajor tertiary hospital, treats children w ith chronic anel/or severe diseases in w hich im m unodepression, the use of invasive procedures, and frequent hospital adm issions often lead to the developm ent of m ulti-resistant G ram -positive bacterial infections. V ancom ycin plays an im
por-tant role in the treatm ent of these infections.
T herefore, w e follow ed 22 children in w hom van-com ycin w as clinically indicated for treating severe
infections caused by suspected C a s e 1 or confirm ed m ulti-resistant C a s e 2
staphyIococci. W e observed
possibIe adverse effects of the C a s e 3
drug through clinicaI and
laboratory follow -up, and C a s e 4
attem pted to relate these C a s e 5
effects to treatm ent length and
plasm a concentrations of the C a s e 6
drug.
R E IS , A .G .A .C .; G R IS I, S .J .F .E . - A d v e rs e e ffe c ts o f v a n c o m y c in in c h ild re n : a re v ie w o f 2 2 c a s e s
1454
occurred w ith sim ultaneous use of other drug's, in one
case am ycacin, and in another, ceftriaxone.
C reatinine
plasm a leveIs returned to norm al after the drugs w ere
w ithdraw n.
Serum concentrations above 40m cg/m l occurred in
tw o of the six children w ho suffered adverse effects, and
in four children the serum concentrations w ere below 40
m cg/m l.
From the analysis of the data above w e can conclude
that:
•
•
Plasm a
concentrations
presented
great
individual
variation,
confirm ing
that the
recom m ended dosage of vancom yci~ is suitable
for initial therapy, but serum concentrations
should be m onitored to adjust dosage;
Significant adverse effects w ere not observed
during infusion, suggesting that adm inistration
standards have a protective role;
A dverse effects w ere transient and rem itted
after vancom ycin w as w ithdraw n.
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R E IS , A .G .A .C .; G R IS I, S .J.F .E . - A dverse effects of vancom ycin in children: a review of 22 cases
