03_antimicrobial prophylaxis for ophthalmic surgery

8/14/2019 03_Antimicrobial Prophylaxis for Ophthalmic Surgery

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SUR VEY OF OP HT HA LM OL OG Y VOLUME 39. NUMBER 6 MAY-JUNE 1995

THER PEUTIC REVIEW OEL MINDEL EDITOR

ntimicrobial Prophylaxis for Ophthalmic SurgeryM I C H A E L B . S TA R R M D 1 A N D J O S E P H M . L A L LY M D 2

1New York New York and 2Charleston S outh Carolina

Abstract. Preopera t ive , in t raopera t ive , and pos topera t ive ant ib io t ic agents have been usedby ophthalm ic surgeons rout ine ly as prophylaxis for pos topera t ive endo phthalm i t i s . Th era t ionale for such prophylaxis and the evidence which suppor ts i t s e ff icacy are wel lfoun ded . The opt imal choice of ant ib io t ic agen t - f rom the s ta ndpo int of efficacy, route o fdelivery, adve rse reactions, and co st - is far less established. This review consid ers theseissues, as well as the role o f topical disinfectants, includin g povido ne-io dine, in pre -opera t ive prophylaxis . (Surv Ophthalmol 39"485-501, 1995)

Ke y words , ant ib io tics 9 ant imicrobia ls 9 ca tarac t surgery 9 dru g del ivery 9endo phtha lmi t i s 9 povidone- iodine 9 prophylac t ic ant imicrobia ls

E n d o p h t h a l m i t i s is o n e o f t h e m o s t d e v a s t a t i n gc o m p l i c a t io n s o f i n t r a o c u l a r s u r g e r y. A r e c e n tr e v ie w o f 3 0 , 00 2 p r o c e d u r e s a t a m a j o r t e a c h i n gh o s p it a l s h o w e d a n i n c id e n c e o f c u l t u r e - p r o v e ne n d o p h t h a l m i t i s o f 0 . 0 72 % i n e x t r a c a p s u l a r c a ta -r a c t e x t r a c t i o n s . 0 . 0 5 1 % i n p a r s p l a n a v i t r e c t o -m i e s , 0 . 11 % i n p e n e t r a t i n g k e r a t o p l a s t i e s ,0 . 0 3 0 % i n s e c o n d a r y i m p l a n t s , a n d 0 . 0 6 1 % i n

g l a u c o m a f il tr a ti o n p r o c e d u r e s ] ~T h e e x p e c t e d i n f l a m m a t o r y r e s p o n s e t o su r-g e r y m a y i n c l u d e d i s c o m f o r t , h y p e r e m i a , c h e -m o s i s , l i d e d e m a , a n d d e c r e a s e d v i s i o n . W h e nt h e s e r e s p o n s e s a r e i n e x c e s s o f t h e u s u a l o r i ft h e y i n c re a s e o v e r t i m e , a n d w h e n t h e y a r e a c-c o m p a n i e d b y h y p o p y o n o r v i tr it is , e n d o p h t h a l -m i t i s s h o u l d b e s u s p e c t e d . D i a g n o s t i c a q u e o u sh u m o r a n d v i t re o u s h u m o r p a r a c e n t e s e s f o r m i -c r o s c o p ic e x a m i n a t i o n a n d c u l t u r e , w i t h o r w i th -o u t a t h e r a p e u t i c v i t r e c t o m y, s h o u l d b e p e r -f o r m e d w i t h i n t r a v i t r e a l i n j e c t io n o f a n ti b io t ica g e n t s t h a t c o v e r a b r o a d s p e c t r u m o f m i c r o o r -g a n i s m s . A n t i b i o t i c s a r e a l s o d e l i v e r e d t o p i c a l -

l y, s u b c o n j u n c t i v a l l y, a n d o f t e n i n t r a v e n o u s l y.T h e u s e a n d t i m i n g o f c o r t i c o s te r o i d s r e m a i n sa c o n t r o v e r s i a l i s s u e a n d s h o u l d b e c a r e f u l l yc o n s i d e r e d .

A n t i b io t ic a g e n t s h a v e b e e n u s e d f o r y e a r s b yo p h t h a l m i c s u r g e o n s b e f o r e , d u r i n g , a n d a f t e rs u r g e r y a s p r o p h y l a x i s a g a i n s t p o s t o p e r a t i v e e n -do p ht h al m iti s . 4'27'~5'53'61's~'1~ T h e es ca la tin g cos ts

o f m e d i c a l c a r e h a v e p r o m p t e d c o s t - be n e f i t r e a p -p r a is a l s o f a c c e p t e d m e d i c a l p r a c ti c e s , a n d t h ec o s t o f a n t i b i o t i c u s a g e is b e i n g r e a p p r a i s e d . I np a r t i c u l a r , t h e p r o p h y l a c t i c u s e o f a n t i b i o ti c s h a sco m e u n d e r scr ut in y. 59,69,v4,gv'~G Es t im ate s ha ves u g g e s t e d t h a t 3 0 % o r m o r e o f a ll a n ti b io t ica g e n t s u s e d i n t h is c o u n t r y a r e u s e d f o r p r o p h y -laxis in su rgic a l p a t ie nts . 66'116 In ad di t io n to eco -n o m i c c o n s i d e r a t i o n s , q u e s t i o n s a b o u t a d v e r s er e a c t i o n s a n d e m e r g i n g b a c t e r i a l r e s i s ta n c e t oa g e n t s t h a t a r e e x t e n s i v e ly u s e d a r e b e i n g e x a m -i n e d . E m e r g e n c e o f n e w s t ra i n s o f an t ib i o ti c -r e s i s t a n t m i c r o o r g a n i s m s h a v e r e k i n d l e d c o n -c e r n a b o u t t h e i n a p p r o p r i a t e u s e o f a n t i m i c r o -

485


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486 Surv Ophthalmol 39 (6) May-June 1995 STARR

TABLE

Results of Culture of Preoperative Conjunctival Swabs

Bacteria Cultured

Numberof

Patients

Staphylococcus epidermidis* 58No growth 24Staphylococcus aureus* 7Haemophilus influenzae* 2Diphtheroids 2Diphtheroids and Staphylococcus epidermidis* 2Coliforms* and Staphylococcus epidermidis* 1Coliforms* 1Haemolytic streptococcus Group C* 1Bacillus sp.*Pseudomonos aeruginosa* 1

*Bacteria capable of causing endophthalmitis.(Reprinted from Walker CB, Claoue CMP:J Roy Soc

Med 79:520,1986, with permission.)

bial agents, including their inappropriate use asprophyl axis for infection , lsa

In this article the use of prophylactic antibi-otics in opht halmic s urgery is reviewed. This ar-ticle updates a 1983 comprehensive review pub-lished in this journa l. 124

R o l e o f N o r m a l O c u l a r F l o r a

A variety of potential sources o f infectious mi-

croorganisms confront the ophthalmic surgeonpreoperatively, but none is as practically signifi-cant or as difficult to contain as the patient's ownskin and conjunctival flora. Despite minor geo-graphic an d temp oral variations, various staphy-lococcal species and corynebacteria usually pre-domi nate in this flora; streptococcal species andgram-negat ive bacilli are less f requent. 3~6a53~31Isolated cases or temporal ly clustered outb reak sof infectious endophthalmitis may be derivedfrom exogenous sources, for example, contami-nated instruments, irrigating solutions, donor

corneas, intraocular lenses, and air-borne con-taminants. These sources, however, probablycontrib ute to a m inorit y of postoperative eye in-fections and are, with rare exception, controlledby meticulous aseptic technique by operatingroom per sonnel and moder n sterilization meth-ods of all instruments and materials used intra-ocularly r topically. 6'41'57'77's2'I22

Although continued diligence in these areasand further improvements in pharmaceuticalquality control minimize these sources of infec-tion, the patient's normal lid and conjunctivalflora remain the most common source of infec-

tious microorganisms. This impression has beensubstantiated by the infrequent identification ofexogenous infectious sources and by the demon-stration o f the imp ortan ce o f local bacterial florain series of bacterial endophthalmitis in whichan infectious source has been sought (Table1).:45.41.82.84

Before the development of bacteriophage typ-ing, the evidence linking normal eye flora withpostoperative endophthalmitis was suggestivebut presumptiv e. Various staphylococcal specieshad long been recognized as the most commonnorm al inhabitan ts of the lids and conjunctiva, aswell as the predominant species causing infec-tions after cataract surgery. 53'127 Furt her more ,attempts to eliminate what were then consid eredto be pathogenic staphylococci (e.g., S. aureusfrom the e xternal eye seemed to reduc e the inci-dence of pos topera tiv e infection. ~:~5

Staphylococci are ubiquitous organisms, pres-ent in the oper ating room envi ron ment as well ason the skin of patients and operating room per-sonnel. Their frequent recovery from infectedpostoperative eyes, therefore, did not firmly es-tablish their origin on the patient's lid or con-junctiva. Then, Locatcher-Khorazo and Gutier-rez s2 an d Loca tcher-Kh orazo et al s4 utilizedphage-typing of staphylococci to demonstrate agreat diversity of strains recovered from the en-viro nmen t and the eyes and skin of infected and

normal patients and directly linked ocularstrains identified preoperatively with strainscausing infections postoperatively. The authorsnoted that of 40 postoperative endophthalmitiscases occ urring in years 1957 thr oug h 1960,there were seven cases which had preoperativeculture results available for evaluation. In all ofthese cases, the phage type staphylococcus pres-ent at the time of postoperative infection wasidentical to the phage-type present preoper-atively. ~2

In a r ecent study, Speaker et al 1-~2 used gene

material typing to identify an organism in thevitreous that was genetically indistinguishablefrom an isolate recovered f rom the patient's eye-lid, conjunct iva, or nose in 14 of 17 (82 ) cases ofendophthalmitis, again implicating the patient'sown ocular surface flora. Ariyasu et al ~I showedthat in 8o f 13 (62 ) eyes from which bacteriawere cultured from the aqueous humor at thecompletion of intraocular surgery, the speciesand antibiotic sensitivities of the or ganisms wereidentical to those of the bacteria cultured fromthe patients' lids and conjunctivae preoperative-ly. (Postoperative endo phthal mitis di d no t devel-


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ANTIMICROBIAL PROPHYLAX IS FOR OPHTHALM IC SURGERY 87

op in any o f the cases in th i s se r i e s. )

P r e o p e r a t i v e C u l t u r e s a n d t h e E f f e c t so f A n t i b i o t i cs o n t h e N o r m a l

O c u l a r F l o r a

T h e e v i d e n c e t h a t t h e p a t i e n t w a s t h e s o u r c e o fm o s t p o s t o p e r a t i v e in f e c t i o n s l e d t o r o u t i n e p r e -o p e r a t i v e c u l t u r i n g o f t h e e x t e r n a l e y e a n d a t -t em pts to e l imina te o r a l t e r th i s f lo ra wi th top ica lan t ib io t i c agen t s .

T h e v a l ue o f p r e o p e r a t i v e c u l tu r e s h a s b e e nthe sub jec t o f som e deba te . 2~ Th e re l iab i l-i ty o f the t e s t i n p red ic t ing the loca l f lo ra p re sen ta t t h e t i m e o f s u rg e r y i n p a t ie n t s w i t h o u t s i gn so f e x t e r n a l o c u l a r i n f e c t io n i s i n d o u b t . N o l a nf o u n d t h a t 3 5 o f 6 5 p a t i e n ts u n d e rg o i r N c a ta -r a c t s u rg e r y h a d c o n j u n c t i v a l c u l t u r e r e s u l t s a tt h e t i m e o f s u rg e r y t h a t w e r e d i f f e r e n t f r o mt h o s e o b t a i n e d t h e p r e v i o u s d a y, a g a i n w i t h o u tadm in i s t r a t ion o f p roph y lac t i c an t imic rob ia l s. l~H e f o u n d t h a t o f 4 3 e y e s t h a t w e r e c u l t u r e -p o s i ti v e f r o m t h e c o n j u n c t i v a f o r v a r i o u s o rg a n -i sm s o n e d a y p r e o p e r a t i v e l y, 2 1 h a d n o g r o w t hf r o m t h e c o n j u n c t i v a a t s u rg e r y, i n s p i t e o f n o tu s i n g p r o p h y l a c t i c a n t i m i c r o b i a l t r e a t m e n t i nt h e i n t e r im . I n a d d i t i o n , o f 66 e y e s w h i c h s h o w e dn o g r o w t h o n e d a y p r e o p e r a t i v e l y, 1 4 e y e s w e r ecu l tu re -p os i t ive a t su rge ry. S imi la r ly, A l l ansmi the t a l f o u n d h e a l t h y a d o l e s c e n t v o l u n t e e r s w h oc u l t u r e d p o s i t i v e f o r t a p h y l o c o c c u s a u r e u sf r o m

the l id ma rg ins to be equa l ly l ike ly to be cu l tu re -nega t ive fo r th i s o rgan i sm as cu l tu re -pos i t ive , i fr e c u t t u r e d m o r e t h a n o n e d a y la t e r ?

Th e s ign i f icance o f cu l tu re r e su l t s is a l so p rob -l emat i c s ince mo s t eyes a re cu l tu re -pos i t ive p re -o p e r a t iv e l y f or o r g a n i s m s c a p a b l e o f c a u s i n gp o s t o p e r a t i v e e n d o p h t h a l m i t i s ( u p t o 9 5 o feyes in one l a rge se r i e s) 4~ and so f ew such cu l -t u r e - p o s i ti v e e y e s g o o n t o d e v e l o p p o s t o p e r a t i v ei n f ec t i on , e v e n w h e n t h e b a c t e r i a a r e p a r t i c u l a r l yviru ien t species . 22'~5'53 Ro ut in e pr eo pe ra t iv e cul-t u r e s m a y b e m i s l e a d i n g , t h e r e f o r e , b y i n a p p r o -

p r i a t e ly r a i s ing the su sp ic ion o f r i sk fo r in fec t ion .S i n c e c u l t u r e s t a k e n b e f o r e s u rg e r y p r o b a b l y d on o t r e l i a bl y p r e d i c t t h e f l o ra p r e s e n t a t t h e t i m eo f s u rg e r y, s u c h r o u t i n e p r e o p e r a t i v e c u l t u r e smay a l so he mis lead ing in g iv ing a f a l se sense o fs e c u r i ty a b o u t t h e n e e d f o r in f e c t io n p r o p h y l a x i sin a cu l tu re -nega t ive pa t i en t . Thus , any dec i s ionto t a i lo r p rophy lac t i c an t imic rob ia l cho ices o r top r o c e e d w i t h o r c a n c e l i n t r a o c u l a r s u rg e r y b a s e do n p r e o p e r a t i v e c u l t u r e r e s u l t s is p r o b a b l y n o tw a r r a n t e d a s a g e n e r a l p r a c ti c e . I t i s i m p e r a t i v e ,h o w e v e r, t o r e c o g n iz e t h e r o l e p r e o p e r a t i v e c u l -tu res mu s t hav e in the pa t i en t w i th c lin ica l ly evi -

den t ocu la r su r face in fec t ion , such as b lephar i t i s ,con junc t iv i t is , cana l icu l i ti s , and da c r yo cy s t i t i s .S u c h p a t i e n t s a r e u n d o u b t e d l y a t i n c r e a s e d r i s kf o r i n t r a o c u l a r i n f e c ti o n i f s u rg e r y is u n d e r t a k e nw i t h o u t f i r s t e r a d i c a t i n g t h e s u r f a c e i n f e c t i o n .T h e s h o r t c o m i n g s o f c u l t u r e a n d s e n si t iv i ty te s t-i n g i n t h e r o u t i n e p r e o p e r a t i v e p a t i e n t h a v e n o tb e e n d e m o n s t r a t e d i n th e p a t i e n t w i th c li n ic a ll yev id en t in fec t ion , s2 and cu l tu re and an t ib io t icsuscep t ib i l i ty t e s t ing be fo re and a f t e r an t ib io t i ct r e a t m e n t m a y b e r e q u i r e d i n a d d i t i o n t o e v a l u a-t i on o f c li n ic a l s ig n s a n d s y m p t o m s t o e n s u r ee r a d i c a t i o n o f t h e i n f e c t io n b e f o r e e l e c ti v e s u r-ge ry.

T hr ee s tud ies by Bu rns ~9'21'22 de m on s t ra t edt h a t t o p i c a l a n t ib i o ti c s d e c r e a s e p o s t o p e r a t i v ebaCte r i a l coun t s . In these s tud ies , pub l i shed be -twe en 1968 and 1972 , gen ta mic in su l fa t e wasf o u n d t o b e s u p e r i o r t o n e o m y c i n s u l f a te , c h lo r -a m p h e n i c o l , a n d s u l f a c e t a m i d e . ( O n e s h o u l dn o t e t h a t t h e s e s t u d i e s p e r t a i n e d t o th e e f f e c t o ft o p ic a l ly a d m i n i s t e r e d a n t i bi o t ic a g e n t s o n p o s t -o p e r a t i v e b a c t e r i a l c o u n t s a f t e r 2 - 3 d a y s o fpa tch ing . ) S tud ies o f an t ib io t i c p rop hy lax i s ing e n e r a l s u rg e r y, 59 s t u d i e s s h o w i n g c o n t a m i n a -t i o n o f t h e c a t a r a c t w o u n d a t t h e t i m e o f c lo -s u r e 26 42 78 a n d t h e a q u e o u s h u m o r a f te r w o u n dclosure,~3,~4,117 an d the us ua l t im e o f on se t o f bac -t e r ia l e n d o p h t h a l m i t i s a ll su g g e s t , h o w e v e r, t h a tthe in t r aopera t ive s t age i s the mos t c ruc ia l t ime

f o r p r o p h y l a x i s , 5 r a t h e r t h a n t h e p o s t o p e r a t i v es tage.

O n e w o u i d e x p e c t t h a t a n y a n t i b io t i c w i th e f fi -c a c y su f f ic i e n t t o r e d u c e b a c t e r ia l c o u n t s w i t hp o s t o p e r a t i v e p a t c h i n g w o u l d b e a t l e a s t a s ef f ec -t iv e i n t r a o p e r a t i v e l y. H o w e v e r, o t h e r a g e n t ss h o w n t o b e le s s e f f e ct iv e u n d e r t h e s t r i n g e n tc o n d i ti o n s o f p a t c h i ng m i g h t b e a d e q u a t e w h e nu s e d p r e o p e r a t i v e l y o r i n t r a o p e r a t i v e l y. I n as t u d y o f b a c t e r i a l c o u n t s t a k e n b e f o r e t r e a t m e n ta n d a g a i n s h o r t l y b e f o r e s u rg e r y, w i t h o u t t h ea d d i t i o n a l i n c u b a t i o n o f m i c r o o rg a n i s m s t h a t

p o s t o p e r a t i v e p a t c h i n g h a s b e e n s h o w n t o e n -c o u r a g e , F a h m y 43 a d d r e s s e d t hi s i s su e . H e r a n -d o m l y a s s i g n e d c a t a r a c t p a t i e n t s t o o n e o f s ixt r e a t m e n t g r o u p s , e a c h o n e r e c e i v i n g a d i f f e r e n ta n t ib i o ti c a g e n t f iv e ti m e s t h e d a y b e f o r e s u rg e r y ,e n d i n g a t b e d t i m e . P e r h a p s n o t su r p r i si n g l y, t h er e s ul ts w e r e n o t d i f f er e n t f r o m t h o s e r e p o r t e d b yB u r n s . A m i n o g l y c o s i d e d r o p s , 0 . 3 w e r e a g a i nthe m os t e ffec t ive in cons i s t en t ly e l imina t ing bac -t e ri a f r o m t h e c o n j u n c ti v a w h e n c o m p a r e d t o th efo l lowing an t ib io t i c s : ch lo ram phe n ico l 0 .5 , su l-p h a m e t h i z o l e 4 , b a c i t r a c in 1 , n e o m y c i n 0 .5 ,r i s toce t in su lph a te 0 .5 , po lym yxin B 0 .25 , a ll


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488 Surv Oph thalm ol 39 (6) May -June 1995 STA RR

d r o p s , a n d o x y t e t r a c y c li n e c h l o r id e 3 % - p o ly -myx in B su lpha te 0 .1% o in tme n t . T he e ff icacyof p re ope ra t iv e an t ib io t ic s in genera l , and anaminog lycos ide in pa r t i cu la r, i n r educ ing bac -t e ri a l f lo r a w a s a ls o d e m o n s t r a t e d b y W h i t n e ye t at , ~ 3 w h o c o m p a r e d p r e - a n d p o s t - t r e a t m e n tcoun t s o f l id ma rg in s t aphy lococca l spec ies andf o u n d g e n t a m i c i n 0 . 1 % d r o p s m o r e e f f e c ti v et h a n c h l o r a m p h e n i c o l 0 .5 % a n d p o l y m y x i n , n e o-m y c i n , g r a m i c i d i n d r o p s a n d p o l y m i x i n B - n e o -m y c i n o i n t m e n t , t h e c o n c e n t r a t i o n s o f w h i c hwere no t spec i f i ed . I t i s no tab le tha t even in theg r o u p o f p a t i e n ts t r e a t e d w i th g e n t a m i c i n d r o p s ,o n l y 4 4% o f e y e s w e r e c u l t u r e - n e g a t iv e f r o m t h el id marg in a f t e r t r ea tmen t .

S e v e r a l c o n c l u s i o n s m a y b e d r a w n f r o m t h es tud ies desc r ibed above . F i r s t , t op ica l an t ib io t i ca g e n t s a d m i n i s t e r e d i n a b r i e f p r e o p e r a t i v e r e gi -m e n r e d u c e t h e a m o u n t o f l id a n d c o n j u n c t iv a lb a c t e r i a c o m p a r e d w i t h u n t r e a t e d c o n t ro l s . T h i so b s e r v a t i o n p r o v i d e s s o m e r a t i o n a l e f o r s u c ha n t ib i o ti c u s e i n t h e p r e v e n t i o n o f p o s t o p e r a t i v ee n d o p h t h a l m i t i s . S e c o n d , t h e d e g r e e t o w h i c hsuch f lo ra wi l l be r educed depends , in pa r t , onthe cho ice o f an t ib io ti c agen t , t he f r equ ency a nddur a t ion o f i ts adm in i s t r a t ion , the bac te r i a l spe -cies present , and thei r ant ibiot ic suscept ibi l i t ies .Las t ly, t he c i t ed s tud ies a re bo th more than adec ade o ld , and suscep t ib il i ty to the aminog lyco-s ides among bac te r i a may have changed s ign i f i -

can t ly s ince these s tud ies were pub l i shed . Fore x a m p l e , i n o n e s t u d y o f p o s t o p e r a t i v e e n -doph tha lmi t i s , 35% (13 /37) o f the coagu lase -nega t ive s t aphy lococca l i so la t e s were r e s i s t an t inv i t ro to gen tamic in f rom the yea r s 1982-1986 ,co mp are d wi th 0% (0 /26) o f the i so la te s f rom1973 -198 1. 32

N e w e r A n t ib i o ti c F o r m u l a t i o n s :T r i m e t h o p r im P o l y m y x i n B

a n d F l u o r o q u i n o l o n e sIn the pas t f ew yea r s , new com merc ia l ly p re -

pa red an t ib io t i c agen t s fo r top ica l ocu la r useh a v e b e c o m e a v a il a bl e . O n e s u c h p r o d u c t , P o ly -t r im | (Al l e rgan Pharm aceu t i ca l s ) , a com bina t iono f t r i m e t h o p r i m a n d p o l y m y x i n B , h a s a w i d e inv i t ro s p e c t r u m o f c o v e r a g e t h a t i n c l u d e s m o s tendo ph tha lmi t i s pa thog ens , wi th the poss ib le ex -cep t ion o fme th ic i l l in - res i s t an t s t aphy lococc i andanae robes , ~29 the fo rm er be ing an inc reas ing lyim por t an t cause o f pos tope ra t ive in fec t ion ? ~-

Po lym yxin B has a h igh l eve l o f e ffi cacy aga ins tm a n y g r a m - n e g a t i v e o rg a n i s m s i n c l u d i n gP s e u -d o m o n a s a e r u g i n o s a ;however, i t i s less effect iveaga ins t P r o t e u s spec ies andSerra t ia marcessans ,as

wel l a s mo s t g ram-pos i t ive and anae ro b ic bac te -r ia . 129 Tr im eth op rim is effect ive against a w iderange o f g ram-p os i t ive and -nega t ive bac te r i a ,wi th Pseudomonas spec ies , Ne i s se r i a spec ies ,an d ana ero be s u sual ly res is tant , t~9 Th e eff icacyo f t r i m e t h o p r i m a s a si n gl e a g e n t h a s b e e n q u e s -t i o n e d b e c a u s e i t m a y e n c o u r a g e t h e e m e rg e n c eof res is tant bacte r ia l s trains .12'129 W he n t r im etho -p r i m i s c o m b i n e d w i t h p o l y m y x i n B , h o w e v e r,t h e s p e c t r u m o f a n ti b a c te r i a l c o v e r a g e is c o m p l e -men ta ry, and synerg i s t i c ac t ion has been foundfor th is an t ib io ti c c omb ina t ion . 85 Tr im e tho pr imis an an t ib io t i c o f the d ia min opy r imid ine c l as s ,unre la t ed s t ruc tu ra l ly to the su l fonamides wi thwhich i t i s usua l ly combined , and i t i n t e r fe reswith fol ic acid synthesis and thus , u l t im ately,wi th bac te r i a l DNA syn thes i s. Th i s ac t ion m ay bebac te r ios t a t i c o r bac te r i c ida l , depend ing on t r i -me tho pr im concen t ra t ion . 115 Po lym yxin B i s apo ly pep t id e an t ib io t ic whos e ac t ion des t roys bac -ter ia l ce l t m em bra ne s . 3'~ T he synergis t ic ac t ion o fthese two an t ib io t ic s m ay be a r e su l t o f be t t e rpene t ra t ion o f each o ne in to the bac te r i a l ce ll a s aresul t of ac t ion of the othe r. 52'a5A s h l e y f o u n d t h a tin v i t ro t e s t ing aga ins t 319 ocu la r bac te r i a li s o l a t e s s h o w e d t h e t r i m e t h o r i m - p o l y m y x i n Bcom bina t ion to be l e ss e ffec tive overa l l t hanc h l o r a m p h e n i c o l o r a c o m b i n a t i o n o f n e o m y c i n -g ram ic id in -po lym yxin B , and mos t e ffec tive o fthe an t ib io t ic s t e s t ed a ga ins t ocu la r i so la t e s o f H .in f luenzae . 2

Limi ted c l in ica l da ta sugges t tha t t r ime tho-p r i m - p o l y m y x i n B i s r o u g h l y c o m p a r a b l e t o ot h -e r top ica l agen t s in t r ea t ing bac te r i a l con junc t iv i-t i s and b lepharocon junc t iv i t i s , based on cu l tu rere sul ts an d clinica l r es po ns e. ~8 49 v5T h e s p e c t r u mo f o rg a n i s m s f o u n d a m o n g t h e y o u n g p a t i e n t swi th ex te rna l in fec t ion in these s tud ies d i ff e r ss ign i f i can t ly f rom the usua l pa t i en t s and o rgan-i sms in endoph tha lmi t i s s tud ies , mak ing the r e l -evance o f th is pub l i sh ed c l in ical da ta to po s toper -a t ive in fec t ion t enuou s . 49 In one p re l im ina ry

s t u d y o f p a t i e n ts u n d e r g o i n g c a t a r ac t s u rg e r y,t r i m e t h o p r i m - p o l y m y x i n B d r o p s w e r e f o u n dc o m p a r a b l e i n e f fi ca c y o f t o b r a m y c i n d r o p s i nreduc ing su r face ocu la r bac te r i a l coun t s a t t het i m e o f s u rg e r y a n d p o s t o p e r a t i v e l y ] A s o f t hi sw r i t i n g , n o p u b l i s h e d s t u d i e s w e r e f o u n d t h a tinves t iga ted the e ff i cacy o f these c omb ina t iond r o p s i n r e d u c i n g p o s t o p e r a t i v e i n t r a o c u l a r b a c -t e r i a l coun t s o r endoph tha lmi t i s .

The f luoroqu ino lone an t ib io t i c s became ava i l -ab le on ly r ecen t ly fo r sys temic and top ica l use .Cur ren t fo rmula t ions ava i l ab le a s eyedrops in -c lude c ip ro f loxac in (C i loxan Alcon Pharm a-


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A N T I M I C R O B I A L P R O P H Y L A X I S F O R O P H T H A L M I C S U R G E R Y 8 9

ceu t i ca ls ) , no r f loxac in (C h ib rox in | Me rck &Co. , Inc . ), and o f loxac in (Ocuf lox Al le rganPharm aceu t i ca l s ) , a ll 0 .3 conc en t ra t io n . F lu -o r o q u i n o l o n e s a r e b e l i e v e d t o a c t b y i n h i b i t i n gt h e b a c t e r i a l e n z y m e , D N A g y r a s e , n e c e s s a r y fo rD N A s u p e r c o i l i n g a n d p r o t e i n s y n th e s is , a s w e l la s b y o t h e r p o s s i b le m e c h a n i s m s , sl F l u o r o q u i n o -lones a re no tab le fo r a ve ry h igh l eve l o f ac t ivi tyi n v it r o a g a i n s t a w i d e s p e c t r u m o f g r a m - p o s i t i v eand -nega t ive bac te r i a , i nc lud ing me th ic i l l in -res is ta nt staphylococci . l~ Lik e a l l ant im icrobia ls ,they a re no t e qua l ly e ffec t ive aga ins t a l l bac te r i a ,a n d t h e i r o c c a s i o n a l i n v i t r o s h o r t c o m i n g s a r et h e a n a e r o b e s a n d s t r e p to c o c c i , a l t h o u g h t h e r e i ss o m e v a r i a b il i ty a m o n g f l u o r o q u i n o l o n e s i n th i srega rd , l~176 o r f loxac in , fo r exam ple , has bee nfou nd to have l e ss ac tiv i ty in v i t ro aga ins t s t r ep to -cocca l spec ies than o f loxac in a s we l l a s c ip ro f lox-acin.Sl,l13,11s Th is has be en sh ow n sp ecifica lly forocu la r i so la t e s o f s t r ep tococc i , a s we l l a s bac te r i af r o m n o n o c u l a r s it es . I n g e n e r a l , o f l o xa c i n h asshown the bes t in v i t ro ac t iv i ty ove ra l l aga ins tocu la r i so la t e s o f a l l t ypes , and c ip ro f loxac in hasshown pa r t i cu la r ly good in v i t ro ac t iv i ty aga ins tp s e u d o m o n a s s p e c ie s , j13 O s a t o e t a l f o u n d t h a ta m o n g 4 1 9 o c u l a r b a c t e r i a l i s o l a t e s c o m p r i s i n g5 5 s p e c ie s , o fl o x a c in h a d a l o w e r M I C 9 0 f o r b o t hg r a m - p o s i t i v e a n d n e g a t i v e o rg a n i s m s t h a n f i v eo the r an t ib io t i c s , i nc lud ing nor f loxac in , gen ta -m i c i n , t o b r a m y c i n , c h l o r a m p h e n i c o l , a n d p o l y -

my xin B . 1~ Al th oug h c ip ro f loxac in w as no t t e s t -ed in th i s s tudy, bo th nor f loxac in and o f loxac inh a d c o m p a r a b l e a c ti v it y a g a i n s t 6 8 o c u l a r i s o -la tes ofPseudomonas aeruginosaa n d b o t h e x c e e d -ed the in v i t ro ac tiv i ty aga ins t th i s o rgan i sm fo rt h e o t h e r a n t i b i o t i c s t e s t e d , i n c l u d i n g t o b r a m y -c in . J e n s e n t e s t e d a ll t h r e e f l u o r o q u i n o l o n e s a n dt o b r a m y c i n , t h e l a t t e r i n b o t h c o m m e r c i a l l y f o r -m u l a t e d a n d f o r t i f i e d c o n c e n t r a t i o n s , a g a i n s t219 ocu la r bac te r i a l i so la t e s . 68 H e fou nd the inci -d e n c e o f r e si s t a n c e t o b e l o w e s t f o r o f lo x a c i n( 3. 7 ) , a n d t h e n i n o r d e r o f i n c r e a s i n g f r e q u e n -

cy o f r e s i s t ance : c ip ro f loxac in (7 .3 ) , no r f loxa c in(16 .9 ) , and tobra my c in (40 ) .

S i m i la r , b u t s l i gh t ly d i f f e r e n t f l u o r o q u i n o l o n e -r e l a t e d a c ti v it ie s w e r e r e p o r t e d b y C u t a r e l lie t a131~ aga inst 96 ba cter ia l i sola tes , w hich unl ik et h e s t u d i e s c i te d a b o v e , w e r e f r o m e x t r a o c u l a r a sw e l l a s o c u l a r s o u r c e s . T h e a u t h o r s f o u n d c i p r o -f l o x ac i n a n d t e m a f l o x a c i n t h e m o s t a c ti v e a g e n tst e s t e d , w i th a n M I C 9 0 o f 1 m i l l ig r a m p e r l it e r(mg/1) , fo l lo we d by of loxa cin 2 mg/1, an d n orf lo x-ac in and pe r f loxac in 4 mg/1 . The au thors a l sotes t ed gen tamic in 32 mg/1 , tob ramyc in 64 rag / l ,a n d c e f a z o li n > 2 0 4 8 m g / 1. N a k a m u r a e t al f o u n d

be t t e r in v i t ro e ffi cacy aga ins t 29 g ram -pos i t iveocu la r i so la t e s which were c ip ro f loxac in - res i s -t a n t, w i t h t w o n e w e r f l u o r o q u i n o l o n e s , s p a r f lo x -ac in an d PD 131 62& 99

Bioava i l ab i li ty o f top ica l ly app l i ed f luoro qu in -o l o n e s is g o o d i n t h e a n t e r i o r s e g m e n t , a l t h o u g ha q u e o u s h u m o r l ev e ls a r e h i gh l y d e p e n d e n t o nd o s i n g f r e q u e n c y, a n d l e v e l s m a y n o t b e b a c t e -r ioc ida l , o r even bac te r ios t a t i c , fo r some bac te r i a(as i s the case fo r mos t an t ib io t i c s ) . Van Guntene t a l fou nd top ica l adm in i s t r a t ion o f 0 .3 o f loxa -c in d r o p s t o a c h ie v e m e a n a q u e o u s h u m o r c o n-c e n t r a t i o n s i n p a t i e n t s u n d e rg o i n g c a t a r a c t s u r -g e r y t o b e 0 . 5 3 - 0 . 6 3 m g / 1 , d e p e n d i n g o n t h es c h e d u l e o f d r o p a d m i n i s t r a t i o n . 13~ T h e s e a r el ev e ls a p p r o a c h i n g t h e M I C 9 0 f o r m a n y o c u l a rp a t h o g en s . l~ B o u c h a r d e t al , u s i n g d i f fe r e n t a d -m i n i s t r a t i o n s c h e d u l e s o f 0 . 3 o f l o x a c in d r o p s ,f o u n d m e a n a q u e o u s h u m o r c o n c e n t r a t io n s o f0 .586 rag /1 in pa t i en t s wh ose l a s t d r op was 30-6 0min u tes p r io r to ca ta rac t su rge ry , and 1 .053 rag /1w h e n t h e l a st d r o p w a s 6 1 - 1 40 m i n u t e s p r e o p e r -a t ive .T D o n n e n f e l d e t a l c o m p a r e d t h e a q u e o u sh u m o r c o n c e n t r a t i o n o f o f l o x ac i n , n o r f l o x a c i n ,a n d c i p r o f l o x a c i n in 3 2 p a t i e n t s u n d e rg o i n gc a t a r a c t s u rg e r y a n d f o u n d o f l o x a c i n t o p e n e -t r a t e in to the aq ueo us a t a s t a ti s ti ca lly s ign if i can tg r e a t e r a m o u n t t h a n n o r f l o x a c i n a n d c i p r o f l o x a -c in , w h i c h w e r e c o m p a r a b l e . 36 T h e a u t h o r s u s e da n i n f r e q u e n t d r o p a d m i n i s t r a t i o n s c h e d u l e o f

t w o d r o p s 9 0 a n d 3 0 m i n u t e s p r e o p e r a t i v e l y,a n d a q u e o u s h u m o r l ev e ls w e r e c o n s i d e r a b lyl o w e r t h a n i n t h e s t u d ie s n o t e d a b o v e : o f l o x a c inmean 0 .338 rag /1 ( r ange 0 .078-0 .625) , c ip ro f lox-a c i n m e a n 0 . 0 7 2 m g / 1 ( r a n g e 0 . 0 2 - 0 . 1 5 3 ) , n o r -f loxac in mean 0 .057 mg/1 ( r ange 0 .046-0 .10) .O ' B r i e n e t al c o m p a r e d t h e a q u e o u s h u m o r p e n -e t r a t i o n o f o f l o x a c in a n d c i p r o f l o x a c in i n r a b -b i ts a f t e r s i n g l e - d r o p a d m i n i s t r a t io n a n d f o u n ds i g ni f ic a n tl y h i g h e r a q u e o u s h u m o r l e ve l s o fo f l o x a c i n c o m p a r e d t o c i p r o f l o x a c i n w h e n t h ec o r n e a l e p i t h e l i u m w a s i n ta c t , a n d c o m p a r a b l e

l e ve ls w h e n 8 m m d i a m e t e r c o r n e a l e p i t h e l ia ld e f e c t s w e r e c r e a t e d b e f o r e d r o p a d m i n i s t r a -tio n.1 03 A q u e o u s h u m o r p e n e t r a t i o n o f n o rf l o x a -c in was s tud ied by Huber-Sp i t z e t a l , a l so inp a t i e n t s u n d e rg o i n g c a t a r a c t s u rg e r y. 6~A d m i n i s -t r a t i o n o f 0 . 3 n o r f l o x a c i n o n c e , 3 0 m i n u t e s t of iv e h o u r s p r e o p e r a t i v e l y i n 2 8 p a t i e n t s r e s u l t e din me an aqu eou s l eve l s o f 0 .255_+0 .249 mg/1( r a n g e 0 . 0 6 2 - 0 . 8 3 8 ) . W h e n d r o p s w e r e g i v e n2 - 5 t i m e s p r e o p e r a t i v e l y a t h a l f h o u r i n t e rv a l su p t o 1/2 h o u r b e f o r e s u rg e r y, m e a n a q u e o u s l ev -e l s r an ged f rom 0 .072 -+ 0 .054 to 0 .660 -+ 0 .378rag /1 . S imi la r l imi ted an te r io r segment pene t ra -


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490 Surv Op hthalm ol 39 (6) May -June 1995 STA RR

tion o f norf loxac in was re po r te d by Oishi e t a l. 104We a r e a w a r e o f o n ly o n e s t u d y o f a q u e o u s p e n e -t r a t ion by f luoroq u ino lo nes a f t e r subcon junc t i -va l in j ec tion . Af te r pe r i l imba l in j ec t ion o f 1 mg o fc i p r o f l o x a c i n i n r a b b i t s , B e h r e n s - B a u m a n n a n d

M a r t e lP (s f o u n d m e a n a q u e o u s h u m o r l ev e ls o f0 .887 rag /1 a f t e r one hour.F luoroqu ino lones a l so ach ieve super io r in t r a -

o c u l a r p e n e t r a t i o n a f t e r p a r e n t e r a l , a n d e v e no r a l a d m i n i s t r a ti o n , c o m p a r e d t o m o s t p r e v io u s -ly avai lable ant ibiot ics . In fact , levels in the poste-r i o r s e g m e n t h a v e b e e n h i g h e n o u g h t o s u g g e s tt h e s e r o u t e s o f a d m i n i s t r a ti o n i n t h e t r e a t m e n t o fe n d o p h t h a l m i t i s . Va n G u n t e n e t al f o u n d m e a na q u e o u s h u m o r l e ve ls o f o f l ox a c i n tw o h o u r sa f t e r 2 0 0 m g b y m o u t h a n d i n t r a v e n o u s l y o f 0 . 38mg/1 an d 0 .33 mg/1, respect ively. ~~ Lesk e t a l ad-min i s t e re d 750 mg c ip ro f loxac in 17 .5 and 5 .5h o u r s p r e o p e r a t i v e l y i n 4 0 p a t i e n t s a n d f o u n dme an aqu eou s hu m or l eve ls o f 0 .53 _+ 0 .25 mg/1and me an vi t reo us levels of 0 .51 -+ 0 .35 mg/1. ~~E1 Baba e t a l admin i s t e red a s ing le o ra l dose o f7 5 0 m g c i p r o f lo x a c i n 5 - 1 7 h o u r s p r e o p e r a t i v e l ya n d f o u n d a m e a n v i t re o u s c o n c e n t r a t i o n o f 0 . 28mg/1 . 37 Even h ighe r aqu eous and v i t r eous l eve l sh a v e b e e n r e p o r t e d i n h u m a n s w i t h o r a l s p a r -f loxac in , a new er th i rd genera t ion f lu oroqu ino -lone. 18b Kow alski e t a l hav e obs erv ed that suchin t raocu la r c ip ro f loxac in l eve l s a re ade qua te tot r ea t on ly 60 o f the i r ocu la r bac te ri a l i so la te s inv i t ro , and tha t such v i t r eous l eve l s , a l thoughh igher than mos t o the r an t ib io t i c s a f t e r sys temicadmin i s t r a t ion , a re too incons i s t en t ly e ffec t iveto be r e l i ed upon fo r endoph tha lmi t i s t r ea t -men t . 7~ Th ese au tho rs a l so b r i e f ly com m en tedon the o ra l adm in i s t r a t ion o f c ip ro f loxac in fo rendo ph tha lmi t i s p rophy la x i s . Th ey fe l t t ha t al -thou gh 60 o f cases o f pos top era t ive in fec t ionm i g h t b e p r e v e n t e d b y r o u t i n e o r a l a d m i n i s t r a -t ion o fc ip ro f loxac in , the cos t -benef i t r a t io migh tno t be f avorab le in us ing such expens ive an t ib i -o t i c s fo r the ve ry in f requen t compl ica t ion o f

p o s t o p e r a t i v e e n d o p h t h a l m i t i s . M c D e r m o t t e t a lf o u n d e x c e l l e n t i n t r a s t r o m a l c o r n e a l p e n e t r a -t ion o f 0 .3 c ip ro f loxac in d ro ps in 12 hu m anp a t i e n t s u n d e rg o i n g p e n e t r a t i n g k e r a t o p l a s t ywith in tact c orne al e pi the l ium pre ope rat iv ely. 9-~M e a n i n t r a s t r o m a l c i p r o f l o x a c i n c o n c e n t r a t i o nwas 5 .25 _+ 3.4 gg/g t i ssue af ter drop s we re givene v e r y 1 5 m i n u t e s f o r o n e h o u r, t h e n h o u r l y f o r1 0 h o u r s p r e o p e r a t i v e l y.

The ab i l i ty to r educe ocu la r f lo ra wi th top ica lf l u o r o q u i n o l o n e a d m i n i s tr a t i o n i n h u m a n s h a sbeen eva lua ted fo r o f loxac in . King e t a l found as ign if i can t r educ t io n in the inc idence o f pos i t ive

a n t e r i o r c h a m b e r c u l t u r e s a f t e r c a t a ra c t s u rg e r ycompared to a h i s to r i ca l con t ro l g roup g ivenpreo pera t ive gen tamic in , v~ Nin e teen pa t i en t s r e -ce ived 0 .3 o f loxac in d rop s eve ry f ive minu tesfo r f ive doses , a t va r i ab le t imes 30 to 140 minu tesp r io r to su rge ry. On e o f 19 pa t i en t s o r 5 .3 hada pos i t ive cu l tu re com par ed to 43 o f pa t i en t sw h o r e c e i v e d p r e o p e r a t i v e g e n t a m i c i n d r o p s .J a c k s o n e t a l c o n d u c t e d a s t u d y c o m p a r i n g 0 .3of loxac in d rops wi th a concur ren t g roup rece iv -i n g t o b r a m y c i n d r o p s a n d c u l t u r e d t h e l i d s a n dc o n j u n c t i v a e , r a t h e r t h a n a q u e o u s h u m o r, i n 4 9pa t i en t s . 6v Th e au th ors fou nd the an t ib io t i c sequal ly eff icacious in s ter i l iz ing the ocular ad-nex ae . S ix o f 49 pa t i en t s had pos i t ive con junc t i -v a l c u l t u r e s i n th e t w o t r e a t m e n t g r o u p s c o m -b ined . Te n o f 26 pa t i en t s (38 ) had nega t ive lidand con junc t iva l cu l tu res p reopera t ive ly a f t e ro f loxac in t r ea tm en t , com par ed to 10 o f 23 pa -t i en ts (43 ) t r ea ted wi th tobram yc in , r e in fo rc ingthe o f t en -made obse rva t ion tha t s t e r i l i z ing theocu la r su r face p reo pera t ive ly wi th any cons is t en -cy is extre m ely di ff icul t , s3 At be st , infe ct ion pro-phy lax i s is p rac t ica l ly me an t to min imize the bac -t e r i a l l oad tha t may ga in access to the in t r aocu la rs p a c e d u r i n g s u rg e r y. F l u o r o q u i n o l o n e s h a v en o t y e t b e e n t e s t e d w i t h r e g a r d t o p r e v e n t i n gendo ph tha lmi t i s in hum ans , a l though the avai l-ab le l abora to ry an d c l in ica l da ta s t rong ly sugges ttha t bas ed o n the i r e ff icacy in o the r se t tings ,these agen t s shou ld a l so be e ffec t ive a s p rophy-lac tic to pic al ag en ts . 54'9


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be used fo r h igh- r i sk pa t i en t s - pa t i en t s wi thv i s i o n i n o n l y o n e e y e , p a t i e n t s w h o h a v e h a de n d o p h t h a l m i t i s i n th e f e l lo w e y e , a n d p a t i e n t sw h o a r e i m m u n o s u p p r e s s e d o r o t he r w i s e a t h i g hr i sk fo r deve lop ing me th ic i l l in - res i s t an t s t aphy-

lococca l in fec t ion , such as pe r s ons in nur s ingh o m e s . I n d i s c r i m i n a t e u s e o f t h e s e p o w e r f u la n t i b i o t i c s c o u l d h a v e u n c e r t a i n c o n s e q u e n c e sf o r t h e w e l l - b e i n g o f p a t i e n ts .

T h e E f f e ct o f P r o p h y l a c t i c n t i b io t i cso n t h e I n c i d e n c e o f E n d o p h t h a l m i t i s

T O P I C A L A N T I B I O T I C S A N D C O L L A G E N

S H I E L D S

A l i e n a n d M a n g i a r a c i n e 4 c o m p a r e d t h e i nc i-d e n c e o f p o s t - c a t a r a c t e n d o p h t h a l m i t i s w i t h a n dw i t h o u t t h e u s e o f p r o p h y l a c t i c t o p ic a l a n t ib i o t-ic s. O f 6 00 o p e r a t i o n s p e r f o r m e d w i t h o u t p r e -o p e r a t i v e p r o p h y l a x i s , p o s t o p e r a t i v e i n f e c t i o no c c u r r e d i n fi v e ( 0 .7 5 % ) . A m o n g 1 9 , 34 0 p a -t i e n t s r e c e i v i n g v a r i o u s p r e o p e r a t i v e a n t i b i o t i cr e g i m e s , 1 7 p o s t o p e r a t i v e i n f e c ti o n s o c c u r r e d( 0 .0 8 % ) , su g g e s t i n g t h a t t h e p r e o p e r a t i v e u s e o ft o p i c a l a n ti b io t i c s r e d u c e s t h e i n c i d e n c e o f p o st -o p e r a t i v e e n d o p h t h a l m i t i s .

A d m i n i s t r a t io n o f t o p ic a l a n t ib i o ti c s p r e o p e r -a t ive ly i s in t e nde d to r ed uc e the loca l ocu la r f lo rab e f o r e s u rg e r y a n d t h e r e b y d e c r e a s e t h e i n c i -den ce o f in fec t ions de r ive d f rom th is source . Giv -en su ff i c i en t ly f r e qu en t dos in g o f top ica l an t ib io t -i c s , a q u e o u s h u m o r a n t i b i o t i c c o n c e n t r a t i o n sm a y b e b a c t e r i o s ta t i c o r e v e n b a c t e r i c i d a l f o r o r -g a n i s m s t h a t g a i n a c c es s t o t h e a n t e r i o r c h a m b e rdu r i ng the pr oc ed ur e . 18'3s'79

In ge nera l , h igh e r an t ib io t i c l eve ls in thea q u e o u s h u m o r, a c h i e v i n g m o r e c o n s i s t e n t b a c -t e r i c i d a l c o n c e n t r a t i o n s , a r e o b t a i n e d w i t h s u b -c o n j u n c t iv a l a d m i n i s t r a t i o n , p r o m p t i n g t h e u s eo f t h is r o u t e i n p r e f e r e n c e t o th e t o p i c a l r o u t e b yso m e clin ician s. ~5.79A s d i s c u s se d b e l o w, h o w e v e r,po ten t i a l adv er se e ffec t s a s soc ia t ed wi th the sub-

c o n j u n c t i v a l r o u t e s h o u l d i n it i at e a r e e v a l u a t i o no f t h e r i s k - b e n e f i t r a t i o o f s u b c o n j u n c t i v a l p r o -p h y l a x is . ( C o m p l i c a t io n s s e e n t o d a y a r e d i f f e r e n tf r o m t h o s e c o n s i d e r e d i n t h e c o n t r o v e r s y r a i s e ds e v e r a l d e c a d e s a g o . )

A n t i b i o t i c - s o a k e d c o l l a g e n s h i e l d s h a v e b e e ni n v e s t i g a t e d a s a d r u g d e l i v e r y d e v i c e w h i c h m a yb e c o m e a n a l t e r n a t i v e t o s u b c o n j u n c t i v a l i n j e c -t i o n a n d d r o p a d m i n i s t r a t io n , w i t h o u t s o m e o ra l l o f the i r po ten t i a l adv er se e ffec ts . An a n t ib io t -i c - s o a k e d c o ll a g e n s h i e ld p l a c e d o n t h e e y e p r e -o p e r a t iv e l y a n d r e m o v e d i m m e d i a t e l y b e f o r es u rg e r y, o r p l a c e d a t t h e c o n c l u s i o n o f s u rg e r y

m a y e n h a n c e a n t i b i o t ic p e n e t r a t i o n i n t o t h ea q u e o u s b y a c t in g a s a d r u g r e s e r v o i r p r o v i d i n g ac o n s t a n t r e l e a s e o f a n t ib i o ti c , r a t h e r t h a n t h ep u l s e d t y p e o f d r u g r e l e a s e a c h i e v e d w i th d r o p sand subcon junc t iva l in j ec t ion . In r abb i t s , co l l a -gen sh ie ld an t ib io t i c de l ive ry has genera l lya c h i e v e d l e v e l s c o m p a r a b l e t o , o r i n s o m e i n -s t a n c e s g r e a t e r t h a n , l e v e l s a c h i e v e d b y t h e s eot he r tw o m et ho ds of ad m ini str ati on . -~'95'111'114Although co l l agen sh ie lds theore t i ca l ly p rov ide ar e s e r v o i r o f a n t ib i o ti c w h i c h m a y b e s l ow l y re -l eased to the p reo cu la r t ea r f ilm , the ac tua l k ine t -i cs o f the i r d ru g re l ease ind ica te tha t th i s va r i e sand i s spec if i c fo r the d r ug in ques t ion . Gen tami -c in a n d a m p h o t e r i c i n B , f o r e x a m p l e , a r e r e -lea sed rap idl y in a pu lse d fas hio n, 9 ~'114whi le van-c o m y c i n a n d d e x a m e t h a s o n e a r e r e le a s e d m o r es lowly wi th mo re subs tan t i a l i n t r acorn ea l l eve lsof va nco my cin co m pa re d to genta mic in . 55'9~'j~1Col lagen sh ie ld an t ib io t i c de l ive ry has a l so beens t u d ie d i n h u m a n s u n d e r g o i n g c a t ar a c t s u r g e rya n d i n o n e s t u d y a p p e a r e d t o b e w e l l t o l e r a t e d ,a l tho ugh an t ib io t i c de l ive ry to the an te r io r seg -me nt was n o t s tud ied . ~t2 Co l l age n sh ie ld an t ib i -o t i c de l ive ry o ffe r s a conven ience no t poss ib lew i t h d r o p s , a n d a m a rg i n o f s a f et y n o t o b t a i n a b l ewi th subcon junc t iva l in j ec t ions , a t l eas t f rom thes t a n d p o i n t o f i n a d v e r t e n t i n t r a o c u l a r p e n e t r a -t i on o f a n e e d l e . T h e r e is so m e q u e s t i o n , h o w e v -e r, o f an t ib io ti c tox ic ity wi th co l l agen sh ie lds un-

de r ce r t a in cond i t ions , such as co rnea l ep i the l i a ld e f e c t s a n d p o o r l y c l o s e d i n c is io n s w h i c h m a ysuff i c ien t ly enh anc e an t ib io t i c pen e t ra t ion to po-t en t i a l ly endo the l i a l t ox ic l eve l s . Nonsu tu redsc le ra l tunne l o r c l ea r co rnea l ca ta rac t inc i s ions(as we l l a s t r ad i t iona l ly su tu red inc i s ions whichd o n o t a c h ie v e th e i n t e n d e d d e g r e e o f w o u n dc losure ) mig h t p e rm i t d i r ec t access o f an t ib io ti c st o t h e a n t e r i o r c h a m b e r a t c o n c e n t r a t i o n s i n-t e n d e d o n l y f o r t h e o c u l a r s u r f a c e .

C e r t a i n a n t i m i c r o b i a ls , w h e t h e r a l o n e , s u c h a scefazol in , 7(~ or in co m bin at io n wi th oth er me di-

c a t i o n s , s u c h a s g e n t a m i c i n a n d m e t h y l p r e d -nisolon e, 7~ cefazol in an d gen tam icin , 1~ an dv a n c o m y c i n a n d c e f t az i d in e , 44 h a v e f o r m e d p r e -c ip i t a te s in so lu t ion o r on co l l agen sh ie lds , wh ichm a y b e s o u r c e s o f t o xi c it y to t h e u n d e r l y i n g c o r -n e a l e p i t h e l iu m . S i m i la r c o n s i d e r a t i o n s a p p l y t ocon tac t l enses soaked wi th an t ib io t i c combina -t ions shown to p rec ip i t a t e on the l enses , such asc i p ro f l ox a c in a n d p r e d n i s o n e p h o s p h a t e a n da c e t a te , s7 C o m p l e x e s o f n o n s o l u b i l iz e d d r u gcom bina t ion s on an d in the sh ie ld a lso r a i se ques -t ions o f b ioava i l ab il i ty o f each d ru g , in add i t io nto mechan ica l and b iochemica l tox ic i ty, and


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492 Surv Ophthalmol 39 (6) May-June 1995 STARR

avoidance of such physically interacting drugcombinations is another consideration in devel-oping collagen shield antibiotic delivery into asafe and effective technique that could be em-ployed widely. Until more clinical data on use inhumans is available, collagen shields should beused with some caution.

S U B C O N J U N C T I V L N T I B I O T I C S

Since the last review of this topic, p-'4 intraoc ula rbioavailability of recently developed antibioticsafter subconjunctival injection has been studi ed.Barza et al injected the newer third generationcephalospor ins ceftizoxime, ceftriaxone, and cef-tazidime , each 100 mg subcon junctiva lly in rab-bits and foun d vitreous levels insufficient to treatmany types o f bacterial endophthalmit is (range3-13 mg/1), even at the slightly highe r levelsfou nd in i nf am ed eyes (range 12-34 mg/1). 4 M-though the levels were comparable to those ofpreviously studied first and second generationcephalosporins, after intravitreal injection theintravitreal half-life was longer for the third gen-eration antibiotics. Barza et al also studied theintravitreal penet rati on o f ceftriaxone (125 mg),ceftazidime (I00 mg), and vancomycin (25 mg)after subconjunctiva l injection in hu ma n eyes. 14Vitreous levels were undetectable in nonin-flamed eyes. Similarly, Rubinstein et al foundmeasurabl e levels o f cefotaxime in h uma n vitre-

ous after subconjunctival injection only in pre-viously opera ted eyes. ~12~ Finally, in the onlystudy we are aware of which investigated the in-traocular penetr ation of subconjunctivally admin-istered fluoroquinolones, Behrens-Baumann andMartell ~6 found mean ciprofloxacin aqueous hu-mor levels of 0.887 mg/1 and 0.094 mg/1 one and 10hours, respectively, after perilimbal injection of 1mg in rabbits, and lower levels after inferior for-nix injection , 0.0267 a nd 0.025 mg/1. A subcon-junctival injection of antibiotics may achieve evenhigher inhibitory or bactericidal aqueous h umor

levels for short periods postoperatively thantopically administered antibiotics, and maythereby decrease the incidence ofendop hthalm i-tis. Since several authors have shown a signifi-cant incidence of contamin ation of corneoscleralincisions and aqueous humor at the end of sur-gery,~ 1,12,22,33,42,78 even short- lived intrao cu lar lev-els of antibiotics might be expected to show someeffectiveness in this regard. This point of viewwas lent some s uppor t by Burns, m who showedthat one subconjunctival injection of 20 mg ofgentamicin at the time of cataract extraction wasnearly as effective in lowering the 48-hour post-

operative bacterial counts as gentamicin dropsor ointment instilled once daily at the time ofdressing changes.

The efficacy and satiety ofsubconjunctival anti-biotics in the prevention of postoperative en-dophthalmitis are controversial. A study byKolker et a172 showed t hat when pencici llin G wasadmini stere d subconjunctivally at the end of sur-gery to 480 patients, only one case of endoph-thalmitis occurred, whereas seven cases occur redin 494 patients who did not receive antibiotics.However, in a large series of over 54,000 casesfrom India and Pakistan in which all patientswere given antibiotics preoperatively, Christyand Lall -'7 foun d no decrease in endopht halmit isin patients who had been given antibiotics sub-conjunctivally compar ed with those who hadnot. A subsequent smaller series by Christy andSommer, 2~ fou nd the combination of topical andsubconjunctival antibiotics in 23,900 patients tobe more effective in reducing postoperative in-fection than different topical antibiotics givenalone; this study included some of the patientsstud ied previously by Chris ty an d Lall. 27

Recent cases of macular infarction after cata-ract surgery have been attributed to inadvertentintraocular antibiotic injections occurring dur-ing subconjunctival prophylactic injections, lead-ing to the suggestion that this route of prophy-laxis is too dangerous to be continued. 23 The

observation o f external ocular fluids gaining ac-cess to the anter ior ch amber with sutureless cor-neoscleral incisions presents another possibleroute by which subconjunctivally injected anti-biotics mi ght reach toxic intr aocula r levels) 9This theoretical possibility awaits clinical con-firmation.

I N T R O C U L R N T I B I O T I C S

Clinical use of intraocu lar antibiotics for pro-phylaxis of infection dates back at least 23 years,but has always been tempered by concerns of

intraocular antibiotic toxicity. Chalkley andShoch discontinued their clinical study of intra-cameral instillation of polymyxin B and neomy-cin because of corneal e ndotheli al toxicity. ~5 Pey-man et al found that patients who receivedintra ocular instillation ofgent amic in 50 btg in 0.2cc dilutent at the conclusion of cataract surgeryhad a lower incidence of infection than patientswho received topical and oral chloramphenicolprophylaxis in eye camps of Southern India (in-fection incidence 0.37% versus 2.9% respective-ly).ll0 The different locations of each treatmentgroup is a notable aspect of this study that may


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d e t r a c t f r o m t h e c o m p a r a b i l i t y o f t r e a t m e n t r e -g i m e s a n d t h e i r r e s p e c t i v e e ff ic a c ie s ; n o m e n t i o no f i n t r a o c u l a r a n t ib i o t ic t o x ic i ty w a s m a d e b y t h ea u t h o r s .

T h e i n t r a o c u l a r u s e o f a n t ib i o ti c s i n t h e i n fu -s i o n f l u id s o f v i t re c t o m y, p h a c o e m u l s i f ic a t i o n ,a n d i r r i g a t i o n - a s p i ra t i o n m a c h i n e s , h a s b e e ns tud ied exp er im en ta l ly a nd c l inica lly in a f ew in-s t ances . Tox ic i ty s tud ies in r abb i t s have beenc o n d u c t e d f o r a n u m b e r o f a n t ib i o ti c s i n vi tr e c -t o m y in f u s i o n fl u id s , u si n g p r e d o m i n a n t l y n o r -m a l e l e c t r o r e t i n o g r a p h y ( E R G ) a s t h e c r i t e r i o no f s a fe t y, a l t h o u g h m o s t a u t h o r s n o t e t h a t i n ra b -b i ts , a n o r m a l E R G i s s o m e t i m e s p r e s e n t w i t hh i s t o p a t h o l o g i c e v i d e n c e o f f o c a l d a m a g e t o th ere t ina . I n these s tud ies , t he doses found tox ica f t e r v i t r e c t o m y w e r e o f t e n l o w e r t h a n t h o s ef o u n d n o n t o x i c w h e n i n s t i l l e d i n t o t h e v i t r e o u swi th ou t v i t r ec tom y, poss ib ly a s a r e su l t o f d i ffu -s i o n t o t h e r e t i n a i n h i g h e r d o s e s a f t e r v i t r e o u sr e m o v a l . P e y m a n e t a l 1~ f o u n d g e n t a m i c i n s a feb y E R G c r i t e ri a a t a d o s e o f 8 .0 g g / m l , a n d n o t a -b l y o b s e r v e d t h a t s u c h p r o p h y l a c t i c u s e o f an t ib i -o t i c s i s r e c o m m e n d e d o n l y i n c a s e s w h e r e c o n -tam ina t ion by bac ter ia is pro ba ble . S ta ine r e t a l ~2:~f o u n d t h e f o l l o w i n g d o s e s o f a nt i b io t ic s n o n t o x i cby ERG c r i t e r i a fo r v i t r ec tomy in r abb i t s : ch lo r-amphen ico l 20 gg /ml , amikac in 10 p tg /ml , tob ra -myc in 10 ~tg /ml , and c l indam yc in 10 ~tg/ml. Th ea u t h o r s a l so n o t e d t h e d i s c r e p a n c y t h a t m a y oc -

c u r b e t w e e n E R G a n d h i s t o p a t h o l o g i c a l e v i -d e n c e o f t o x ic i t y a n d s u g g e s t e d t h a t d o s e s o f 5[~g /ml o f the an t ib io t ic s t e s t ed m igh t p ro v ide am a r g i n o f s a fe t y b y b o t h t y p e s o f c r i te r ia . C a z e a ue t a123 fou nd no ER G cha nges in r abb i t s w i thv i t r ec tom y in fus ion f lu id con ta in ing me th ic i l l ino r l incomyc in up to 50 gg /ml , o r oxac i l l in up to2 0 p g / m l; t h e a u t h o r s a l so l o o k e d f o r h i s t o p a t h o -l o gi c e v i d e n c e o f t o x ic i t y a n d f o u n d n o n e a tdoses o f 10 gg /ml fo r these th ree an t ib io t i c s . In as i m i l a r s t u d y u s i n g v i t r e c t o m i z e d r a b b i t s , M o r-gan e t a l vs fou nd no tox ic i ty by ER G c r i t e r i a on ly,

w h e n g e n t a m i c i n 8 ~ t g/ m l, w a s c o m b i n e d w i t ho n e o f t h e f o l lo w i n g i n t h e v i t r e c t o m y i n f u s io nf luid: methic i l l in 25 gg/ml , oxac i l l in 10 gg/ml ,an d c l ind am ycin 10 ~tg/mg.

T h e e x t r a p o l a t i o n o f t h e s e s t u d ie s i n r a b b it s t oc li ni ca l u s e in h u m a n s u n d e rg o i n g v i t r e c t o m yh a s b e e n m o s t f r e q u e n tl y u n d e r t a k e n i n t h et r e a t m e n t o f s u s p e c t e d o r e s t a b l i s h e d in t r a o c u l a rin fec t ion , pa r t i cu la r ly in ins t ances o f pen e t ra t ingt r a u m a w h e r e t h e r i s k o f i n f e c ti o n i s c o n s i d e r a b l ea n d t h e c o n s e q u e n c e s o f i n f e c ti o n a r e o f t e n d e v -astat ing.~~ Bec ause o f the r i sks o f ex t ra po la t inga n i m a l t o h u m a n s a f et y d a t a , a n d t h e p a u c i t y o f

h u m a n s t u d ie s , p r o p h y l a c t i c u s e o f v i t r e c t o m yinfus ion f lu ids con ta in ing an t ib io t i c s has no tb e e n t r a d it i o n a ll y u n d e r t a k e n e x c e p t , a g a i n , ini n s ta n c e s o f p e n e t r a t i n g o c u l a r tr a u m a . P e y m a nh a s a d v o c a t e d p r o p h y l a c t i c u s e i n s u c h i n s t a n c esw h e n s u rg i ca l r e p a i r o f th e p e n e t r a t i n g t r a u m an e c e s s i t a t e s v i t r e c t o m y o r l e n s e c t o m y, e v e nwhen in fec t ion i s no t suspec ted a t the in i t i a l su r-g e r y, H~s a n d m o r e r e c e n t l y P e y m a n a n d D a u mh a v e a d v o c a t e d t hi s r o u t e f o r v i t r e c t o m y d o n ef o r i n d i c a ti o n s o t h e r t h a n p e n e t r a t i n g t r a u -ma . 10a, Th e rou t ine use o f in fus ion f lu id an t ib io t -i cs fo r p roph y lax i s in v i t r ec tom y fo r such ind ica -t ions , eve n i f e ffec t ive , r a i ses a s ye t un ad dre sse dques t ions abou t r i sk -benef i t r a t io , g iven the lowi n c i d e n c e o f p o s t - v i t r e c t o m y e n d o p h t h a l m i t i s f o rn o n t r a u m a t i c i n d i c a t io n s ( 0. 05 i n o n e s t u d y ) ] ~

Th e p rop hy lac t i c use o f an t ib io ti c s in ir r iga t -i n g f l u i d s i n a n t e r i o r s e g m e n t s u rg e r y h a s b e e ns u g g e s t e d b y G i l l s) ~ H e r e p o r t e d o n e i n f e c ti o n i n20 ,000 ca ta rac t cases in which ge n tam ic in 8gg /ml was used , one in fec t ion in 9928 us ing van-comyc in 20 gg /ml , and no in fec t ions in 25 ,000cases us ing bo th an t ib io t i c s . Th e au t ho r a l so sug-ges ted use o f a f il t e r fo r al l i r r iga t ing f lu ids , bu tp r o v i d e d n o f u r t h e r d e t a il s as to t h e t y p e u s e d i nth is s tudy. In a su bse que n t s tud y, H en ry e t a l 5~s tud ie d the e ffec t o f i r r iga t ing f lu id gen tamic ino n t h e i n c i d e n c e o f po s i ti v e c u lt u r e s f r o m t h ea q u e o u s h u m o r i n p a t ie n t s u n d e r g o i n g p h a c o e -

muls i f i ca t ion wi th in t r aocu la r l ens implan ta t ion .T h e a u t h o r s u s e d g e n t a m i c i n 8 gg / m l, i n c h i ll e dand unch i l l ed i r r iga t ion f lu id , a s we l l a s ir r iga -t ion f lu id wi thou t gen tamic in , ch i l l ed and un-ch i l led , in 200 pa t i en t s , a nd fou nd no s t a t is t ica l lys ign i f ican t d i ff e re nce in the inc idenc e o f pos i t ivea q u e o u s h u m o r c u l t u r e s i n t h e f o u r t r e a t m e n tg roups ( r e spec t ive ly,2 , 0 , 4 , an d 6 posi -t ive cu l tu res ) . Th e a u tho rs no te d a h igh inc i -d e n c e o f p o s i ti v e c o n j u n c ti v a l c u l t u r e s p r e o p e r -a t ive ly, ( r ange 80 -88 ) in the fou r g rou ps , and al o w in c i d e n c e o f p os i ti v e a q u e o u s c u l t u r e s, c o m -

p a r e d t o s i m i l a r p r e v i o u s l y p u b l i s h e d s t u d i e s ,e v e n i n t h e g r o u p s t r e a t e d w i t h o u t i n f u s io n f l u idantibio tics.~ ,J 1,22,34,41,78,117 T h is la st s tu d y ra is es aq u e s t i o n a b o u t t h e a d v a n t a g e o f i n f u s io n f l u idan t ib io t i c s fo r p rophy lax i s in rou t ine , noncon-t a m i n a t e d i n t r a o c u l a r s u rg e r y.

T h e r e is a p a u c i t y o f d a t a r e g a r d i n g t o x ic i tys t u d ie s i n h u m a n s . I n a f e w a n e c d o t a l r e p o r t s ,s ignif icant toxic i ty was not ob se rv ed 34a'5~ an da g r e e m e n t o n s a f e a n d e f f ec t iv e d o s i n g f o r s o m eant ibiot ics is lacking. ~27a In a m or e exte nsiv es tudy by W ood e t a l 1a5 108 consecu t ive pene t ra t -i n g k e r a t o p l a s t y p a t i e n t s r e c e i v e d i n t r a o c u l a r


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494 Surv Oph thalm ol 39 (6) May -June 1995 STA RR

van com ycin 1000 ,ug/ml in bala nce d sal t solut ion,as bo th an i r r iga t ion f lu id dur in g su rge ry and b yins ti l la t ion to f il l t he an te r io r cha mb er a t the con-c lus ion o f su rge ry ; no co rnea l tox ic i ty was no ted .T h e a u t h o r s a l so p e r f o r m e d e l e c t r o n m i c r o s c o p yo n h u m a n c o r n e a s b a t h e d f o r u p t o t w o h o u r s i na vancomy c in so lu t ion o f 1000 btg/ml, and foun dno ev idence o f tox ic i ty. Add i t iona l da ta o n thesafety and eff icacy of th is ro ute of ant ibiot ic del iv-e r y w o u l d b e r e a s s u r i n g b e f o r e w i d e l y e m b r a c -ing th is t echn iq ue o f p roph y lax i s fo r rou t ine in-t r aocu la r su rge ry.

To p ica l n t i s ep t i c s on t heCon junc t iva and Sk in

Per iocu la r sk in p re pa ra t ion wi th an t i sep t i c sh a s l o n g b e e n r e c o g n i z e d a s p a r t o f a s t a n d a r dp r e v e n t i v e a p p r o a c h t o p o s t o p e r a t i v e i n fe c ti o n.M aum ene e and Mick le r 9~ t e s t ed va r ious sk inprep ara t ion s and the i r e ffec ts on l id bac te r i a lco lony coun t s a t t he end o f ocu la r su rge ry. Var-ious combina t ions o f agen t s w ere t e s t ed inc lud-ing sa line , soap , 1 :100 0 t inc tu re o f me r th io la t e ,3 h e x a c h l o r o p h e n e , 1 : 1 0 0 0 ti n c t u re o f z e p h i-ran (benza lko n ium ch lo r ide ) , 3 t inc tu re o f co -d e i n e , a n d 7 0 e t h y l a l c oh o l. T h e a u t h o r s f o u n dthe mos t e ffec t ive com bina t ion to be 3 hexa-ch lo r oph ene , fo l lowed by s te r i le sa l ine r inse andapp l i ca t ion o f 3 .5 iod ine and 70 a l coho l .S ince pub l i ca t ion o f th is pape r, hexach lo ro -

phene has been iden t i f i ed a s a subop t ima l sk ind i s in fec tan t , b ecau se o f it s poor ac t iv i ty aga ins tg ram-nega t ive bac te r i a and i t s po ten t i a l fo rneuro tox ic i ty a f t e r sk in absorp t ion , pa r t i cu la r lyin p re m atu re in fan ts . ~9 S imi lar ly, The od or esubseq uen t ly d r ew a t t en t ion to the l ack o f e ffi ca-cy o f benz a lkon ium ch lo r ide a s a sk in d i s in fec -t an t , pe rh aps in pa r t be cause o f i ts ca r t ion ic ne tcha rge which in te r fe res po ten t i a l ly wi th the an -ion ic cha rge o f soap , which was o f t en used fo rsk in p rep a ra t io n in pas t decades . ~28 T he od or er e c o m m e n d e d u s e o f t in c t ur e o f i o di n e o n t h e

per ioc u la r skin , fo l lowed by 70 a l coho l .Iod ine has been recogn ized as hav ing exce l -l en t an t i sep t i c p roper t i e s , and has been us ed as ad i s in fec tan t s ince 1839. 47 W hen com bine d wi thalcohol as a topical d is infectant , i t s usefulness isl imi ted by the tox ic ity o f a l coho l fo r sk in andmucosa , a l tho ugh fo rmu la t ions o f iod ine in a l co -h o l m a y b e m o r e b a c t e ri c i da l t h a n n o n a l c o h o li csolut ions . 12'~ W he n co m bin ed with the nona nt i -bac te r i a l wa te r so lub le po lymer, pov idone (po ly -v iny l pyr ro l idone) , t he tox ic ity o f a l coho l i savo ide d and sa fe r d i s in fec t ion o f pe r ioc u la r sk ini s poss ib le . 56 M tho ugh usua l ly em ploy ed as a 10

so lu t ion fo r sk in d i s in tec t ion , pov idone iod ineh a s r e c e n t l y b e e n c o m m e r c i a l l y m a r k e t e d a s a5 so lu t ion su i t ab le bo th fo r use on the sk in andfor top ica l con junc t iva l d i s in fec t ion (Be tad ine5 S te r i le Op h tha lm ic P rep So lu t ion Esca lonO p h t h a l m i c s , I n c . a n d T h e P u r d u e F r e d e r i c kCo . ) . Th e 10 so lu t ion is m ore s t ab le than the5 so lu t ion , wi th r e spec t ive exp i ra t ion pe r iod so f th r e e a n d t w o y e a rs ,T b u t u n p u b l i s h e d i nv i t r o s t u d i e s h a v e d e m o n s t r a t e d c o m p a r a b l ean t imic rob ia l e ff icacy fo r bo th con cen t ra t ionsaga ins t S. aureus S . pyogenes P. aeruginosa and N.catarrhalis as de te r m ine d by k il l t imes (W elch JS ,Assoc ia te Di rec to r, Medica l Se rv ices and DrugS u r v e il l an c e , T h e P u r d u e F r e d e r i c k C o : P e r s o n -a l com mun ica t ions , 12 /10/92 and 1 /22/93) . No inv ivo s tud ies d i rec t ly com par i ng the sk in deger m-ing cabab i l it i e s o f the 5 and 10 fo rmu la t ionsh a v e b e e n c o n d u c t e d t o d a t e .

Ano the r sk in d i s in fec tan t fo r genera l su rg ica lsk in p re pa ra t ion wi th h igh ly e ffec tive b ro adspec t rum ac t ion i s t i nc tu re o f ch lo rhex id ine . 119I n a d v e r t e n t c o r n e a l c o n t a c t w i t h c h l o r h e x i d i n eg l u c o n a t e 4 ( H i b i cl e n s u s e d f o r p r e o p e r a t i v efac ia l sk in p repa ra t ion , however, has been re -p o r t e d t o c a u s e s e v e r e c o r n e a l d a m a g e a n ds h o u l d t h e r e f o r e b e a v o i d e d f o r o p h t h a l m i c s u r -ge ry. (Se nsor ineu ra l dea fness a l so occurs i f t h isagen t ga ins access to the midd le ea r th ro ugh ape r fo ra ted tym pan ic membrane) .l -~~ S imi la r co r-

n e a l d a m a g e m a y o c c u r w i t h e x p o s u r e t o p o v i -d o n e i o d i n e c o m b i n e d w i t h d e t e rg e n t s , a n d u s eof the n ond e te rge n t so lu t ion is e s sen t ia l fo r usein oph th a lm ic sk in p repa ra t ion . 86

Di rec t con junc t iva l in s ti l la t ion o f an t i sep t i c sh a s b e e n u s e d f o r m a n y y e a r s w i t h s u c h a g e n t s a s1 : 3 aq ue ou s zep hira n, 9~ s i lver n i t ra te , s i lverp ro te in , and pov ido ne iod ine . 64 Re duc in g theb a c t e r i a l p o p u l a t i o n d e n s i t y o n t h e c o n j u n c t i v ah a s a ls o b e e n a t t e m p t e d w i t h s i m p le m e c h a n i c a li r r iga t ion wi th so lu t ions devo id o f inhe ren t an t i-mic robial ac t iv i ty, such as sa l ine , Ringe r ' s lac ta te ,

o r a b a lance d sa lt so lu t ion . 6a I sen ber g e t a l foundirr igat ion wi th s ter i le sa l ine to actual ly increasethe con junc t iva l bac te r i a l co lony coun t by 18a n d t h e s p e c ie s c o u n t b y 2 3 , c o m p a r e d t o n o n -i r r iga ted eyes , in 40 pa t i en t s unde rgo ing eye su r-g e r y Y I n a n o t h e r s t u d y, t h e s e a u t h o r s f o u n dconju nct iva l ins t i lla t ion of 20 s i lver pro te in so-lu t ion fo l lowed by s t e r i le sa l ine i r r iga t ion to haveno s ta t is t ica lly s ignif icant effect on conju nct iva lc o l o n y a n d s p e c ie s c o u n t s c o m p a r e d t o f e ll o we y e s r e c e iv i n g n o s u c h p r e p a r a t i o n . 64 T h e o d o r eh a d a l so n o t e d m a n y y e a r s p r e v i o u s ly t h a t s i lv e rp ro te in so lu t ion w as a po or an t i sep t i c , bu t tha t i t


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ANTIMICROBIAL PROPHYLAXIS FOR OPHTHALMIC SURGERY 95

was used for its ability to coagulate debris andmucus in the tear film, and thereby helped iden-tify surface contaminants t hat could be ir rigatedfrom the ocular surface. 128 Previous use of silvernitr ate 1 was limited by its irrit ating effect onthe ocular surface and its potential for causingcorneal and conjunctival scarring when used intoo g rea t a c oncent rat ion . 12s Similarly, a 1:3000dilution of aqueous zephiran (benzalkoniumchloride) was foun d too toxic when u sed topical-ly on the conjunctiva, producing excessive hy-peremia. 91

As not ed above, 5 povid one iodine has beenadvoca ted as safe and effective conjunctival anti-sepsis. Apt et al s fou nd that when povidone-iodine was placed in the conjunctival cul-de-sacas part of the preoperative preparation of theeye, the nu mbe r o f bacterial colonies and specieswas reduced as compar ed to the u ntrea ted felloweye. Isenberg et al 6~ com par ed the antibacterialeffect of povidone-iodine admini stered just be-fore surgery with that of a broad-spectr um anti-biotic agent given for three days before surgery.Individually, each regimen caused a similar de-crease in the n umb er of colonies and species cul-tured. T her e was a more striking decrease whenboth agents were u sed in the same eye. Apt et al 9found that a three-day course of a topical antibi-otic was more effective than a three-day courseof povidone-iodine in the reductio n of bacterial

flora when both were followed by a povidone-iodine preparation, again suggesting an im-proved antibacterial effect when the two agentsare used in ta ndem . A repor t by Boes et al I7confirmed povidone-iodine's effect in reducingbacterial recovery, and the authors found thatirriga tion with saline solution after the povidone-iodine preparation had no significant effect onthe composition of bacterial species.

Given its effect on the normal ocular flora,povidone-iodine might be expected to reducethe incidence of postoperative infection. Speak-

er and Menikoff >-~ dem ons tr ate d jus t that. Intheir series they found a lower incidence ofculture-pr oven endophtha lmitis (2 of 3489 cases[0.06 ]) in a suite of oper atin g rooms where thetopical povidone-iodine preparation was usedcompared with a similar suite where a topicalsilver pro tei n solut ion was used (0.24 [11 of4594 cases]).

Garc ia-Fer rer et al 4c~have recently drawn at-tenti on to the potential corneal endothel ial toxic-ity of povidone-iodine and the need to removethis solution by irrigating prior to intraocularsurgery. The clinical relevance of these findings

may be challenged by other studies in which noobservable corneal toxicity was found in clinicalu s e T a s welt as studies that demonstrated in-creased num bers ofconj uncti val bacterial speciesrecovered after sterile saline irrigation withoutconjunctival povidone-iodine preparationY Thisissue has not yet been resolved, however, andthe FDA-approved package insert provided with5 povidone-iodine solution for preoperativeskin and conjunctival preparation recommendsflushing of the solution with sterile saline aftertwo minutes.

C o n s i d e r a t i o n s R e g a r d i n g t h eU s e o f P r o p h y l a x i s

EFFICACY OF PROPHYLAXIS

The prep onde ranc e of evidence shows that theincidence of postoperative en dophthalmi tis is re-duced when antibiotics are used preoperativelycompared with the incidence of infection whenthey are not. Speaker and Menikoffs study sug-gests that the preoperative use of topical povi-done- iodin e also reduces the inc idence of post-opera tive infection. 121 Th e prophylacti c use ofthese agents is suppor ted by evidence that dem-onstrates normal ocular flora as the predomi-nant source of bacteria in postoperative en-dophthalmitis, the high incidence of positiveaqueous cultures at the conclusion ofint raocu larsurgery, and the evidence that demonstrates the

ability of some antibiotics and povidone-iodine to reduc e this flora and to red uce t he inci-dence of positive aqueous culture and intraocu-lar infections. Many other questions have not yetbeen answered with a compelling body of evi-dence. For instance, which antibiotic agent orcombination of antibiotic and antiseptic agentsconstitutes the most effective prophylaxis?Which route of delivery has the best risk-benefitratio? What is the optimal timing and dosage ofprophylaxis? One can find a numb er of answersto each question, depe ndin g on t he study cited in

support of one's viewpoint, yet no one study issufficiently designed or executed to t horou ghlyand convincingly address these issues. The oph-thalmologis t may find some helpf ul data, howev-er, with regard to optimal timing of prophylaxisin the nono phthalmolo gic literature. For exam-ple, a recent study of general surgery patientst~bund that the best time for administration ofantibiotics to preven t wo und infection was in thetwo hours before surgery? 9

The pharmacokinetics of the usual routes ofantibiotic delivery to the eye are such that a two-hour preoperative adminis tration period for eye


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496 Surv Ophthahnol 39 (6) May-June 1995 STARR

surgery should achieve prophylactic efficacycomparable to that reported for general surgery.This awaits the confirmat ion of a clinical study,however. Topical medications can convenientlybe delivered in this two-ho ur time fi'ame (exceptwhen surgery is scheduled for early morning),but subconjunctival antibiotic injections are giv-en most conveniently at the conclusion of sur-gery, not within the recommended two-hourpreoperative period. With current short-actingsedation, amnestic anesthesia and painless localanesthetic administration and surgery, it is im-practical to give snbconjunctival prophylaxis twohours preoperativ ely without sedation; however,it migh t be given effectively at the time that localanesthesia is administered.

Sound arguments have been made againstsubconjunctival injections based on the dangersof inadvertent intraocular injections and retinalantibiotic toxicity. 2a'93 Other argumen ts , less wellsubstantiated but no less worthy of consider-ation, suggest a delayed onset of endophthalmi-tis with a poorer visual outcome when subcon-junctival prophylaxis is used. 25 The studies f romwhich such conclusions may be dra wn were con-ducted in an era when delayed-onset endoph-thalmitis was less well described and recognizedthan it is today. If so, delayed onset and b lunti ngof the severity of signs, if they are in fact morecommon with subconjunctival prophylaxis, may

not currently result in the poorer visual out-comes of an ear lier clinical era. Conversely , topi-cal antibiotics have also been implicated inchanging the typical presentation of postoper-ative infection by possibly selecting for mo re vir-ulent host flora. Orme rod et al I~ f oun d a shorteronset of infection in a retrospective series of60 patients with coagulase negative staphylococ-cal endophthalmitis when antibiotic prophylaxiswas given topically comp ared with patients whoreceived subconjunctival prophylaxis. The au-thors, however, found no difference in visual

outcome in these two groups of patients.The controversy about subconjunctival deliv-ery of prophylaxis is far from resolved. Systemicand intraocular routes of delivery have greaterpotential for severe adverse effects than localroutes. Thu s, these routes, especially the intraoc-ular route, should be carefully studied clinicallyfor each antimicrobial before they are widelyused and consi dered as a community standard ofcare.

The most commonly asked question aboutprophylaxis concerns choice of antibiotic agent.Little, if any, useful and convincing data exists

to make confident statements about antibioticchoices. Well-designed and executed studieswith concurrent prospective comparison of theendoph thal mitis rate with one prophylactic regi-men versus anoth er have not been done. Conclu-sions have been based instead on the effect ofdifferent regimens on ocular flora, and the rela-tionship between this effect and postoperativeinfection is not complet ely clear. For example, ifone antibiotic reduces the colony counts of resi-dent ocular flora by 90 and another by 45 , isthe relative incidence of infection a similar 1 to 2ratio? There are other unanswered questions re-lating to the choice between two antibiotics:Which choice is preferred when the more effec-tive agent is two times more costly, or ten times?What if the more effective agent causes mild butfrequent ocular surface toxicity, or serious butrare systemic toxicity? What if the single mosteffective and least toxic agent is also the mosteffective in treating established infections, butwidespread use is likely to increase resistant bac-terial strains, thus leading to its demise as aneffective agent?

Until these questions are answered, the oph-thalmic surgeon's choices for prophylacti c antibi-otics and antiseptics, and t heir ma nne r of admin-istration, must remai n a matter of individualpreference.

OBJECTIONS TO PROPHYL XIS

Despite the consensus that prophylactic antibi-otics and antiseptics are effective in reducing theincidence of postoperative ophthalmic infec-tions, a numbe r of objections have been raised ascaveats against their use. These include the po-tential for toxic and allergic reactions, alterationof protective normal host flora, inductionof drug resistance amon g microorganisms, andmone tary cost. Some of these have been touc hedon already.

To x i c i t y a n d l l e rg i c R e a c t i o n

The considerat ion of toxicity and allergic reac-tion enters into every physician's routine deci-sion making regarding the use of an antibiotic.Adverse effects, of course, vary with the particu-lar agent chosen for prophylaxis. The toxicityand idiosyncratic reactions related to shorttermuse of currently available topical antibioticswould not, however, be a factor of significantproportion in the calculation of the risk-benefitratio, with the possible exception of chloram-phenicol, which has been reported to be associat-ed with fatal aplast ic anemia. 4~


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A N T I M I C R O B I A L P R O P H Y L A X I S F O R O P H T H A L M I C S U R G ER Y 9 7

R e g a r d i n g s u b c o n j u n c t i v a l p r o p h y l a x i s , t h er is k s o f o c u l a r p e n e t r a t i o n a n d a n t i b i o t ic t o x ic i t yn e e d t o b e s e ri o u s l y c o n s i d e r e d , a s n o t e d a b o v e .S o m e s u r g e o n s h a v e b e g u n u s i n g c o ll a g e ns h i e l d s as a n a l t e r n a t i v e m e a n s o f d e l i v e r i n g i n -t r a o p e r a t i v e a n t i b i o t i c s .

A l t er a t io n o f N o n p a t h o g e n i c O c u l a r F l o ra

T h e p r o t e c ti v e r o l e o f t h e n o r m a l o c u l a r f lo r ah a s b e e n s t r o n g l y s u g g e s t e d , b u t t h e r e i s l i t t l ee v i d e n c e t o s u g g e s t t h a t u s e o f s h o r t t e r m t o p ic a la n t i b io t i c s l e a d s t o c o l o n i z a t i o n b y m o r e v i r u l e n tb a c t e r i a l s t r a i n s . 57 A l t h o u g h t h e s u g g e s t i o n h a sb e e n m a d e t h a t s o m e t o p i c a l a n t i b i o ti c s m a y e n -c o u r a g e t h e g r o w t h o f f u n g i , t h e e v i d e n c e ism e a g e r r e g a r d i n g c o n j u n c t i v a l g r o w t h . P o vi -d o n e - i o d i n e m a y e v e n be c o m p e t e n t a g a i n s ts o m e f u n g i , l:~ Te m p o r a r y s u p p r e s s i o n o f t h er e s i d e n t b a c t e r i a l f l o r a o f t h e l i d s a n d c o n j u n c t i -v a is , a f t e r a ll , t h e a i m o f s h o r t t e r m p r o p h y l a c t i ca n t i b i o t ic u s e , a n d t h e r e is g o o d r e a s o n t o b e l i ev et h a t w h e n s u c h s u p p r e s s i o n is d i s c o n t i n u e d , t h ep r e t r e a t m e n t f l o r a q u i c k l y r e t u r n s , s'~

D e v e l o p m e n t o f R e s i s ta n t O r g a n i s m s

T h e r e a p p e a r s t o b e l it tl e q u e s t i o n t h a t th ep r o l o n g e d a n d e x c e s s iv e u s e o f a n t i b io t i c s p l a y s ar o l e in t h e d e v e l o p m e n t o f r e s i s t a n t b a c te r i a ls t r a ins , 1~ pa r t i cu la r ly in ins t i tu t iona l env i ron -m e n t s w h e r e l a rg e d o s e s o f s y st e m i c a l ly a d m i n i s -

t e r e d m e d i c a t i o n s e x e r t s e l ec t iv e p r e s s u r e o n m i -c r o o rg a n i s m s t o d e v e l o p i n t o a n t i b i o t i c r e s i s t a n ts t ra in s , ls~ A n i m p o r t a n t a n d u n a n s w e r e d q u e s-t i o n , h o w e v e r, is w h e t h e r s h o r t t e r m t o p i c a l ( o rs y s t e m i c) a n t ib i o t ic s c a n c o n t r i b u t e i n a q u a n t i t a -t ive ly s ign i f i can t way to such re s i s t ance . T he e f -f e ct o f s h o r t t e r m p r o p h y l a x i s o n t h e r e s i s ta n c e o fl o ca l o c u l a r f l o r a m a y s e e m u n l i k e l y, as m a y t h ee f f e ct o n g a s t r o i n t e s t i n a l f l o r a . S u c h s m a l l d o s e so f a n t i b io t i c s i n i n d i v i d u a l p a t i e n t s w h e n t a k e nc u m u l a t i v e ly, h o w e v e r , m i g h t c o n c e iv a b l y h a v ea n i m p a c t o n i n s ti t u ti o n a l a n d c o m m u n i t y - w i d e

m i c r o b i a l r e s i s t a n c e t o a s m a l l b u t s i g n i f i c an t e x-t e n t . T h e u s e o f a n t ib i o t ic s , t h e r e f o r e , b e c o m e sn o t j u s t a m a t t e r o f p r e v e n t i n g a p o s t o p e r a t i v ei n f e c t i o n in a g i v e n p a t i e n t , b u t a m a t t e r o f t h ep o t e n t i a l m o r b i d i t y a s s o c i a t e d w i t h i n f e c t i o n i na l l pa t i en t s ) '- ' The re is li t tl e ev iden ce o n th i s top icr e g a r d i n g p r o p h y l a x i s fo r o p h t h a l m i c s u r g e r y,b u t i t w o u l d s e e m p r u d e n t f o r o p h t h a l m i c s u r -g e o n s t o s e r i o u s l y c o n s i d e r t h e i r p r o p h y l a c t i cc h o i c e s i n t h i s c o n t e x t , ss'~ 2~ a n d n o t o f f h a n d e d l yd i s m i s s t h e r e l e v a n c e t o o u r s p e c i a lt y o f a p p e a l st o c a u t i o n i n t h e j u d i c i o u s u s e o f a n ti -biotics.~Sa'Us'~2~

TABLE 2

Prophylactic Antibiotic Costs

Non

Generic Generic

7bpical

Gramicidin-Neomycin-Poly-myx in B (Neosporin 4.34 15.50Trim ethoprim - Polymyxin B

(Polytrim N/A 15.79Gen tamic in (Genoptic | 5.10- 5.63 13.47Tobramy cin (Tobrex N/A 17.25Ofloxacin (Ocuflox N/A 17.50Norfloxacin (Chib roxin N/A 16.42Ciprofloxacin (Ciloxan N/A 19.7524 ho ur collagen shield 20.00 N/A

Subconjunctival and intraocular N/A N/AGe ntam icin 2 ml vial (80 rag) 1.04 N/ATob ramy cin 2 ml vial (80 mg) 6.97- 7.50 N/ACefazolin pow der (500 mg) 1.43- 5.88 N/AVancomycin (500 rag) 7.00 N/A

*Prices are averag e wholesale price (AWP ) as ofMarch, 1994.

**Smallest comm ercially available volum e o feye dro pslisted. Cost to patien t app roxim ately AWP + 5.00.

***One single u se vial sufficient to fo rm ulate m edica-tion for either route of administration. Cost to patientapproxim ately 2 x AWE

NA = No t available.SOURCE: Elaine Daphnis, R.Ph, Director of Pharm a-

cy, M anha ttan Eye, Ear, & Th roa t Hospital , New York,NY, March 1994.

C o s t C o n s i d e r a t io n s

A n o t h e r o b j e c t i o n r a i s e d t o p r o p h y l a c t i c a n t i -b i o t i c s i s b a s e d o n c o s t c o n s i d e r a t i o n s . T h ec h o i c e o f a n t i b i o ti c a n d r o u t e o f d e l i v e r y s h o u l db e m a d e w i t h c o s t e f f e c ti v e n e s s i n m i n d . C o s tm a y e v e n t u a l l y p l a y a s c ru c i a l a ro l e a s a n y o t h e rf a c to r in d e t e r m i n i n g f u t u r e g u i d e l in e s f o r p r o -p h y l a c t i c a n t i b i o ti c u s e , b u t s h o u l d n e v e r o v e r -r i d e p a t i e n t b e n e f i t a s a c o n s i d e r a t i o n . 69 R e p r e -s e n t a t i v e c os t s o f s o m e c u r r e n t l y a v a i l a b lea n t i b i o t i c s a r e s h o w n i n Ta b l e 2 .

ummaryI n a p r i o r r e v i e w o f p r o p h y l a c t i c a n t i b i o t ic u s e

i n o p h t h a l m i c s u rg e r y p u b l i s h e d 1 2 y e a r s a g o , 124f e w d e f i n i t e r e c o m m e n d a t i o n s c o u l d b e m a d ea b o u t t h e o p t i m a l c h o i c e , a d m i n i s t r a t i o n r e g i -m e n , a n d a d m i n i s t r a t i o n r o u t e o f p r o p h y l a c t i ca n t i b i o ti c s b a s e d o n t h e c l i n ic a l d a t a t h e n a v a il -a b l e , e x c e p t t o s a y t h a t p r o p h y l a c t i c a n t i b i o t i c sa p p e a r e d e f fe c ti v e i n r e d u c i n g t h e i n c i d e n c e o fp o s t o p e r a t i v e i n t r a o c u l a r i n f e c t i o n . S i n c e t h a tt i m e , t h e r e i s p r e c i o u s l i t t l e a d d i t i o n a l d a t a o nw h i c h t o b a s e s u c h r e c o m m e n d a t i o n s , h o w e v e r ,


14/17

498 Surv Oph tha hno l 39 (6) May -ju ne 1995 STARR

a s t h is u p d a t e d r e v i e w h a s e m p h a s i z e d , t h e r e i sn o t e w o r t h y n e w c l i n i c a l i n f o r m a t i o n p e r t a i n i n gto s eve ra l impor t an t r e l a t ed i s sues i nc lud ing :c o r r o b o r a t i o n o f p r e v i o u s s t u d i e s s u g g e s t i n g t h ep a t i e n t a s th e s o u r c e o f i n f e c ti n g o rg a n i s

03_antimicrobial prophylaxis for ophthalmic surgery

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