Orig ina lia ______
O. P. va n Bijsterveld, Y. el Batawi, F. S. Sobhi, M. W. Nassar Fusidic Acid in Infections of the External Eye
Summary: A newly developed 1% eye preparation of philus aegyptius (10%), Streptococcus pneumoniae the potent antistaphylococcal antibiotic fusidic acid , (13%) and Neisseria gOllorr/weae (6%). The overall showed an excellent clinical effect in 206 Egyptian chil clinical success rate in children with bacterial conjunc· dren with external eye infections. The 248 patients in tivitis was 85% with fusidic acid, compared to 48% cluded in the study were randomized, in the ratio 5:1. wi th chloramphenicol (p < 0.001). The better effect of to either fusidlc acid or chloramphenicol 0.5% eye fusidic acid could be ascribed to a lower frequency of drops. Both preparations were given four to six times in vitro resistance (16%) in comparison to chlor dai ly for one week. Bacterial conjunctivitis was diag amphe ni col (55 %). Both drugs were apparently well nosed in 56% of the children. Offending eye pathogens tolerated and no side-effects we re observed. were mainly Slaphylococcus aureu.s (60%), Haemo-
Zusammenfassung: Fusidinsiiure wr Be}umdlung I'on Cll.\' aurells (60%), Haemophilus aegypliw (10%), eXlemen Augenllljeklionen. Einc ncuentwickehe Streptococcus plleumoniae (13%) und Neisseria gonor 1%ige ophthalmologische Priiparation des gegen Sta· rhoeae (6% ). Mit Fusidinsiiure wurde bei 85 % der phylokokken hochwi rksamen Antibiotikums Fusidin Kinder mi t bakterie ller Konjunktivitis ein Therapieer saure erwies sich bei 206 iigyptischen Kindem mit ex folg erzielt. mit Chloramphenicol in 48% der Fii ll e terncn Augcninfektionen ab hervorragend klinisch (p < O,OOL). Die therapeutische Oberlcgenheit von wirksam. Die im Rahmen der Studie behandehen 248 Fusidinsaure lieB sich darauf zuriickfilhren, daB die In Kinder erhielten oath Randomverfahren im Verhalt· vitro-Resistenz der Erreger mi t 16% der Isolate in der nis 5: I entweder I %ige Fusidinsaure· oder 0,5%ige Fusidinsaure-Gruppe geringer war als in der Chlor Chloramphenicol·Augentropfen. Beide Priiparate amphenicol-Therapiegruppe mit einer Resistenzrate wurden cine Woche lang vier- bis sechsmal tiiglich vcr· vo n 55% deT Isolate. Beide Medikamente wurden of abreicht. Bei 56% der Kinder wurde cine b(lktericlle fensichtlich gut vert ragen, Nebenwirku ngen wurden Konjunktivitis diagnostiziert. Die haufigsten pathoge nicht beobachtet. nen Erreger der Augeninfektionen waren Staphylococ-
Introduction Emerobacleriaceae and Pselldomonas spp. (8). Thus. the antibacterial spectrum of fusidic acid covers the majority External bacterial infections of the eye are most frequent of the common eye pathogens. In view of the increase in ly caused by the common skin b(lcteria. In acute conjunc· bacterial resistance. increasing reports on idiosyncratic tivitis the organisms recovered in order of their frequcncy depression of the hematopoetic system, as well as allergic have been reported to be staphylococci, streptococci, contact reactions (II), there would seem to be a need for Haemophilus spp., Moraxella spp., Pseudomollas spp., alternative eye anti-infecti ves. Recent ly. fusidic acid has Neisseria spp., and ElIlerobaCleriaceae; and in chronic been introduced as a I % viscous aqueous suspension, and conjunctivitis staphylococci arc by far the most common we report here the resu lts of one of the fi rst clinical stud bacterial palhogen (I). Fusidic acid is potent anti-sta a ies with this new eye anti-infective in the treatment of phylococcal antibiotic which, since ils introduction in conjunctiVitis in children where chloramphenicol eye L962, has been used both systemically in severe staphylo drops have been chosen as t he active control preparation. coccal infections and topicall y in skin infections (2-7). Fu· sidic acid acts by inhibition of hacterial protein synthesis. Patients and Methods It is not inactivated by 0-lactamases, and there is no cross· resistance between fusidic acid and other antibiotics in I'Uliell/s: The siudy includes 248 children, who during a onc clinical use (S--IO). Most staphylococci, regardless of thei r month period - July 1983 - were consecutively admitted wilh an susceptibility to other antimicrobial drugs or their produc· tion of penicillinase, are very sensitive to fusidic acid , Received: 18 Junc 86tAccepled: 29 Septcmber 86 with MIC values of 0.01 to 0.5 mgtl. Fusidic acid is also moderately active against streptococci, diplococci, gono O. p. "all Hi;Sl~rveld. M.D .• Ph.D .. Koninklijk Nederlands voor Oog· lijders. Utrecht , Holland; cocci and some J-Jaemophilus species including Haemo Y. e/ Halow;. M .D .. Ph.D .. F. S. SQbhi . M .D .. Ph. D .. M. W. Nosser, philus aegYPlius and Moraxefla spp., but inactive against M.D .. University of Cairo. Egypt.
16 / 20 Infcction 15 (1987) Nr. t C! MMV Mcdizin Vulag GmbH MUnchcn. MUnchen 1987 O. P. van BijSlerveld et al.: Fusid ic Acid in Eye Infections
Table 1: Demographic data and type of conjunctival infection in 248 children included in the study.
S" Age (in yean) Infection type Diagnosis Single So'" F M <2 2-<> 7-l5 'Y' 'Y~ Bacterial 63 76 97 33 9 15 I" Mixed 12 23 27 6 2 I 34 Viral 29 " 'I 23 10 I' 60 Total I" '" 165 62 21 30 218 external eye infection 10 the Paediatric Clinic at Kasr el-Aini te ri al pathogens. Thirty-five children were diagnosed as Hospital, Cairo University. The group of children comprised having a mixed bacteriaVviral infection, characte rized by 144 males and 104 females. 165 subjects were under twO years of a serous conjunctival exudate , but with a positive bacterial age. 62 were aged two to six, and 21 we re between seven and 15 culture, which in most cases revealed diphtheroids. Final years of age (Table I). There were no drop-ouls. ly, 74 children with negative baclerial culture but clinical Methods: At the first visit 10 the clinic the children were signs of conjunctivitis were classified as having viral con diagnosed as follows: Acute conjunclivitis, defined as a disease junctivitis (Table I). with a history of less than one week, as subacute cases, with a disease hislOry from one to four weeks, or as chronic cases. Con The clinical response to treatment was evaluated imme· junctival exudale was ch3Tacteriud as mucoid , mucopurulent , diately after the seven-day course. Children with a bacte· purulent. or serous, and the following clinical signs and symp rilll conjunctivitis who received fusidic acid were found to toms were graded on a scale 0 = absent to 3 .. severe according have a success rate of85% (97/ 11 4), an im provement rate to the amount of conjunctival exudate, degree of conjunctival of 8% (91114) , and a fai lure rate of 7% (8/114). Corre injection, conjunctival oedema , periorbital oedema, corncal in spondi ng figures for chloramphenicol treatment were 48% fil tration, corneal erosions and staining intensity with Rosel3en (\2125), 4% (1125), and 48% (12/25). These differences gal. At the second clinic visit, after olle week of treatment, the are stalistically highly signicifant (p < 0.0001; Chi-square same clinical signs were graded, and th e overall clinical effect of test). In children with mixed bacteriallviral conj unctivitis, treatment was reco rded as either success, improvement, failure, there were no cases o f complete clinical success. Fusidic or not evaluable. acid produced an improvement in 16 of 27 children, and Test drugs: Fusidic acid was used as a 1% microcrystalline sus chloramphenicol in two of eight chi ldren (p := 0.12; Chi pension in a carbopol gel. with benzalkonium chloride and square tesl). Among children with vira l conjunctivilis, all EDT A used as presetvative (Fucithalmictetracycline 4 mgll, penicillin 2 mg/l, methi and one strain of PseudomonQS sp. were isolated. In the cillin 3 mgll, erythromycin 0.5 mg/l , neomycin 2.5 mg/l and fusidic acid group, treatment fai lures were observed in in gentamicin I mgll. fections caused by S. aureus (n = 6), H. aegyptius (n = 2), Pseudomonas (n = 1), and E. coli (n = I). AU strains Results were resistant to fusidic acid in vitro. In the chloramphen icol group, aU12 treatment fa ilures were caused by S. au 206 children received fusidic acid and 42 children received reus >resistant in vitro to the drug. Children who showed the chloramphenicol eye preparation. Prior to treatment only partial clinical sucCeSS, were in nearly all cases infec the two treatment groups were comparable with regard to ted by in vitro resistant pathogens, whi le children who age, sex distribution, and the score for the severity of showed complete clinical success, were, without excep signs and symptoms (Table I). tion, infected with pathogens which we re sensitive in vilro Of the 248 children included in the study, 139 had bacte to the lest drug given (Table 3). rial conjunctivitis, characterized by purulent o r mucopu The sensitivity pattern towards 11 range of other antibacte rulent conjunctival exudate and significant growth of bac- rial agents was tested in 144 of the bacterial eye patho-
Infection 15 (1987) Nc. I ~ MM V Medizin Ve rlag GmbH Miinchen, Munchen 1987 21 1 17 O. P. van Bijsterveld et al.: Fusidic Acid in Eye Infecfions
Table 2: Overall clinical effect of 1% fusidic acid and 0.5% chloramphenicol eye drops in the treatment of conjunctivitis, when evaluated after a one-week treatment.
Treatment Fw;idic add (206 patieQls) ChlOl"llmphenicQl (42 patients) Diaposis SUO:CC5S Improve- Failure .success Improve- FaiJure ~" ~" Bacterial Acute 6 1 9 0 9 conjunctivitis Subacute "37 1 , 3 1 2 Chronic 9 2 2 1 TOlal' 97 9 8 12 1 12
Mixed Acu te 9 , 1 4 ba<:terial Subacute , 5 1 2 viral Chronic 3 1 conjunctivitis
TOlal" 16 11 2 6
Viral Acute 1 1 33 6 conjunctivitis Subacute 3 Chronic ", Total 1 1 63 9 p < 0.0001 (chi-square , two-tailed) p . 0.12 (chi-square-two. tailed)
gens. Gentamicin showed the lowest resistance rate (8%), the children. Because of a language barrier, it was not followed by neomycin, methicillin and fusidic acid (16%). possible to evaluate subjective tolerance such as slinging Resistance to erythromycin , tetracycline, and chloram when dripping the eyes with medication accurately. phenicol was high (29% to 75% ) (Table 4). Strains resist ant to fusidic acid showed generally no cross-resistance Discussion to the other antibacterials tested. Out of 12 such strains. only one was resistant to gentamicin, and two were resist In this open, randomised study, 248 Egyptian children re ant to neomycin (Table 4). ceived either fusidic acid viscous eye drops (n -= 206) or Tolerance: There were no signs or symptoms of hypersen chloramphenicol eye drops (n = 42) for a one-week pe sitivity reaction or other objective side-effects in any of riod. Indications for treatment were bacterial conjunctivi-
Table 3: Pre-treatment eye pathogens in 139 children with bacterial conjunctivitis.
Clinical E)·c pathogen Fusidic acid Chlonlmpheniool eff~ct (114 patienl$) '(25 patient,,) Staphylo Staphylococcus aureus 6' 12' H(I£mophilus aegyptius ,. Failure EKherichia coli I' PseudomolUlS sp. I' Some of the chi tdren had double infections. • Resistant In vitro !O test drug. 18 I 22 InfeClion 15 (1987) Nr. 1 e MMV Medizin Verlag GmbH Miinchcn. Miinchen 1987 O. P. va n Bijstervekl et al.: Fusidic Acid in Eye Infections Table 4: Pre-treatment sensitivity pattern of 144 eye pathogens isolated from children with bacterial conjunctivitis. % of strains Peni- Melhi- Chloram· Terra· Oent:"!- N~ Fusidic E""",," tillin dOin phenicol cydine micio mydn acid myom Sensilive 39 45 2S 92 84 84 71 Resistant 61 "i6 " 75 8 i6 I' 29 tis (n = 139), bacterial/viral conjunctivitis (n "" 35), and better relative effect seen with fusidic add in this study viral conjunctivitis (n = 74). The overall clinical eHect of can thus be ascribed to the [act that eye pathogens in treatment showed a success in 85% of the children receiv Egypt exhibit a much lower resistance rate to fusidic acid ing fusidic acid and in 48% of the children receivingchlor than to chlora mphenicol. Both drugs were well tolerated amphenicol for bacterial conjunc tivitis (p < 0.001). Fu and no side-effects were recorded. In conclusion, we find sidic acid was also marginally superior in mixed infections that the new eye formulation of fusid ic acid is effective in (p = 0.12). Ne it her treatment showed any effect in con the treatment of bacterial conjunctivit is caused by suscep junctivitis cases considered of viral origin. Offending eye tible pathogens. The fact Ihat fusidic acid is especiall y ac pathogens were S. aure!ls (60%), S. p"e!lmonioe (13%), tive against gram-positive organisms, which predominate N. gonorrhoeae (6%), sireptococci (6%), and Haemophi as the etiology of bacterial conjunctivitis, shows a low {us spp_ (11 %). There was only one case infected with resistance rate with no cross-resistance to ot her antibiot Emerobacteriaceae (E. coli) and one case with Pse!ldomo ics, is devoid of any severe si de-effects and rarely gives nas sp. All children wi th bacterial conjunctivitis who rise to hypersensitivi ty reactions, makes fusidic acid a showed clinical success, we re infected with pathogens sus promising alternative to currently available anti-infective ceptible in vitro to the test drug. All cases with clinical eye preparations. failure we re infecled with in vitro resistant strains. The Litetlturt Med. Res. Opin. 5 (t97mB) 289-294_ 7. Baldwin , R. J . T., Cranneld, R.: A multi-centre general practice l. Fedukol'"iu, H. B. , Stenso n, S,: External infections of the eye. trial comparing fucidin ointment alld fueidin cream. Sr. J. Clin_ Third editioll. Appleton-Cemury-Crofts. Norwalk, Connecticut PraCl. 35 (1981) 157-160. 1985. B. Godtrredl>f:o, W" Robolt, K., Tybrin" L.: Fuddin. A new orally 2. lKey, R. W.: Treatment of staphylococcal infections. J. Antimi aCli~e antibiOTic . LallCet I (1962) 928--93l. crob. Chemother. 9 (1982)~. 9. VaraJdo, P. E., Cipriani , P., F(H.;a, A., Getld, C_, Giordano. A., 3. Gransden, W. R., E)·kyn, S. J .• Philli ps. I.: Slapky/ococcusuureus Madeddu, M. A .. Om, A., Pompei. R.• Prenna, M .• Rept Ho, A_ . bacteraemia; 400 episodes in St. Tbomas's Hospital. Sr. Med. J. Ripa, 5., Ros.wlli , P., RuS$O, G .. Scauoccbio, F., Sla5lii, G.: Idell 288 (1984) 300--31)3. tification, clinical distribution, and susceptibility 10 methicillin and 4. O' Brie n, T., McManus. Y., MacAuley, 1-' _ H_. Ennis, J. T.: Acute 18 additional antibiotics of clinical swphy/ocoCCU$ isolates; nation haemotogenous osteom),elitis. J. Bone Joi'" Surg. 64 B (\982) wide illvcstigatioll ill Italy, J. Clin. Microbiol. !9 (1984) 83S-843. 450-453. 10. Chokka~e lu , v .• Chandrase kar, P., Rolston, J(., LeFrOl:k. J. L., 5. Cassels_Oro .. n. G.: A comparative studyof tuddin ointment and d ~ hell , R. F.: ACli~ity of eleven antimicrobial agents agailL'it methi calnn cream in the treatment of impetigo. Or. J. Clin. Pra~1. 35 cillin-, mcthieiUin_ and rifampin-resistant SUlphy/OI:OCcus QUTeUS. (1981) 153-155. Chemotherapy 30 (1984) 97-101. 6. Pakrooh, H.: A comparison of sodium fusidate ointmc'" (Fucidin') II. Aplastic anaemia due to chloramphenicol. Merl. LeI!. Drugs Ther. alone veAUS oral 3",ibiotie therapy in soft-tissue infections. Curro 22 (1976) 569_ Illfection 15 (1987) Nr. I C MMV Mcdizin Verlag GmbH Munchen , Munchen t987 23 / 19