Eradication of methicillin-resistant Staphylococcus aureus from the lower respiratory tract of patients with cystic fibrosis

Division of Infectious Diseases, Vancouver Hospital and Health Sciences Centre; Division of Respiratory Medicine, St Paul’s Hospital; and Division of Medical Microbiology, The University of British Columbia, Vancouver, British Columbia Correspondence: Dr DR Burdge, Division of Infectious Diseases, Vancouver Hospital, Room 452, ‘D’ Floor, 2733 Heather Street, Vancouver, British Columbia V5Z 3J5. Telephone (604) 875-4588, Fax (604) 875-4013 Received for publication April 19, 1994. Accepted June 22, 1994 DR BURDGE, EM NAKIELNA, MA NOBLE. Eradi ca tion of methicillinresistant Staphy lo coc cus au reus from the lower res pi ra tory tract of pa tients with cys tic fi bro sis. Can J In fect Dis 1995;6(2):97101. Two of 95 pa tients fol lowed in an adult cys tic fi bro sis clinic con sis tently grew methicillinresistant Staphy lo coc cus au reus (MRSA) on spu tum cul ture. Spu tum Gram stain con sis tently showed +4 poly mor pho nu clear leu ko cytes and +4 Grampositive cocci in clus ters. Both pa tients were coinfected with Pseu do mo nas ae rugi nosa and re quired mul ti ple hos pi tali za tions for treat ment of pul mo nary ex ac er ba tion, re sult ing in sig nifi cant in fec tion con trol con cerns. Mul ti ple courses of an ti bi ot ics, in clud ing cipro floxa cin and clin da my cin regi mens, failed to elimi nate the MRSA. A com bi na tion of oral ri fampin and clin da my cin was suc cess ful in eradi cat ing the or gan ism from both pa tients. Over a 12month pe riod fol low ing ther apy, in both pa tients none of 13 spu tums showed Grampositive cocci in clus ters on Gram stain and none of 13 spu tum cul tures grew MRSA. Suc cess ful eradi ca tion of MRSA has greatly sim pli fied in fec tion con trol meas ures on sub se quent hos pi tali za tions, re duc ing costs and en hanc ing pa tient com fort.

C YS TIC FI BRO SIS (CF) RE MAINS THE MOST COM MON SEMI LE - THAL ge netic dis ease of Cau ca sians (1).While the major ity of CF pa tients die pre ma turely of res pi ra tory fail ure, many are now reach ing adult hood.Re cent Ca na dian Cys tic Fi bro sis Foun da tion data in di cate that the me dian age of survival for Ca na dian CF pa tients reached 30.9 years in 1991 (2).CF, there fore, has clearly be come an adult dis ease that in ternists, chest phy si cians and gas tro en ter olo gists will en coun ter with in creas ing fre quency.
Pa tients with CF de velop chronic lower res pi ra tory tract infec tion, usu ally ini tially with Staphy lo coc cus au reus and later with Pseu do mo nas ae rugi nosa (3,4).Once in fec tion de velops, it usu ally per sists, and in fec tion com bined with host inflam ma tory and im mune re sponse leads to pro gres sive pul mo nary dam age, bron chiec ta sis, chronic ob struc tive pulmo nary dis ease, and even tu ally res pi ra tory fail ure and death.Al though chronic S au reus in fec tion of the lower res pi ra tory tract is ex tremely com mon in this pa tient group, methicillinresistant strains of S au reus (MRSA) have been in fre quently en coun tered (3,5).Two of 95 pa tients fol lowed in our adult CF clinic con sis tently grew MRSA on spu tum cul ture.Spu tum Gram stain con sis tently showed +4 poly mor pho nu clear leuko cytes (PMNs) and +4 Gram-positive cocci in clus ters, and MRSA was be lieved to be in fect ing the lower res pi ra tory tract.Both pa tients were chroni cally co-infected with P ae rugi nosa and re quired mul ti ple hos pi tali za tions for treat ment of pul monary ex ac er ba tion.Given the po ten tial for MRSA to cause se rious no so comial in fec tion (6)(7)(8)(9), each hos pi tali za tion re sulted in con sid er able anxi ety about po ten tial spread of the or ganism.In ac cor dance with rec om mended in fec tion con trol practices (6,9) strict iso la tion pre cau tions were in sti tuted.This re sulted in in creased ex pense and de creased pa tient comfort.The clini cal sig nifi cance of MRSA in the lower res pi ra tory tract of these pa tients was not to tally clear, but be cause it may have been con trib ut ing to pul mo nary dis ease, and be cause of the ma jor in fec tion con trol im pli ca tions, we elected to try to eradi cate the or gan ism from the lower res pi ra tory tract.

CASE PRES EN TA TIONS
Case one: A 28-year-old fe male with known CF re quired several hos pi tali za tions each year for treat ment of pul mo nary exac er ba tion.Pul mo nary func tion test ing re vealed forced ex pi ra tory vol ume in 1 s (FEV 1 ) of 2.19 L (70% pre dicted) and forced vi tal ca pac ity (FVC) of 2.97 L (77% pre dicted).Shwachman score was 85/100.Spu tum con sis tently grew P ae rugi nosa.Methicillin-sensitive S au reus (MSSA) was iso lated from spu tum cul tures in Oc to ber and No vem ber 1987.Through out 1988 and 1989 no S au reus was iso lated from spu tum.MRSA was first iso lated Janu ary 18,1990 and sub sequently grew from 10 of 11 spu tum cul tures be tween Janu ary 1990 and June 1991.Spu tum Gram stains con sis tently demon strated +3 or +4 PMNs and +3 or +4 Gram-positive cocci in clus ters in ad di tion to Gram-negative rods.Dur ing the 18 months that MRSA was con sis tently iso lated from spu tum, four courses of oral cipro floxa cin, and four courses of high dose par enteral to bra my cin and cef tazidime ther apy were ad min istered.None of these in ter ven tions, di rected pri mar ily against P ae rugi nosa in fec tion, eradi cated MRSA.A three-week course of oral ri fampin 600 mg daily and clin da my cin 600 mg tid was given in June 1991.Over the sub se quent 12 months (July 1991 to July 1992), none of 13 spu tum Gram stains showed Gram-positive cocci in clus ters, and none of 13 spu tum cul tures grew MRSA.Since eradi ca tion of MRSA there has been no ob vi ous change in her clini cal status, or in the fre quency of hos pi tal admis sions.Case two: A 31-year-old fe male with known CF av er aged four hos pi tal ad mis sions yearly for treat ment of pul mo nary ex ac erba tion.Pul mo nary func tion test ing re vealed FEV 1 of 1.0 L (27% pre dicted) and FVC of 1.68 L (37% pre dicted).Shwachman score was 40/100.For many years, the spu tum con sis tently grew P ae rugi nosa and no S au reus.MRSA was first iso lated from spu tum in No vem ber 1988, and sub se quently grew from 20 of 29 cul tures through June 1991; 12 of 12 cul tures from June 1990 through June 1991 grew MRSA.Dur ing this time spu tum Gram stain con sis tently dem on strated +3 or +4 PMNs, +3 or +4 Gram-positive cocci in clus ters and Gram-negative rods.Af ter the first iso la tion of MRSA, five courses of par enteral to bra my cin, cef tazidime and clin da my cin, two courses of tobra my cin and cef tazidime, one course of to bra my cin, ceftazidime and cipro floxa cin, one course of to bra my cin and ti car cil lin, and mul ti ple courses of oral cephalexin and ciprofloxa cin were ad min is tered for treat ment of pul mo nary ex ac erba tion.None of these in ter ven tions eradi cated the MRSA.A two-month course of oral ri fampin 600 mg daily and clin da mycin 600 mg tid was in sti tuted in June 1991.Over the sub sequent 12 months (July 1991 to July 1992), none of 13 Gram stains showed Gram-positive cocci in clus ters, and none of 13 spu tum grew MRSA.In 1992 the pa tient be came in fected with Pseu do mo nas ce pa cia, and sub se quently de te rio rated and died in March 1993 of P ce pa cia pneu mo nia.

MI CRO BIO LOGI CAL METH ODS
Ex pec to rated spu tum from all CF pa tients was rou tinely in ocu lated onto 5% sheep blood agar (with S au reus streak), Mac Con key agar, colistin-nalidixic acid agar and P ce pa cia agar.A man ni tol salt agar plate con tain ing Dmannitol 10 g/L and so dium chlo ride 75 g/L, highly se lec tive for S au reus, was added to the rou tine CF spu tum pro to col for a three-month pe riod from June 1991 through Sep tem ber 1991.Dur ing this time, 95 spu tum speci mens were cultured from 49 adult CF pa tients; 35 of 95 (37%) cul tures grew S au reus, but no MRSA was de tected.It was con cluded that the rou tine CF spu tum mi cro bi ol ogy pro to col was highly sen si tive for the de tec tion of MRSA, and that other CF pa tients in the authors' cen tre were not colo nized or in fected (10).
S au reus iso lates were iden ti fied ac cord ing to stan dard meth ods.Sus cep ti bil ity test ing was per formed at the Uni versity Hos pi tal, Van cou ver mi cro bi ol ogy labo ra tory.All S au reus iso lates were tested for clox acil lin re sis tance to 4 mg/mL by agar di lu tion method.Ini tial screen for in trin sic me thi cil lin resis tance was ac com plished us ing an amoxicillin-clavulanate disc; a 20 mm or greater zone of in hi bi tion was in ter preted as hyperbeta-lactamase pro duc tion, while less than 20 mm was in ter preted as in trin sic me thi cil lin re sis tance (11).Mini mum in hibi tory con cen tra tion test ing was per formed by mi cro broth di lu tion tech nique (Sen si ti tre, Ra di ome ter/Co pen ha gen Company, Ohio) us ing a sensi titre AG PMI mul ti ti tre panel in ac cordance with the manu fac tur er's in struc tions.S au reus ATC 29213 was run as a si mul ta ne ous con trol with pa tient iso lates.

MI CRO BIO LOGI CAL RE SULTS
Iso lates from both pa tients had zone sizes of 16 to 17 mm around the amoxicillin-clavulanate disc, con sis tent with in trinsic me thi cil lin re sis tance.In vi tro sen si tiv ity data are sum marized in Ta ble 1.

DIS CUS SION
Fac tors as so ci ated with ac qui si tion of MRSA in clude du ration of hos pi tali za tion, prior ad mini stra tion of one or more an tibi ot ics and du ra tion of prior an ti bi otic ther apy (7).Pa tients with CF who re ceive mul ti ple courses of pro longed com bi nation an tipseu do mo nal an ti bi otic ther apy there fore ap pear to be at par ticu larly high risk of colo ni za tion and in fec tion with MRSA.There is, how ever, sur pris ingly lit tle pub lished in for mation re gard ing MRSA in this popu la tion.Szaff and Hoiby (5) report that MRSA in CF pa tients in Den mark is a 'rare oc cur rence', and in a re cent re view of the mi cro bi ol ogy of air way dis ease in pa tients with CF, Gil li gan (3) states only that his ex pe ri ence con firms that MRSA is 'not a con cern' in the CF popu la tion.Boxer baum and col leagues (12) ret ro spec tively re viewed throat and spu tum cul tures from 452 CF pa tients dur ing 1986 and found that 14 (3%) pa tients at Rain bow Ba bies and Chil dren's Hos pi tal, Cleve land, Ohio were colo nized with MRSA.None of these pa tients was treated spe cifi cally for the MRSA, and the study is lim ited by its ret ro spec tive na ture and the lack of patient follow-up.There is no other pre vi ously pub lished study on MRSA in this popu la tion.
In gen eral, in fec tion of the lower res pi ra tory tract in CF patients, once es tab lished, is very dif fi cult to eradi cate.This is par ticu larly true of chronic P ae rugi nosa in fec tion where even pro longed courses of com bi na tion par enteral an tipseu do monal ther apy usu ally fails to eradi cate the or gan ism from the lung.Mi chel (13) re viewed the pub lished stud ies of an tipseudo mo nal ther apy in CF pa tients be tween 1980 and 1987 and re ported that only 13 of 64 stud ies had more than 30% patients with nega tive spu tum cul tures af ter ther apy.MSSA has proven to be less prob lem atic than P ae rugi nosa in these patients, and the preva lence of MSSA in fec tion de creases with age (3,4).Szaff and Hoiby (5) re ported rea son able suc cess in con trol ling MSSA in fec tion by re peat edly treat ing pa tients with posi tive spu tum cul tures with fu si dic acid in com bi na tion with ox acil lin.Nev er the less, chronic MSSA in fec tion can also be extremely dif fi cult to eradi cate.In a study of clin da my cin ther apy of staphy lo coc cal in fec tion in CF pa tients, Shapera et al (14) noted that MSSA per sisted in 59% of treated pa tients.Pitt man et al (15) stud ied the phage type of S au reus iso lated from CF pa tients and found that, in 65 pa tients from whom S au reus was iso lated on more than one oc ca sion, the phage type remained con sis tent in 52, sug gest ing per sis tent in fec tion with the same or gan ism de spite pro longed an tis taphy lo coc cal ther apy.
Given the dif fi culty in eradi cat ing P ae rugi nosa or MSSA from pa tients with CF, it is an tici pated that eradi ca tion of MRSA from the lower res pi ra tory tract would be ex tremely dif fi cult.Fré nay et al (16) re cently re ported an adult CF pa tient with long term car riage of MRSA in whom re peated courses of neomycin-bacitracin and mu pi ro cin na sal creams, hexa chloro phane dis in fec tant soap and oral van co my cin all failed to eradi cate the or gan ism.Sev eral courses of in tra ve nous an tibi ot ics were also un suc cess ful, and MRSA con tin ued to be pres ent in the an te rior nares, throat and spu tum over the 27month study pe riod.To date, we know of no other pub lished re port of any at tempt to eradi cate MRSA from a pa tient with CF.
It is note wor thy that in both of the pres ent cases, the load of MRSA in the lower res pi ra tory tract was very heavy as assessed by spu tum Gram stain, where +3 and +4 Grampositive cocci in clus ters were con sis tently re ported.In both pa tients mul ti ple nonrifampin-containing an ti bi otic regi mens failed to eradi cate the or gan ism.
Cipro floxa cin has been re ported to be use ful in treat ment of MRSA (17)(18)(19), but mul ti ple courses of cipro floxa cin failed to eradi cate the or gan ism in ei ther of these in di vidu als.In our sec ond pa tient, mul ti ple clindamycin-containing an ti bi otic regi mens also were un suc cess ful at eradi cat ing MRSA.Only when ri fampin in com bi na tion with clin da my cin was used was eradication suc cess ful.Ri fampin is thought to be the drug that most ef fec tively eradi cates MRSA from mu co sal sur faces (20), al though fail ure can oc cur when it is used alone (21).Most authors cur rently rec om mend the use of ri fampin in com bi na tion with a sec ond ac tive drug such as cipro floxa cin, clin da my cin, trimethoprim-sulfa methoxa zole or van co my cin when at tempt ing eradi ca tion of MRSA (8,18,22).We chose to use clin da my cin in com bi na tion with ri fampin be cause of good ab sorp tion by the oral route, ac tiv ity in vi tro against our two pa tients' iso lates, and abil ity to con cen trate in macrophages and PMNs (23).More pro longed ther apy than is usually em ployed for eradi ca tion of MRSA from mu co sal sur faces  (20), al though fail ure can oc cur when it is used alone (21).Most authors cur rently rec om mend the use of ri fampin in com bi na tion with a sec ond ac tive drug such as cipro floxa cin, clin da my cin, trimethoprim-sulfa methoxa zole or van co my cin when at tempt ing eradi ca tion of MRSA (8,18,22).We chose to use clin da my cin in com bi na tion with ri fampin be cause of good ab sorp tion by the oral route, ac tiv ity in vi tro against our two pa tients' iso lates, and abil ity to con cen trate in macrophages and PMNs (23).More pro longed ther apy than is usually em ployed for eradi ca tion of MRSA from mu co sal sur faces was ad min is tered be cause we be lieved that we were deal ing with lower res pi ra tory tract in fec tion in pa tients with bronchiec ta sis on the ba sis of CF lung dis ease.Many stud ies have shown that treat ment of MRSA can result in only very tran sient eradi ca tion of the or gan ism and that recolo ni za tion fre quently oc curs (19,22).The ab sence of MRSA on mul ti ple spu tum cul tures from our two pa tients over a one-year pe riod post-treatment is strong evi dence for success ful long term eradi ca tion.
Suc cess ful treat ment of MRSA in these in di vidu als has greatly sim pli fied in fec tion con trol meas ures on sub se quent hos pi tali za tions (in clud ing to the ob stet rics hos pi tal).Substan tial cost-savings have been re al ized by this suc cess, and the pa tients have been much more com fort able out of strict iso la tion.While the role of treat ment of car ri ers as an in fec tion con trol meas ure re mains de bat able, an ti mi cro bial ther apy has pre vi ously been re ported to be use ful in as sist ing in the con trol of an out break of MRSA and in pre ven tion of sig nifi cant clini cal in fec tion (20,24).

CON CLU SIONS
Pro longed eradi ca tion of MRSA from the spu tum of CF patients may be pos si ble by use of ri fampin and clin da my cin ther apy.These re sults may also be of prac ti cal in ter est in the man age ment of MSSA in fec tion in pa tients with CF.Fur ther inves ti ga tion into the preva lence and role of MRSA in pa tients with CF is war ranted.

TA BLE 1 Re sults of in vi tro sen si tiv ity test ing An ti bi otic MIC (mg/L) Pa tient 1 iso late Pa tient 2 iso late
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