ccidioidl Meningitis The Use of Amphotericin B in Tretment HAS E. ESTE, M.D., CHARLES W. HOLEMA, JR., M.D., LEWS L. SADDGE, M.D., nd DAVD H. HOLDE, M.D., Bkersfield THE EED for n effective therpeutic gent in the deep mycotic diseses hs long been recognized. Well over fifty drugs hve been given clinicl trils,2'5'7'9 yet until recently none hs shown sufficient promise to wrrnt extensive investigtion. The serch hs continued unbted, however, since in endemic res the deep mycotic lesions continue s mjor cuse of morbidity nd minor but significnt cuse of deth.2'2 The southern Sn Joquin Vlley is the most highly endemic re of coccidioidl infection16'23 with severl thousnd new cses nnully. Of these bout.2 per cent develop into disseminted disese,22 usully ccompnied by complement fixtion titer of 1:32 or higher.25 n bout 25 per cent of these cses, meningitis,1'15'19 which hs been considered to be universlly ftl,3' will develop. Some of the nonmeningel disseminted cses lso terminte ftlly due to generlized dissemintion or chronic progressive disese involving bones nd viscer. Amphotericin B, n ntifungl gent obtined from species of Streptomyces found on the shores of the Orinoco River in Venezuel,7'29 is the first extensively investigted drug in the tretment of the deep mycotic infections. The problems in evluting the results of therpy in disseminted coccidioidl disese were discussed with gret clrity by Fiese.5 ccidioidl meningitis is resonbly predictble in its behvior. n view of its invribly ftl outcome the ultimte test of ny therpeutic modlity is the demonstrtion of its bility to ffect coccidioidl meningitis, since for nonmeningel disseminted disese there is high incidence of spontneous remission nd cure. one of the drugs used in the pst hs ffected the course of coccidioidl meningitis. The present report summrizes our experience in the use of mphotericin B in the tretment of coc- From the ccidioidl Study Group, Kern unty Generl Hospil, Bkersfield. Supported in prt by the Clude Bbcock Memoril Fellowship, Kern unty Tuberculosis nd Helth Assocition. Submitted Mrch 3, 1961. * Amphotericin B is the first gent to lter fvorbly the course of coccidioidl meningitis. The morbidity nd toxicity of the drug re t present its chief limiting fctors. Although no cures were obtined in series of 11 cses, significnt remissions usully followed course of therpy. mprison with similr groups showed significnt prolongtion of life in dutely treted cses. cidioidl meningitis nd is chiefly concerned with our observtions of the effectiveness of the drug. METHODS AD MATERALS n period of three yers 11 consecutive ptients with coccidioidl meningitis hve been treted with mphotericin B in essentilly the mnner described by Winn.32 ecropsy ws performed in ll ptients who died. Dignosis ws estblished by the following lbortory criteri: Spinl fluid findings: 1. Pleocytosis. 2. Elevted protein. 3. mplement fixtion titer of t 1:2 dilution25 or higher, on more thn one specirnen. or. Positive culture for ccidioides immitis. The spinl fluid pressure ws usully elevted nd first-zone colloidl gold curve ws lmost lwys present, but these findings were not considered essentil to the dignosis. Amphotericin B ws dministered intrvenously six dys ech week t dose of 1 mg. per kilogrm of body weight dily. During the first hlf of the reporting period, mphotericin B ws given intrvenously only nd ws temporrily discontinued when zotemi developed. More recently, both intrvenous nd intrspinl therpy were used in view of the poor trnsference of the drug cross the bloodbrin brrier.6"18'21 During this period tretment ws not interrupted becuse of zotemi; insted, if the blood ure nitrogen rose bove 5 mg. per VOL. 9. O. 6 * JUE 1961 339
1 cc. the intrvenous dose ws temporrily decresed by hlf nd then slowly incresed gin. Amphotericin B for intrvenous use ws mixed with 5 per cent dextrose. nd wter to concentrtion of 1 mg. per 1 ml. nd heprin ws dded. Erly in the study diphenhydrmine ws dded to the intrvenous solution s suggested by Winn,32 nd in some instnces we dded pyridoxine nd scorbic cid. More recently we hve dded only heprin, 3 mg., s the ptients seemed to hve less difficulty with chills nd fever when other drugs were not dded to the solution. ntrspinl mphotericin B ws dministered three times weekly in doses of.5 to 5. mg. ech with 25 mg. of hydrocortisone. Rest ws stressed only when ptients were cutely ill. When elevted, spinl fluid pressure ws lowered by tpping nd withdrwl dily. Het lmps nd extr blnkets were used during the dministrtion of intrvenous mphotericin B nd seemed to be of some benefit in decresing the incidence nd severity of febrile rections. Pipmzine, prochlorperzine or chlorpromzine ws dministered s needed to llevite nuse. Antihistmines nd spirin were used in n ttempt to control febrile rections. Plnned intervl therpy ws used during the lst yer of the reporting period, including weekly, qurterly nd seminnul courses. The more prolonged courses of mphotericin B, in most instnces, hd to be discontinued becuse of thrombophlebitis which mde further intrvenous drug dministrtion impossible. n some cses polyethylene ctheter ws plced in vilble veins to fcilitte further dministrtion of the drug in very ill ptients. COTROLS o truly comprble group ws vilble to ct s control, nd plcebo therpy ws imprcticl. Therefore, in order to supplement previously published informtion on life expectncy, the hospitl records of ll ptients with dignosis of coccidioidl meningitis during the preceding ten-yer period were reviewed. The following criteri were estblished for inclusion in this "control" series: 1. The dignosis must hve been confirmed in ccord with the criteri used for the current series, or necropsy findings hd to be conclusive. 2. Some resonble estimte of durtion of meningitis could be estblished from the records. 3. The ptient must not hve received mphotericin B. Sixty consecutive chrts were reviewed nd 31 were found to meet these criteri. These were nlyzed in terms of survivl time only (Tble 1). Buss, Gibson nd Gifford reviewed 53 cses of coccidioidl meningitis seen in Kern unty before 3 TABLE l.-mprtive Two-Yer Survivl n ccidloldl Meningitis o Amphotericin Cses from Treted with Preceding 1- Tbulted from Amphotericin Yer Period Buse, et l.$ Ptients: Followed two yers or until deth...7 31 7* Living one yer fter onset...5 2 9 Living two yers fter onset... 5t 'Fifty-three ptients in originl report, durtion of disese not reported in six of these cses. ttwo of these ptients hve now lived 3 yers, two hve died t 27 nd 3 months respectively nd one is still living but hs been followed less thn 3 yers. 195.3 The durtion of meningitis ws unknown in three of the cses nd three ptients were still living t the time of their report. Of the remining 7 ptients (Tble 1), 15 died within three months of onset, 23 others died within 12 months, seven lived more thn one yer nd two lived lmost two yers. RESULTS With one exception ll ptients showed some evidence of clinicl nd lbortory improvement when mphotericin B ws used initilly (Tble 2). mprovement in spinl fluid findings consisted of decrese of cell count nd fll in the complement fixtion titer. The spinl fluid pressure decresed nd there ws clering of sensorium nd relief of hedche. Symptomtic improvement ws generlly significnt. Four ptients died while under ctive therpy. Deth in these ptients occurred t four nd hlf, ten, twenty-seven nd thirty-four months fter onset. n ll instnces there ws evidence of ctive coccidioidl meningitis t utopsy. n three cses ccidioides irunitis ws cultured from the surfces of the brin nd meninges. The specimen for culture ws indvertently discrded in the fourth cse, but spherules of ccidioides inmitis were demonstrted in tissue sections. The seven surviving ptients hd lived 7, 7, 9, 18, 21, 36 nd 37 months, respectively, t the time of this report. These seven ptients hd received totl of 15 courses of therpy nd hd shown improvement during ech course. n no instnce hs cure yet been obtined in this series. Symptoms usully recur in three to six months fter ctive therpy is terminted. At tht time, the spinl fluid shows n increse in pleocytosis nd fruently n increse in complement fixtion titer. The surviving ptients re ll crrying on their usul ctivities except when under ctive therpy. CALFORA MEDCE
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Difficulty in the dministrtion of mphotericin B nd drug toxicity ws similr to tht previously reported.* This hs included hedche, generlized pin, norexi, nuse, occsionlly vomiting, chills, fever, zotemi, nemi nd thrombophlebitis. The ltter, in prticulr, mkes very protrcted intrvenous dministrtion difficult. Presthesis nd trnsient rchnoiditis occurred during intrspinl dministrtion of the drug, the ltter severe enough in two cses to force discontinunce of intrspinl therpy. The more severe rections were ssocited with intrspinl doses of 2.5 mg. or greter. COMMET Longevity of ptients treted with mphotericin B is compred with tht in ptients who received no mphotericin in Tble 1. Despite the very rre cse of chronic coccidioidl meningitis which my follow very indolent course with survivl of five to ten yers fter onset,8 1'17 deth, in the untreted ptient, usully occurs within the first yer, nd seldom does the ptient survive two yers."1 ls3 n virtully every course of therpy, totling over 2, the morbidity nd toxicity of the drug ws the deciding fctor forcing discontinuing its use. This my well be the reson for the invrible relpses in the present series. nduced drug resistnce hs been demonstrted, nd it hs been speculted tht such resistnce my emerge in clinicl prctice.12'26'28 However, in this series the subsuent courses generlly were s effective s the initil one, t times ruiring less drug nd time to chieve uivlent clinicl nd lbortory results. This grees with the observtions of Littmn." A fungisttic but not fungicidl effect my well explin the drug ction in clinicl prctice. More effective mens of meliorting the toxicity of mphotericin B re needed so tht much more prolonged courses of therpy might be employed. The use of long term intermittent dministrtion my help overcome some of the obstcles. However, the possibility remins tht the orgnism my eventully develop resistnce to the drug. The ddition of secondry or tertiry ntifungl gents my be of vlue. Some of these venues re currently being explored, nd specil studies on the zotemi nd nemi so generlly observed re in progress. ACKOWLEDGMET The uthors re indebted for the performnce of serologicl studies to C. E. Smith, M.D., University of Cliforni School of Public Helth, Berkeley, nd C. Ross Hmpson, Ph.D., Kern unty Deprtment of Public Helth, Bkersfield. The clinicl nd ntomicl pthology ws done in the lbortory of Robert W. Huntington, Jr., M.D., t Kern unty Generl Hospitl. 117 iles Street, Bkersfield (Holemn, Jr.). References 2,, 6, 1, 11, 13, 18, 21, 32. REFERECES 1. Abbott, K. H., nd Cutler,..: Chronic coccidioidl meningitis, Arch. Pth., 21:32, Mrch 1936. 2. Appelbum, E., nd Shtoklko, S.: Cryptococcus meningitis rrested with mphotericin B, Ann. nt. Med., 7:36, Aug. 1957. 3. Buss, W. C., Gibson, T. E., nd Gifford, M. A.: ccidioidomycosis of the meninges, Clif. Med., 72:167, Mrch 195.. lwell, J. A.: Remission in disseminted coccidioidomycosis produced by mphotericin B, Ann. nt. Med., 5: 128, April 1959. 5. Fiese, M. M.: ccidioidomycosis, Chrles C. Thoms, Springfield, llinois, 1958. 6. Fitzptrick, M. J., Rubin, H., nd Poser, C. M.: The tretment of cryptococcl meningitis with mphotericin B, new fungicidl gent, Ann. nt. Med., 9:29, Aug. 1958. 7. Gold, W., Stout, H. A., Pgno, J. F., nd Donovick, R.: Amphotericins A nd B ntifungl ntibiotics produced by streptomycete.. n vitro studies, Antibiotics Ann. 1955-1956, p. 579, Medicl Encyclopedi, nc., ew York, 1956. 8. Jenkins, V. E., nd Postlewiter, J. C.: ccidioidl meningitis: Report of four cses with necropsy findings in three cses, Ann. nt. Med., 35:168, ov. 1951. 9. Lehn, P. H., Ytes, J. L., Brsher, C. A., Lrsh, H. W., nd Furcolow, M. L.: Experiences with the therpy of sixty cses of deep mycotic infections, Dis. Chest, 32:597, Dec. 1957. 1. Littmn, M. L.: Preliminry observtions on the intrvenous use of mphotericin B, n ntifungl ntibiotic, in the therpy of cute nd chronic coccidioidl osteomyelitis, Proceedings of Symposium on ccidioidomycosis, U. S. Public Helth Service Bull., o. 575, p. 86, 1957. 11. Littmn, M. L., Horowitz, P. L., nd Swdey, J. G.: ccidioidomycosis nd its tretment with mphotericin B, Am. J. Med., 2:568, April 1958. 12. Littmn, M. L., Pisno, M. A., nd'lncster, R. M.: nduced resistnce of Cndid species to nysttin nd mphotericin B, Antibiotics Ann. 1957-1958, p. 981, Medicl Encyclopedi, nc., ew York, 1958. 13. ewcomer, V. D., Sternberg, T. H., Wright, E. T., nd Reisner, R. M.: Current tretment of the systemic fungus infections, J. Chron. Dis., 9:353, April 1959. 1. ormn, D. D., nd Miller, Z. R.: ccidioidomycosis of the centrl nervous system, cse of ten yers durtion, eurology, :713, Sept. 195. 15. O'Lery, D. J., nd Curry, F. J.: ccidioidomycosis. A review nd presenttion of 1 consecutively hospitlized ptients, Am. Rev. Tuber., 73:51, April 1956. 16. Plmer, C. E., Edwrds, P. Q., nd Allfther, W. E.: Chrcteristis of skin rections to coccidioidin nd histoplsmin, with evidence of n unidentified source of sensitivity in some geogrphic res, Proceedings of Symposium on ccidioidomycosis, U. S. Public Helth Service Bull., o. 575, p. 171, 1957. 17. Rosen, E., nd Belber, J. P.: ccidioidl meningitis of long durtion: Report of cse of four yers nd eight months with necropsy findings, Ann. nt. Med., 3:796, Mrch 1951. 18. Rubin, H., nd Furcolow, M. L.: Promising results in cryptococcl meningitis, eurology, 8:59, Aug. 1958. 19. Schlumberger, H. G.: A ftl cse of coccidioidomycosis with culturl studies, Am. J. M. Sc., 29:83, April 195. 2. Scogins, J. T.: mprtive study of time loss in coccidioidomycosis nd other respirtory diseses, Proceedings of Symposium on ccidioidomycosis, U. S. Public Helth Service Bull., o. 575, p. 132,1957. 21. Sebury, J. H., nd Dscomb, H. E.: Experience with mphotericin B for the tretment of systemic mycoses, Arch. nt. Med., 12:96, Dec. 1958. 22. Smith, C. E.: ccidioidomycosis, M. Clin. orth Americ, 27:79, My 193. 32 CALFORA MEDCE
23. Smith, C. E., Berd, R. R., Rosenberger, H. G., nd Whiting, E. G.: Effect of seson nd dust control on coccidioidomycosis, J.A.M.A., 132:833, Dec. 7, 196. 2. Smith, C. E., Pppginis, D., nd Sito, M. T.: The public helth significnce of coccidioidomycosis, Proceedings of Symposium on ccidioidomycosis, U. S. Public Helth Service Bull., o. 575, p. 3, 1957. 25. Smith, C. E., Sito, M. T., nd Simmons, S. A.: Pttern of 39,5 serologicl tests in coccidioidomycosis, J.A.M.A., 16:56, Feb. 18, 1956. 26. Sorensen, L. J., Mcll, E. G., nd Sternberg, T. H.: The development of strins of Cndid lbicns nd ccidioides immitis, which re resistnt to mphotericin B. Antibiotics Ann. 1958-1959, p. 92, Medicl Encyclopedi, nc., ew York, 1959. 27. Sox, H. C., nd Dickson, E. C.: Experimentl therpy in coccidioidl grnulom, J.A.M.A., 16:777, Mrch 7, 1936. 28. Stout, H. A., nd Pgno, J. F.: Resistnce studies with nysttin, Antibiotics Ann. 1955-1956, p. 7, Medicl Encyclopedi, nc., ew York, 1956. 29. Vndeputte, J., Wchtel, J. L., nd Stiller, E. T.: Amphotericins A nd B ntifungl ntibiotics produced by streptomycete:. The isoltion nd properties of the crystlline mphotericins, Antibiotics Ann. 1955-1956, p. 587, Medicl Encyclopedi, nc., ew York, 1956. 3. Winn, W. A.: The clinicl development nd mngement of coccidioidomycosis, Proceedings of Symposium on ccidioidomycosis, U. S. Public Helth Service Bull.,. 575, p. 1, 1957. 31. Winn, W. A.: Dignosis, medicl nd surgicl tretment of coccidioidomycosis, Pper presented t Fifth nterntionl ngress on Diseses of the Chest, Tokyo, Jpn, Sept. 8, 1958. 32. Winn, W. A.: The use of mphotericin B in the tretment of coccidioidl disese, Am. J. Med., 27:617, Oct. 1959. Biliry T-Tube Dringe A Simple Method HARRY PERELMA, M.D., Los Angeles o FULLY SATSFACTORY METHOD for drining bile into collection bottle from T-tube plced in the common bile duct hs yet been presented. f it is lrge, the dringe tube my be so hevy tht it pulls the T-tube out of the common duct or out of the bdominl wound; nd sometimes ptient's thrshing bout in bed immeditely fter opertion will cuse the T-tube to become dislodged. To prevent such n occurrence, some surgeons keep covering of dressings over the T-tube for dy fter opertion. Usully the dressings become bilesoked nd irrittion of the skin of the bdomen results. Some observers hve recommended ttching smll bottle directly to the T-tube nd keeping it in plce with dressings. With this method, however, bile is likely to spill from the bottle onto the bed s the ptient turns from side to side. For severl yers hve used simple system tht serves well yet voids the dngers nd inconveniences mentioned. After completion of the opertion, the T-tube is ttched to plstic intrvenous tubing set such s is ordinrily used to dminister fluids. The proximl end of the set is detched by cutting the tube with scissors. The distl end, which hs needle dpter, redily fits into the T-tube (Figure 1). After it is ttched to the T-tube, which is fixed to the bdominl wll with either sutures or dhesive strpping, the long intrvenous tubing is brought This work ws ided by grnt from the sc Brotmn Foundtion of the Culver City Hospitl, Culver City. Submitted Februry 23, 1961. Figure 1._-Plstic intrvenous tubing with needle dpter (inset) fits redily into the distl end of T-tube. Tubing photogrphed (Vcoset V-1 ws supplied by Don Bxter, nc., Glendle. out from beneth the dressings nd is llowed to hng over the side of the bed to collecting bottle. Being both light in weight nd long enough to permit the ptient good del of freedom of motion without drwing it tut, the plstic tubing does not put trction on the T-tube. Even should the ptient indvertently pull directly on the plstic tubing, the trction seprtes it from the T-tube t the point of ttchment. When the ptient rises to wlk bout, the plstic tubing cn be coiled nd the distl end plced into smll collecting bottle pinned to the bdominl dressing, nd when he returns to bed it cn be uncoiled nd the end put into dringe bottle t the side of the bed gin. 61 Wilshire Boulevrd, Los Angeles 36. VOL. 9, O. 6 * JUE 1961 33