Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation

6

Infecttous Diseases Newsletter 11(1) January 1992

to be evaluated. How otten smgledose AUC measurements would have to be repeated would depend on the stabdlty of the renal impatrment.

Monitoring Hearing Hearing should be momtored for patients believed to be at nsk (eg, those receiving total doses beyond the manufacturer's guidelines, those with renal impairment). Much useful data is never collected because of the mrstaken belief that control audiograms can be taken only before therapy is initiated, or on the fast day of therapy. In fact, our animal studies predict that control audiograms could be obtamed even for 3 days after an ototoxic amount of drug has already been delivered. In practice, however, efforts should be made to have the first auchogram taken within about 5 days of starting a normal course of therapy (earlier if renal insufficiency is presen0. In the case of very sick patients it may even be advisable not to administer an auchogram too early because the patient may be in better condition to take a heating test once therapy ha progressed a httle. The highest hearing frequency possible should be included in a monitormg program because high frequency hearing is the most sensitive to ototoxiclty. If high frequency heanng loss is noted during therapy, dosing should cease unless alternative therapy is not feasible. If the Ingh frequency loss is due to aminoglycoside anUbiottc therapy, further progression of hearing loss can be expected even though dosmg has ceased. Our animal studies reveal that amfl~acm-mduced bearing loss is, for the most part, irreversible.

Any heanng loss that undergoes a reversal must therefore be looked upon w~th suspicion because there is a strong chance that the loss was due to other causes. In addmon to momtoring heanng during therapy, an audiogram should be measured about 10 days or more to after therapy is completed to include any delayed ototoxicity that might occur.

Summary Animal experiments have shown the mcidence of amikacin ototoxicity to be a sigmoid function of cumulative plasma AUC regardless of plasma levels. They further suggest that the key determinant of ototoxicity is cumulaave perilymph AUC, which is directly proportional to both cumulative plasma AUC and total dose. Hence, both cumulatwe plasma AUC and total dose estimate the likelihood of ototoxmty, but the former is superior since it takes into account individual &fferences in plasma levels. There are not enough human data for any aminoglycoside antibiotic yet to accurately esttmate the sigmoid curve relating the incidence of ototoxic~ty to cumulatwe serum AUC or total dose. It is possible, however, to calculate a sigmoid relationship of incidence of ototoxicity to kanamycin total dose based on rough estimates from prevmus publications of human data. Although these results have yet to be fully verified in humans and for all aminoglycoside antibiotics, it would seem wtse to take steps to ensure that dosing adjustments adequately compensate for the increased serum AUC

that would occur in patients with reduced renal function.

Bibliography Beaubten AR, Dosjardu~ S, Ormsby E, et al: Incidence of amikaem ototoxicity: A stgrnoid function of total drug exposure mdependent of plasma levels. Am J Otolaryngol 10:23-24, 1989. Beaubten AR, Desjardins S, Ormsby E, et ah Delay m hearing loss following drug administration: A consistent feature of amlkacm ototoxicity.Acta Otolaryngol

(Stockh) 109:345-352, 1990. Beaubien AR, Onnsby E, Bayne A, et al: Evidence that amikacin ototoxicity is related to total perilymph area under the concentration-ttme cm've regardless of concentratmn. Antimicrob Agents Chemother 35:1070-1074, 1991 Bernstein JM, Gorse GJ, Linzmayer, MI et al: Relative efficacy and toxicity of nettlm~cmand tobramycin m oncology pahents. Arch Intern Meal 146:2329-2334, 1986. Brummett RE, Morrison RIB:The mcadence of anunoglycostde antibiotic-induced hearing loss. Arch Otolaryngol Head Neck Surg 116:406--410, 1990. Cheung R, Clark P, Nicholson PW et al: Screening for ammoglycoside auditory

toxicity m the old. Br J Clm Pharmac 30.1-11, 1990. Frost JO, Hawkins JE, Duly JF: Kanamycm. II. Ototoxicity. Am Rev Resp Dis 82.23-30, 1960. Govaerts PJ, Clues J, Van De Heymng PH et al: Aminoglycoside-induced ototoxictty Toxlcol Lett 52:227-251, 1990. Sataloff J, Wagner S, Menduke H: Kanamycm ototoxiclty in healthy men. Arch Otolaryngol 80:413-417, 1964 Address correspondenceto ArthurR Bewblen, PhD, Biopharmaceuttcsmd Plmrmacodynamtcs Dtvmon, Bureau of Drug Research,2W, Frederick G. BantmgBuddmg,Tunney'sPasture, Ottawa, Ontario, CanadaKIA 0LZ

COMMENTS ON CURRENT PUBLICATIONS Sullivan KM, Kopecky KJ, Jocom J, et al: Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation. N Engl J Med

323:705-712, 1990. In this randomized trial, 382 bone marrow transplant recipients were given lmmunogiobulin (500 mg per kilo@1992 Elsevier Science Pubhshmg Co., Inc 0278-2316/92/$0 00 + 3 00

gram weekly until day 90, then monthly until day 360 posttransplantation) and compared with controls not given tmmunoglobulin. Among the 308 patients who were seropositive

7 Infectious DiseasesNewsletter 11(1) January 1992

for CMV, 22% of control patients and 13% of immunoglobulin recipients cona'acted interstitial pneumonia caused by cytomegalo virus (CMV) (p = 0.021). Control patients had an increased risk of Gram-negative septicemia (relative risk: 2.65, p = 0.0039) and local infection (relative risk: 1.36, p = 0.029). Although there was no alteration of the risk of relapses nor survival, there was in patients > 20 years old a reduction in the incidence of acute graft-versus-host disease (51% m controls versus 34% in immunoglobulin recipients; p = 0.0051) as well as a decrease in deaths due to transplant-related causes after transplantation of HLA-identical marrow (46% versus 30%; p = 0.023). The authors conclude that passive immunoglobulin decreases the risk of acute graft-versus-host disease, intersatml CMV pneumonia, and other refections after bone marrow transplantation. Comment Interestingly, in this study the overall survival rate was not improved. By chance, however, the immunoglobulin group included more patients with advanced-stage neoplasms. Proportionalha7ards analysisof the recurrence of neoplasms confirmed that the presence of advanced-stage disease was associated with an increased risk of relapse (p = 0.0001). The toxicity of tmmunoglobulin therapy was minimal. Importantly, platelet recovery improved in the immunoglobulin recipients with the period during which platelet Iransfusions were needed, bemg decreased by 21 days. The recovery of myeloid function in the two groups was similar, thus differences in the rates of septicemia and infection with candida or aspergillus were not due to differences in the rates of neulrophil recovery. The decreased rate of CMV pneumonm is particularly encouraging. Altogether, this study convincingly demonslrates that immunoglobulin therapy significantly reduced the early complications of bone marrow transplantation. Further

studies are needed to evaluate the long-term effectiveness. CWS

[] Rogers TR, Haynes KA, Barnes RA: Value of antigen detection in predicting invasive pulmonary aspergillosis. Lancet 336:1210-1213. In order to establish the value of antigen detection in the diagnosis of aspergillus infection, this study evaluated two ELISA methods for the diagnosis of aspergillus infectton in high-risk neutropemc patients. One method was a high-titer human anti-aspergillus serum and the other a rat IgM monoclonal antibody to A fumigatus. Both ELISAs gave positive and negative predictive values for invasive pulmonary aspergillosis. The presence of antigen correctly predicted development of mvasive pulmonary aspergiUosis in 16 patients of 12] studies. In two other cases, antigen appeared after the clinical diagnosis had been made, whereas in only one case was antigen not detected. In 11 of 13 episodes of climcally suspected fungal infection, antigen was detected before the clinical diagnosis was made. The response to empmc therapy initiated on the basis of climcal evidence alone was, as expected, poor, with only 5 of the 31 patients surviving. If the basis for initiating empmc therapy was a positive antigen test, then 27 patients would have received therapy a median of 21 days earlier. It is likely that such earlier therapy would improve the surwval rate. Comment The diagnosis of invasive pulmonary aspergillus is exlremely difficult, resuiting in delayed therapy with amphotericin B. Although amphotericin B is initiated empirically based upon clinical suspicion alone, the therapeutic response remains poor. Clearly, the ©1992 Elsevier Scaence Publishing Co., Inc. 0278-2316/92/$0.00 + 3.00

initiation of therapy a median of 3 weeks earlier is likely to improve the response to amphotericin B in these patients. Controlled trials comparing early treatment with conventional treatment needs to be done. CW5

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Wolinsky SM, Rinaldo CR, Kwok S, et al: Human immunodeficiency virus type 1 (HIV.1) infection a median of 18 months before a diagnostic Western blot. Ann Intern Med 1/1:961-972, 1990. This study used the polymerase chain reaction technique to monitor the presence of HIV-1 proviral sequences in peripheral blood mononuclear cells from persons enrolled in a longitudinal study. In 20 of the 24 men, HIV-1 was detected before HIV-I antibody seroconversion. In the four other men, the HIV-1 was detected concurrent with confLrmation of antibody seroconversion by Western blot, the length of time before antibody seroconversion by Western blot. The time period before antibody seroconversion was as long as 42 months (two cases) and was 18 months in eight cases (median time).

Comment This study indicates that HIV- 1 can have a long and variable interval between virus infection and the manifestation of detectable immunologic abnormalities. In this study, the p24 antigen-capture assay did not detect HIV-1 before a diagnostic antibody response. The results of this study also suggest that there may be a silent reservoir of HIV-1 harbored by persons who are serologically negative. CWS

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