Adjunctive Salvage Therapy with Inhaled Aminoglycosides for Patients with Persistent Smear-Positive Pulmonary Tuberculosis

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1 MAJOR ARTICLE Adjunctive Salvage Therapy with Inhaled Aminoglycosides for Patients with Persistent Smear-Positive Pulmonary Tuberculosis Leonard V. Sacks, a Stella Pendle, Dragana Orlovic, Marie Andre, Miriana Popara, Gavin Moore, Leif Thonell, and Solly Hurwitz Sizwe Tropical Diseases Hospital, Johannesburg, South Africa A proportion of patients with drug-resistant and drug-susceptible tuberculosis (TB) have sputum that is smear and culture positive for Mycobacterium tuberculosis for a prolonged period of time, despite conventional therapy. Among such patients with refractory TB, an unblinded, observational study was undertaken that used conventional TB therapy and adjunctive aerosol aminoglycosides. Patients with persistent smear- and culture-positive sputum for M. tuberculosis (despite 2 months of optimal systemic therapy) were selected for adjunctive treatment via inhalation with aminoglycosides, and microbiological responses were monitored. Thirteen of 19 patients converted to smear negativity during the study: 6 of 7 with drug-susceptible TB and 7 of 12 with drug-resistant TB. Among patients with drug-susceptible TB, the median time to sputum conversion was 23 days, a shorter time than for a population of historical control patients. Recurrent infection was not observed. Adjunctive aerosol aminoglycosides may expedite sterilization of sputum among certain patients with refractory TB and diminish the risk of transmission. Although uncomplicated drug-sensitive tuberculosis (TB) generally responds well to appropriate therapy, with 85% of subjects converting to smear negativity for Mycobacterium tuberculosis within 2 months [1], some patients remain smear and culture positive for prolonged [2] and, in some cases, indefinite periods of time. The most obvious cause for prolonged sputum positivity is drug resistance [3]. However, even patients with drug-sensitive TB may fail to convert. This is often associated with extensive cavitary disease [4], in which Received 7 January 2000; revised 26 May 2000; electronically published 12 December Verbal informed consent was obtained from participating patients. a Present affiliation: Center for Drug Evaluation and Research, Division of Special Pathogens, Rockville, MD. Reprints or correspondence: Dr. Leonard Sacks, Center for Drug Evaluation and Research, Division of Special Pathogens, 9201 Corporate Boulevard, HFD 590, Rockville, MD (SacksL@cder.fda.gov). Clinical Infectious Diseases 2001; 32: by the Infectious Diseases Society of America. All rights reserved /2001/ $03.00 systemic antimicrobial drugs fail to reach the sites of infection. The efficacy of systemic therapy is limited by constraints on drug dosage, by adverse drug reactions (especially common among patients concurrently infected with HIV [5]), and by inadequate drug distribution within the sites of pathology. Apart from standard usage in bronchospasm, aerosols have proved efficacious as a delivery system for pentamidine in the prophylaxis of Pneumocystis carinii pneumonia [6], and inhaled tobramycin has been used with some benefit in the management of cystic fibrosis [7]. In pulmonary TB, aerosol delivery of interferon [8] has shown some possible benefit as an adjunct to systemic therapy in refractory cases. Given the particular problem of intractable sputum positivity in patients with pulmonary TB, we examined the use of aerosol aminoglycosides as an adjunctive salvage therapy for patients with TB who were not responding to conventionally administered standard therapy. Aminoglycosides are an important component of 44 CID 2001:32 (1 January) Sacks et al.

2 therapy for TB. Unfortunately, using them for long periods of time has considerable side effects, particularly deafness resulting from the long-term use of streptomycin. Other aminoglycosides, such as gentamicin and kanamycin, cannot be used systemically on a long-term basis because of toxicity. Limited information suggests that these agents may also be effective against mycobacteria in vitro, but at concentrations greater than those attainable by systemic administration [9, 10]. Aerosol aminoglycosides are generally safe [11], although in patients with asthma a decrease in the forced expiratory volume of air in 1 s has been reported [12]. Studies in animal models confirm that gentamicin administered by aerosol is not systemically absorbed [13]. Therefore aerosol aminoglycoside therapy offers the possibility of delivering high concentrations of the agent at the site of infection with no systemic toxicity. We investigated patients who were not responding within a reasonable period of time to optimal systemic regimens of TB therapy. They were treated while they were in the hospital with adjunctive gentamicin or kanamycin, which was delivered via inhalation to expedite drug delivery. PATIENTS AND METHODS Sizwe Tropical Diseases Hospital is a referral center for patients with complicated TB from the greater Johannesburg area. Drug-resistant cases of TB and cases of advanced disease are commonly seen. Approximately 260 inpatients occupy the hospital at any one time. Sixty percent of the patients are infected with HIV, and multidrug-resistant TB is present in 16%. Baseline investigations performed for patients admitted with TB include a sputum smear, culture for M. tuberculosis, and a drug susceptibility test. Patients are tested for HIV infection, with their consent. A CD4 cell count was performed on those who tested positive for HIV. Patients are checked daily while in the hospital, and data are captured at admission, at week 2 after admission, at week 4 after admission, and then monthly. At the time of each data capture visit and, more frequently, at the clinician s discretion, sputum acid-fast bacillus (AFB) smears are performed and are examined by use of Ziehl Neelsen staining until 2 negative smears are obtained or until the patient stops coughing. Sputum cultures are repeated at 8 weeks for patients who are still coughing. Most patients are referred to the hospital from primary-care facilities within a week of the confirmation of the diagnosis of TB. Some patients with drug-resistant TB are referred by tertiary-care institutions once drug resistance is identified, and appropriate therapy is initiated in the hospital. All data are captured on standardized flow sheets and stored in a central computerized database. Treatment. Patients with drug-sensitive TB are treated with a standard short-course regimen consisting of isoniazid (INH), rifampin, ethambutol, and pyrazinamide for 8 weeks and INH and rifampin for 16 more weeks. Directly observed therapy is implemented while patients are hospitalized. Patients often remain in the hospital until sputum smears are negative and clinical improvement is evident. Therapeutic regimens for patients with isolates resistant to at least INH and rifampin are selected on a hierarchical basis from the following: pyrazinamide, ethambutol streptomycin, ethionamide, thiacetazone, ofloxacin, kanamycin, terizidone, clofazimine, roxithromycin, and amoxicillin-clavulanate. Drugs to which the isolate is resistant or drugs to which the patient is intolerant are omitted. Thiacetazone is not given to HIV-positive patients. Where possible, a minimum of 5 effective drugs is given to each patient with a drug-resistant isolate. Since 1996, patients who failed to respond to clinical therapy were offered empiric therapy with gentamicin or kanamycin administered via aerosol as an adjunct to their existing treatment regimens, which were administered orally. In patients with drug-resistant TB, kanamycin was selected if drug sensitivity tests confirmed kanamycin susceptibility. Drug sensitivity testing was not performed for gentamicin. It was used because of its availability and its low cost, and because of its theoretical potential for high local drug delivery by aerosol. One 80-mg ampoule of gentamicin sulfate was diluted in 2 3 ml of saline and administered by nebulizer (Micro Mist Nebulizer, Hudson Respiratory Care) at a dose of 80 mg every 8 h. Kanamycin sulfate was administered at the same dose. The duration of therapy administered via aerosol was dictated by practical considerations and sputum smear conversion times. Patients remained hospitalized while they received aerosol therapy. Patients who failed to respond to therapy were identified as those receiving optimal systemic drug regimens for whom sputum smears remained positive for more than 2 months after the start of therapy. In most patients, smear positivity had persisted for longer. Where possible, the case definition was supported by a recent positive sputum culture. Patients with positive sputum smears and concurrent negative sputum cultures were excluded from the study. Patients!18 years old were also excluded. A control population for patients with drug-susceptible refractory TB was developed from the hospital database. Qualifying cases required a positive sputum AFB smear despite 2 months of appropriate therapy. Isolates from these patients were required to be fully susceptible to all first-line anti-tb agents, and no form of aerosol treatment was permitted. Because there were inadequate numbers of patients, it was not possible to identify a meaningful control group for patients with any degree of drug resistance. Radiological scoring. Radiological scoring of baseline Aerosol Aminoglycosides for TB CID 2001:32 (1 January) 45

3 chest radiographs was performed as described elsewhere [14]. Briefly, a transparent grid of squares 3 cm 3 cm was placed over each radiographic image, and the number of squares that showed predominant cavitation was expressed as a percentage of the total number of squares that showed lung tissue on the posteroanterior image. Scores were allocated independently by 2 medical officers, and the mean of their results was used as the final score. Drug sensitivity testing. Sputum samples were cultured in Middlebrook 7H12 with the Radiometric BACTEC system (BD Biosciences). Susceptibility testing was performed with a modified proportion method [15] with a critical drug concentration by the Radiometric BACTEC system [16] for INH, rifampin, ethambutol, and streptomycin. Lowenstein-Jensen and Middlebrook 7H11 media were used to test ofloxacin, terizidone, ethionamide, thiacetazone, and kanamycin. Statistical analysis. Kaplan-Meier curves were generated to compare proportions of subjects who were smear positive at each month of therapy (S-plus 2000; Mathsoft). Fisher s exact test was used to compare the 1-month response rates in the experimental and control groups. RESULTS Twenty-four patients received aerosol aminoglycoside therapy from February 1997 through July 1998 on the basis of a positive smear for AFB at the time that aerosol therapy was introduced and a prolonged history of sputum smear positivity despite appropriate therapy for TB. Five of these patients were withdrawn from the study when mycobacterial cultures performed on sputum samples obtained before starting aerosol therapy were found to be negative, despite positive sputum smears. The mean age of the patients was 36 years (range, years). Four were women. Most patients were men because the study was begun in a male ward. Six patients were HIV positive, with a mean CD4 cell count of cells/l. Drug-resistant TB was present in 12 of 19 patients. Resistance to INH alone was present in 2 patients; to INH and rifampin in 4; to 3 5 agents (including INH and rifampin) in 3; and to 6 agents in 3. Resistance to streptomycin was present in 3 patients with multidrug-resistant isolates, and concurrent resistance to kanamycin was present in 1. The choice of gentamicin or kanamycin was made according to the physician s preference and according to the availability of the medication. Gentamicin alone was given to 13 patients; gentamicin and kanamycin were given at different times to 4 patients, 2 of whom had drug-resistant infections. Kanamycin alone was given to 2 patients, both of whom had drug-resistant infections. The mean interval of documented smear positivity on conventional treatment, before institution of aerosol therapy, was 96 days (range, days). Three patients with highly drug-resistant isolates were referred to our hospital; the referring institutions reported that smears and cultures had been persistently positive for 1, 3, and 4 years. We accepted these patients as having satisfied our requirement for positive smears for at least 2 months while on effective therapy. The patients were administered aerosol aminoglycosides without waiting an additional full 2 months for documentation of positive sputum samples in our hospital. For several patients, the period of smear positivity while on appropriate systemic therapy was underestimated because accurate dates of previous smear positivity from referring institutions were not available. For these patients, the duration of smear positivity while undergoing therapy was determined while the patient was in the hospital. Duration of aerosol therapy. Aerosol therapy was continued for a mean of 58 days (range, days). Several patients who did not respond to therapy and who had no therapeutic options received prolonged therapy. In the 9 patients who converted to negative sputum within!2 months, the mean duration of aerosol therapy was 33 days. None of the patients reported hearing loss, tinnitus, or dizziness while on therapy. Control patients. From a hospital database of 618 patients with TB admitted from 1996 through 1998, 26 patients with drug-susceptible isolates who remained smear positive after 2 months of appropriate systemic therapy were identified. We could not find enough patients with drug-resistant isolates to provide a meaningful control group for patients with drugresistant TB. Sputum smear results. All patients were sputum smear positive at the time that aerosol aminoglycoside therapy was initiated. Thirteen (68%) of 19 patients converted to smear negativity within the period of the study. Seven patients with drug-susceptible isolates who had been smear positive for a mean of 3.7 months (range, 2 6 months) were identified. After initiating aerosol therapy, 6 (86%) of 7 patients converted to smear negativity by the time the next sputum sample was obtained (all within 1 month). The remaining patient was persistently smear positive for the duration of the study. In the control population, 12 (46%) of 26 patients converted to smear negativity within 1 month, a further 4 within 2 months, and 3 within 3 months (figure 1). Follow-up data for 7 patients who remained smear positive after 1 month were unavailable. A comparison of the proportion of smear conversions at 1 month between aerosol-treated patients and control patients suggested a trend to more rapid sputum conversion in the experimental group ( P p.095). Seven of 12 patients with drug-resistant isolates converted to smear negativity over a longer time (figure 2). The median interval between instituting aerosol therapy and the first negative smear was at most 23 days among patients who converted to negative smears. Because the time of sputum collection after 46 CID 2001:32 (1 January) Sacks et al.

4 infection were observed during the study period in the patients who responded to therapy. Two patients died a mean of 196 days after starting aerosol therapy, 1 of ongoing multidrug-resistant TB and 1 of presumed respiratory failure. Baseline chest radiographs demonstrated extensive cavitation in all the patients. The mean percentage of visible lung occupied by cavitation was 20% (range, 5% 48%). DISCUSSION Figure 1. Kaplan-Meier curves demonstrating the proportion of patients remaining smear positive, by month of treatment in experimental and control patients with drug-susceptible tuberculosis after the introduction of aminoglycosides administered as aerosol at month 0. starting aerosol therapy was left to the clinician s discretion, sputum conversion may have occurred before the physician elected to obtain the first specimen. For patients with drugsensitive isolates, the median time to sputum conversion was 23 days (range, 9 39 days), and for patients with drug-resistant isolates, it was 46 days (range, days). Sputum culture results. Sputum cultures were positive for 14 of 19 patients within 1 month before starting aerosol aminoglycoside therapy, for 4 of 19 patients within the 2 months before aerosol therapy, and for 1 patient within the 4 months preceding aerosol therapy. Sputum cultures were available after the onset of aerosol therapy for 9 patients. Among the patients with drug-sensitive isolates, 2 of 3 cultures were negative within the first month. The remaining positive culture in this group was obtained from a patient whose smears remained persistently positive after aminoglycoside therapy. Among 12 patients with drug-resistant isolates, 6 had cultures performed within 3 months after introduction of aerosol aminoglycoside therapy; 3 cultures were negative. Discordant sputum smear and culture results were seen for 2 drug-resistant cases of TB; in both instances, cultures were negative and smears were positive. Durability of responses. In 7 of 13 patients whose sputum samples converted to negative, follow-up microbiological data were available for 1 month beyond conversion to smear negativity. One patient with a drug-resistant infection had a recurrence of a positive sputum smear but a concurrent negative culture some time during follow-up. The smear result may have represented residual nonviable organisms. In 5 patients, smears remained negative or coughing ceased. For 1 patient with a multidrug-resistant infection, posttreatment cultures were negative although positive smears persisted, again suggesting the presence of nonviable organisms. Except for the 1 patient who produced a single positive smear and a negative concurrent culture 1 month after sputum conversion, no recurrences of We examined the effectiveness of adjunctive aerosol aminoglycosides as salvage therapy for a population of 19 patients with TB who failed to respond to traditional therapy. Patients were selected if they remained sputum smear positive for at least 2 months despite optimal antimicrobial therapy for TB. Most had extensive cavitary disease, and clinicians had judged drug penetration to the site of pathology to be a problem. The population included patients with drug-susceptible and drugresistant TB, and both HIV-positive and HIV-negative patients. Aerosol gentamicin or kanamycin was administered every 8 h by inhalation for days. Overall, 68% of the patients converted from smear positivity to negativity while receiving the therapy: 7 of 12 drug-resistant patients and 6 of 7 drug-sensitive patients. The treatment was well tolerated. Among the patients with drug-susceptible TB treated with aerosol gentamicin, sputum conversion occurred rapidly. In all 6 (86%) who converted, this occurred within 1 month of starting aerosol therapy. The median time to conversion was 23 days, and even shorter times to sputum conversion might have been observed had sputum samples been obtained and examined sooner. Control patients with refractory Figure 2. Kaplan-Meier curves demonstrating the proportion of patients remaining smear positive after the introduction of treatment with aminoglycosides administered as aerosol at month 0. Curves represent findings for 3 groups of patients: patients with fully drug-susceptible tuberculosis (TB), patients with TB with intermediate drug resistance to 1 or 2 first-line agents, and patients with TB with high-grade resistance to 3 9 agents. Aerosol Aminoglycosides for TB CID 2001:32 (1 January) 47

5 drug-susceptible TB converted more slowly, and only 12 (46%) of 26 converted within the first month of observation. The small numbers of patients provided limited statistical power to confirm a difference in conversion rates, and alternative study designs with less demanding entry criteria will be required to confirm the advantages of aerosol therapy for treating refractory TB. AFB sputum smears alone may remain positive for a long time [17]. In many cases, concurrent cultures are negative, and the positive smears are presumably due to dead organisms. In others, mycobacteria other than TB or drug-resistant organisms are discovered. The patients in our study were selected for aerosol therapy on the basis of a recent positive culture where the species was confirmed as M. tuberculosis, and presence or absence of drug resistance was determined. Cures determined by smear were not always confirmed by culture, but prolonged clinical follow-up supported the results of smear tests. Our findings suggest a favorable response to adjunctive aerosol therapy, particularly in individuals with drug-susceptible isolates. However, we recognize many caveats in the interpretation of our data. Studies of response rates to therapy among patients with TB are fraught with problems. The slow evolution of the disease results in a broad spread of response rates even under conditions of conventional therapy. Under the best of circumstances, many study patients would be needed to compensate for such variability. However, difficulties both in identifying and assembling large cohorts of patients with TB who are failing to respond to conventional therapy make such projects impractical. Other studies of adjunctive therapy for TB illustrate just these difficulties. Johnson et al. [18] reported on 35 patients in a 3- arm study that compared treatment with 2 doses of adjunctive intradermal recombinant human IL-2 and treatment with placebo in a group of multidrug-resistant patients with TB who were not responding to therapy. Because the number of patients was small and the response rates were variable for patients in all 3 arms of the study, the authors could do no more than identify a trend towards benefit in the high-dose treatment arm. Five of 8 of their high-dose patients, 2 of 7 of their low-dose patients, and 3 of 9 of their patients taking placebo showed reduced or cleared sputum AFB loads during the study period. In an uncontrolled trial, Condos et al. [8] reported adjunctive therapy with aerosol IFN-g in 5 patients with drug-resistant disease and persistent smear positivity. Their results were inconclusive. Four converted to smear negativity within 1 month; however, all remained culture positive. Further, the response was short-lived, and 4 of 5 patients reverted to smear positivity a month after aerosol therapy was stopped. Because of where our hospital was located, and because of financial considerations, we looked at a relatively inexpensive aerosol approach to antibiotic therapy and had encouraging results. Since our intervention was not conceived as a clinical trial but was offered to despairing patients as an empirical salvage therapy, we could not work within the rigid framework of a controlled trial. The fact that aerosol therapy rather than spontaneous recovery was responsible for sputum conversions was suggested by prolonged periods of smear positivity on conventional treatment before starting aerosol therapy and rapid response times after therapy was introduced. The high response rate among patients with refractory drug-susceptible TB (6 of 7 patients) lent further support to the efficacy of aerosol aminoglycosides. Responses in patients with drug-resistant strains of TB were poor despite in vitro sensitivity to aminoglycosides. Other factors such as anatomical or immunological defects may have impaired the responses in these patients. Clearly the durability of responses remains a central question. Even optimal conventional therapy for uncomplicated drugsensitive TB carries a relapse rate of up to 9% for short-course regimens [19], and relapse rates in complicated disease are higher. Further studies will be required to examine this issue. In the short term, however, there is an obvious advantage in sterilizing patients rapidly while in the hospital to avoid the substantial risks of nosocomial transmission [20, 21]. The therapeutic impact of aerosol aminoglycoside therapy remains to be clarified. Residual aminoglycoside in sputum expectorated from large cavities could conceivably inhibit intracavitary bacterial growth and prevent transmission without affecting the organisms inside macrophages. The respective roles of aerosol and systemic therapy in eradicating infection, and the required duration of therapy, will require further study. The distribution of aerosol aminoglycosides in the lung also requires further investigation to confirm they penetrate into lung cavities. Such information may motivate more liberal use of inhaled aminoglycosides and, indeed, other antimicrobial agents among patients with refractory TB. Acknowledgment We thank Karen Higgins for her help with the statistical analysis. References 1. American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994; 149: Goble M, Iseman MD, Madsen LA, Waite D, Ackerson L, Horsburgh CR. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993; 328: Fischl M, Daikos G, Uttamchandani RB, et al. 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