Gitelman-like syndrome: A rare complication of using aminoglycosides in tuberculosis - A case report.

Aminoglycosides are known to cause electrolyte disturbances. Approximately 8-26% of patients who receive an aminoglycoside for several days develop mild renal impairment that is almost always reversible (Brunton et al., 2013). A 46 year old male with multi-drug-resistant pulmonary tuberculosis with resistance to kanamycin is being presented, who was on injectable Capreomycin, Levofloxacin, Ethionamide, Cycloserine, pyrazinamide, linezolid and clofazamine for a period of four months. He presented to us with generalised weakness and pain in the lower limb muscles. Investigation revealed hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalceuria and hypocalcemia. This features mimic Gitelman's syndrome which is an autosomal recessive disorder affecting kidneys causing electrolyte disturbances. The drug was immediately withdrawn and electrolyte correction was given and the condition reversed gradually.

Second-line injectable induced ototoxicity in drug resistant tuberculosis: A systematic review of Indian studies.

Second-line injectables (SLIs) form an essential class of agents in the treatment of drug resistant (DR) tuberculosis (TB). However, their use is sometimes limited due to serious adverse events like ototoxicity and hearing loss, leading to permanent hearing loss if SLIs are continued. Globally as well as in India a wide variation in incidence of ototoxicity/hearing loss has been reported in patients with DR-TB. In this systematic analysis, we attempt to ascertain the ototoxicity of SLIs in Indian patients with multidrug resistant tuberculosis (MDR-TB) wherein ototoxicity onset was assessed using audiometry performed at both pre- and post-SLI treatment initiation. Twenty two studies were identified based on the inclusion criteria. Ototoxicity was observed in 10.12% [349/3447] patients within 3.8 ± 2.6 months of treatment initiation when the ototoxicity was assessed either with or without audiometry assessment. Only five studies reported ototoxicity assessment with PTA at both pre- and post-SLI initiation and ototoxicity was observed in 27.01% (121/448) patients in these five studies. Sensorineural loss was observed in three studies (high frequency loss: capreomycin, 25.0% [1/4 patients]; amikacin, 19.7% [12/61]; kanamycin, 13.3% [22/166]; streptomycin, 11.8% [2/17]; flat loss: amikacin, 8.2% [5/61]; streptomycin, 5.9% [1/17]; kanamycin 4.8% [8/166]). Most of the patients experiencing ototoxicity were managed by discontinuing (49.6% [120/242]) or replacing SLI treatment (40.8% [49/120]). The study identified high prevalence of ototoxicity in Indian patients with DR-TB treated with SLI when ototoxicity was monitored regularly using PTA (27.01%), warranting a need to develop unified guidelines for monitoring ototoxicity, improving physician awareness and educating patients/caregivers for reporting symptoms of hearing loss.

Nephrotoxicity and ototoxic symptoms of injectable second-line anti-tubercular drugs among patients treated for MDR-TB in Ethiopia: a retrospective cohort study.

BACKGROUND: Nephrotoxicity and ototoxicity are clinically significant dose-related adverse effects associated with second-line anti-tubercular injectables drugs (aminoglycosides and capreomycin) used during intensive phase of treatment of multi-drug resistant tuberculosis (MDR-TB) patients. Data are scarce on injectable-induced nephrotoxicity and ototoxicity in Ethiopian MDR-TB patients. The aim of this study was to assess the prevalence, management of nephrotoxicity and ototoxic symptoms and treatment outcomes of patients treated for MDR-TB with injectable-based regimens. METHOD: This was retrospective cohort study based on review of medical records of about 900 patients on MDR-TB treatment from January 2010 to December 2015 at two large TB referral hospitals in Addis Ababa, Ethiopia. Nephrotoxicity in study participants was screened using baseline and monthly measurement of serum creatinine and clinical diagnosis and patient reports. RESULTS: Overall, 473 (54.2%) of participants were male. Children accounted for 47 (5.5%) of cases and the mean age of participants was 32 ± 12.6 years with range of 2-75 years. The majority (n = 788, 84.6%) of participants had past history of TB. The most commonly used injectable anti-TB drug was capreomycin (n = 789, 84.7%), while kanamycin and amikacin were also used. There was a statistically significant increment (p<0.05) in the mean serum creatinine values from baseline throughout intensive phase of treatment with a 10-18% prevalence of nephrotoxicity. Based on clinical criteria, nephrotoxicity was detected in 62 (6.7%) and ototoxic symptoms were detected in 42 (4.8%) participants. Nephrotoxicity and ototoxic symptoms were clinically managed by modification of treatment regimens including dose and frequency of drug administration. CONCLUSION: Nephrotoxicity and ototoxic symptoms were significant problems among patients on follow-up for MDR-TB treatment. Based on laboratory criteria (serum creatinine), nephrotoxicity remained significant adverse events throughout intensive phase of treatment, indicating close monitoring of patients for successful outcome is mandatory until countries adopt the recent injectable-free WHO guideline and under specific conditions.

Risk of Nephrotoxicity in Patients With Drug-Resistant Tuberculosis Treated With Kanamycin/Capreomycin With or Without Concomitant Use of Tenofovir-Containing Antiretroviral Therapy.

BACKGROUND: The intersection of HIV and drug-resistant (DR) tuberculosis (TB) presents the challenge of managing convergent drug toxicities. METHODS: We conducted a retrospective study of adult patients with DR-TB treated with a kanamycin/capreomycin-based (KM) regimen, with or without concomitant antiretroviral therapy (ART). We estimated the incidence of nephrotoxicity (defined as an increase in serum creatinine greater than 26.5 µmol, or an increase in serum creatinine to 1.5 times the baseline value, or a decline in glomerular filtration rate to less than 60 mL/min/1.73 m), and evaluated the association between reported drug use and nephrotoxicity using Kaplan-Meier plots. RESULTS: A total of 215 patients with DR-TB were treated with a kanamycin/capreomycin-based regimen, with or without concomitant ART. The incidence rate of nephrotoxicity was 3.6 [95% confidence interval (CI): 1.4 to 7.3], 6.9 (95% CI: 5.2 to 9.0), and 12 (95% CI: 3.3 to 30.9) cases per 100 person-months of follow-up in the KM only group (n = 42), the KM + TDF (tenofovir disoproxil fumarate) group (n = 163), and the KM + Other ART group (n = 10), respectively. Using the KM only group as a reference, the hazard ratio was 2.06 (95% CI: 0.92 to 4.63) in the KM + TDF group, and 4.09 (95% CI: 1.17 to 14.25) in the KM + Other ART group. Advancing age was an independent predictor of nephrotoxicity (adjusted hazard ratio 1.29, 95% CI: 1.14 to 1.46). CONCLUSIONS: Our findings provide evidence of a significant risk of nephrotoxicity during treatment with a kanamycin/capreomycin-based DR-TB regimen, with or without concurrent treatment with ART. This study lends further support to calls for the substitution of TDF during the intensive phase of DR-TB treatment and for close monitoring of renal function during DR-TB treatment, especially in settings where the use of kanamycin/capreomycin is unavoidable.

Adverse Effects and Choice between the Injectable Agents Amikacin and Capreomycin in Multidrug-Resistant Tuberculosis.

The prolonged use of injectable agents in a regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) is recommended by the World Health Organization, despite its association with ototoxicity and nephrotoxicity. We undertook this study to look at the relative adverse effects of capreomycin and amikacin. We reviewed the case notes of 100 consecutive patients treated at four MDR-TB treatment centers in the United Kingdom. The median total duration of treatment with an injectable agent was 178 days (interquartile range [IQR], 109 to 192 days; n = 73) for those with MDR-TB, 179 days (IQR, 104 to 192 days; n = 12) for those with MDR-TB plus fluoroquinolone resistance, and 558 days (IQR, 324 to 735 days; n = 8) for those with extensively drug-resistant tuberculosis (XDR-TB). Injectable use was longer for those started with capreomycin (183 days; IQR, 123 to 197 days) than those started with amikacin (119 days; IQR, 83 to 177 days) (P = 0.002). Excluding patients with XDR-TB, 51 of 85 (60%) patients were treated with an injectable for over 6 months and 12 of 85 (14%) were treated with an injectable for over 8 months. Forty percent of all patients discontinued the injectable due to hearing loss. Fifty-five percent of patients experienced ototoxicity, which was 5 times (hazard ratio [HR], 5.2; 95% confidence interval [CI], 1.2 to 22.6; P = 0.03) more likely to occur in those started on amikacin than in those treated with capreomycin only. Amikacin was associated with less hypokalemia than capreomycin (odds ratio, 0.28; 95% CI, 0.11 to 0.72), with 5 of 37 (14%) patients stopping capreomycin due to recurrent electrolyte loss. There was no difference in the number of patients experiencing a rise in the creatinine level of >1.5 times the baseline level. Hearing loss is frequent in this cohort, though its incidence is significantly lower in those starting capreomycin, which should be given greater consideration as a first-line agent.

Differences in VigiBase® reporting of aminoglycoside and capreomycin-suspected ototoxicity during tuberculosis treatment.

PURPOSE: To evaluate the association between the use of streptomycin, amikacin, kanamycin and capreomycin in tuberculosis (TB) treatment and the pharmacovigilance reporting of ototoxicity (deafness or hearing loss, tinnitus and vertigo). Second, to analyze patient demographic and geographic factors that influence the reporting of ototoxicity in TB treatment. METHODS: A case/non-case disproportionality analysis of the VigiBase® individual case safety reports (ICSRs) of patients treated for TB using multidrug regimens that contain either of streptomycin, amikacin, kanamycin or capreomycin. Cases were reports of ototoxicity; non-cases were other adverse drug reactions (ADRs). The unit of analysis was the drug-ADR pair. We calculated reporting odds ratios (RORs) and their 95% confidence intervals (CI). The referent drug was streptomycin. RESULTS: By June 2014, there were 3361 drug-ADR pairs in VigiBase® (1693 ICSRs) where the parenteral administration of the four drugs for TB treatment was suspected of causing the reported ADRs. Deafness, tinnitus and vertigo were reported in 576 drug-ADR pairs (cases), the rest being other ADRs (non-cases). Reporting of deafness was most disproportionately associated with amikacin use (ROR 9.3; 95%CI 3.8-23.0), followed by kanamycin use (ROR 4.3; 95%CI 1.3-14.2). Reporting of vertigo was inversely associated with capreomycin use (ROR 0.1; 95%CI 0.01-0.4). Geographic region affected the reporting of ototoxicity while age and sex did not. CONCLUSION: Spontaneous reporting of deafness cases within VigiBase® was most disproportionately associated with amikacin use, followed by kanamycin. There were regional variations in the global reporting of ototoxicity. These findings should be verified through a follow up study. Copyright © 2016 John Wiley & Sons, Ltd.

The safety and tolerability of the second-line injectable antituberculosis drugs in children.

INTRODUCTION: A growing number of children globally are being treated for multidrug-resistant tuberculosis (MDR-TB). The second-line injectable antituberculosis medications amikacin, kanamycin and capreomycin, traditionally a mainstay of MDR-TB treatment, cause important adverse effects including permanent sensorineural hearing loss, nephrotoxicity, electrolyte abnormalities, injection pain and local injection site complications. Areas covered: To characterize the safety and tolerability of the second-line injectables in children treated for MDR-TB, we reviewed data on the mechanism of injectable associated adverse effects, risk factors for their development, and the incidence of injectable-associated adverse effects in adults and children treated for MDR-TB. Expert opinion: Despite a substantial evidence base in adults demonstrating the frequent and potentially serious adverse effects of second-line injectables, important knowledge gaps remain. Improved characterization of the incidence of injectable-associated adverse effects will inform rational guidance on monitoring children with TB on injectables. Eliminating the need for injectables in MDR-TB treatment regimens is a high priority, and will rely on the use of novel antituberculosis TB drugs. Strategies to reduce the risk of adverse effects of injectables, if used, deserve evaluation. This includes evaluation of potentially otoprotective medications N-acetylcysteine or aspirin, high frequency hearing screening for earlier detection of ototoxicity and therapeutic drug monitoring.

Phase I, single-dose, dose-escalating study of inhaled dry powder capreomycin: a new approach to therapy of drug-resistant tuberculosis.

Multidrug-resistant tuberculosis (MDR-TB) threatens global TB control. The lengthy treatment includes one of the injectable drugs kanamycin, amikacin, and capreomycin, usually for the first 6 months. These drugs have potentially serious toxicities, and when given as intramuscular injections, dosing can be painful. Advances in particulate drug delivery have led to the formulation of capreomycin as the first antituberculosis drug available as a microparticle dry powder for inhalation and clinical study. Delivery by aerosol may result in successful treatment with lower doses. Here we report a phase I, single-dose, dose-escalating study aimed at demonstrating safety and tolerability in healthy subjects and measuring pharmacokinetic (PK) parameters. Twenty healthy adults (n = 5 per group) were recruited to self-administer a single dose of inhaled dry powder capreomycin (25-mg, 75-mg, 150-mg, or 300-mg nominal dose) using a simple, handheld delivery device. Inhalations were well tolerated by all subjects. The most common adverse event was mild to moderate transient cough, in five subjects. There were no changes in lung function, audiometry, or laboratory parameters. Capreomycin was rapidly absorbed after inhalation. Systemic concentrations were detected in each dose group within 20 min. Peak and mean plasma concentrations of capreomycin were dose proportional. Serum concentrations exceeded 2 µg/ml (MIC for Mycobacterium tuberculosis) following the highest dose; the half-life (t1/2) was 4.8 ± 1.0 h. A novel inhaled microparticle dry powder formulation of capreomycin was well tolerated. A single 300-mg dose rapidly achieved serum drug concentrations above the MIC for Mycobacterium tuberculosis, suggesting the potential of inhaled therapy as part of an MDR-TB treatment regimen.

Efecto de la capreomicina sobre la función renal en pacientes con tuberculosis multidrogoresistente / Effect of the capreomycin on the renal function in patients with tuberculosis multidrogoresistent

Objetivos: - Determinar el efecto de la Capreomicina en la depuración de Creatinina Calculada, en pacientes con diagnóstico de Tuberculosis Multidrogoresistente. - Determinar el perfil epidemiológico; la frecuencia de uso de Capreomicina; si existe deterioro de la Depuración de Creatinina Calculada; el uso de fßrmacos AntiTBC como terapia asociada a Capreomicina y establecer la condición de egreso de los pacientes con Tuberculosis MuItidrogoresistente. Método: Se realizó un estudio descriptivo, de tipo retrospectivo en pacientes con Tuberculosis Multidrogoresistente, que fueron atendidos en el Servicio de Neumología del HNGAI entre los a±os 2000-2002, que recibieron la droga Capreomicina como tratamiento Individual izado complementario Resultados: Se revisaron 358 Historias Clínicas de pacientes, que recibieron tratamiento individualizado entre los a±os 2000 al 2002 inclusive, de los cuales 105 pacientes recibieron Capreomicina, 100 pacientes cumplieron con los criterios de inclusión, la cual es la muestra total; el 62 por ciento de pacientes, fueron del género masculino, el 70 por ciento de la población estuvo comprendido entre los 15 a 45 a±os, el 59 por ciento tuvo educación secundaria, el 79 por ciento de pacientes de la serie salió curado. El tiempo de tratamiento promedio de Capreomicina fue de 18.42 meses, el 59 por ciento de la muestra recibió tratamiento entre 12 a 24 meses, el 15 por ciento recibió tratamiento de 24 a 42 meses; las drogas asociadas usadas con mayor frecuencia fueron: Capreomicina (100 por ciento), Cicloserina (100 por ciento), Amoxicilina/Clavulanico (94 por ciento), Ofloxacina (71 por ciento), Pirazinamida (60 por ciento), con un promedio de 4.94 drogas; el 73 por ciento de pacientes de la serie recibieron Dosis de Capreomicina entre 150 a 350 grs como dosis - total, con un valor promedio de la serie de 273.73 grs, El estudio de sensibilidad de las cepas demostró...

Objectives: To determine the effect of Capreomycin in the purification of calculated Creatinine in patients with a diagnose of "Multidrugresistant Tuberculosis". To determine the epidemic profile; the frequency of use of Capreomycin; if deterioration of purification of calculated Creatinine exists; the use of AntiTBC drugs such as therapy associated with Capreomycin and to establish the condition of discharged patients with "Multidrugresistant Tuberculosis". Method: A retrospective descriptive study was carried out in patients with "Multidrugreststant Tuberculosis," that were treated in the Pneumonia Unit of the "HNGAI" between 2000-2002 and who received the Drug Capreomycin as a complementary individualized treatment. Results: 358 Clinical Histories were checked of patients, that received individualized treatment between 2000 and 2002 inclusive; of those, 105 patients received Capreomycin, 100 patients fulfilled the inclusion approaches, which is the total sample; 62 per cent of patients were men, 70 per cent were aged between 15 and 45 years old, 59 per cent had secondary education, 79 per cent of patients came out cured, the average treatment time for Capreomycin was of 18.42 months, 59 per cent of the sample received treatment for between 12 and 24 months, 15 per cent received treatment from 24 to 42 months, the associated drugs used with more frequency...

Hypokalemia among patients receiving treatment for multidrug-resistant tuberculosis.

INTRODUCTION: Between January 1999 and December 2000, 125 patients in Lima, Peru were enrolled in individualized treatment for multidrug-resistant tuberculosis (MDR-TB). Hypokalemia was observed to be an important adverse effect encountered in this cohort. OBJECTIVE: To identify risk factors associated with the development and persistence of hypokalemia during MDR-TB therapy, and to review the incidence and management of hypokalemia in patients receiving MDR-TB therapy. METHODS: A retrospective case series of 125 patients who received individualized therapy for MDR-TB between January 1, 1999, and December 31, 2000. RESULTS: Among 115 patients who were screened for electrolyte abnormalities, 31.3% had hypokalemia, defined as a potassium level of < 3.5 mEq/L. Mean serum potassium at time of diagnosis was 2.85 mEq/L. Diagnosis of low serum potassium occurred, on average, after 5.1 months of individualized therapy. Multivariate analysis of risk factors for this adverse reaction identified two causes: administration of capreomycin, and low initial body weight. Normalization of potassium levels was achieved in 86% of patients. CONCLUSIONS: Electrolyte disturbance was frequently encountered in our cohort of patients with MDR-TB. Successful screening and management of hypokalemia was facilitated by training the health-care team in the use of a standardized algorithm. Morbidity from hypokalemia can be significant; however, effective management of this side effect is possible without sacrificing MDR-TB treatment efficacy.

Renal magnesium wasting associated with therapeutic agents.

Renal magnesium wasting is an important cause of hypomagnesemia observed in hospitalized patients. The purpose of this review is to present an index case of symptomatic hypomagnesemia associated with renal magnesium wasting during capreomycin therapy, and to survey the available literature regarding the various therapeutic agents associated with the causation of this syndrome. Finally, we have considered the pathophysiologic mechanisms that may contribute to the development of the multiple electrolyte abnormalities observed in these patients, and have outlined the current strategies to treat this syndrome.

A Bartter's-like syndrome from capreomycin, and a similar gentamicin tubulopathy.

Marked renal potassium and magnesium wasting, alkalosis, and a progressive increase in plasma renin and eventual hyperaldosteronemia developed during a 15-month course of in-hospital capreomycin therapy that was necessary for drug-resistant pulmonary tuberculosis. A prominent feature of the present case was renal chloride wasting, a feature of the capreomycin syndrome that has previously received little attention. Similar potentially life-threatening metabolic abnormalities, which resemble those found in Bartter's syndrome, can occur during prolonged therapy with the antibiotic gentamicin. In the present case, electrolyte abnormalities were unaffected by three days of indomethacin therapy but were partially corrected by large doses of spironolactone. Capreomycin, viomycin (an antibiotic closely related to capreomycin), and gentamicin are highly basic polypeptide antibiotics that may induce strikingly similar and potentially fatal syndromes of renal tubular dysfunction that can feature multiple electrolyte abnormalities.

Acid-base and electrolyte abnormalities due to capreomycin.

We report a patient with tuberculosis treated with a five-drug regimen who experienced severe acid-base and electrolyte abnormalities including hypomagnesemia, hypokalemia, hypocalcemia, and a hypochloremic metabolic alkalosis. These disturbances are believed to be due to treatment with capreomycin, which produced renal magnesium wasting and possible tubular damage. Therefore, we recommend frequent determinations of serum electrolytes, magnesium, and calcium in patients treated with capreomycin.

[Experimental and clinical study test of capreomycin]. / Opyt éksperimental'nogo i klinicheskogo izucheniia kapreomitsina

Data on the experimental and clinical study of capreomycin in the treatment of tuberculosis are presented. It was shown that capreomycin had low activity with respect to the sensitive strain of Mycobacterium tuberculosis H37 Rv in vitro and the respective infection caused by it in mice. The activity of capreomycin in vitro with respect to streptomycin resistant strains was the same as that with respect to the sensitive strains, while in vivo it increased 3 times. Capreomycin showed a tendency to decreasing its activity with respect to strains highely resistant to canamycin only in vitro. The effect of capreomycin on tuberculosis infection caused by strains resistant to different concentrations of canamycin was the same as that on tuberculosis infection caused by sensitive strains. Cross resistance between florimycin (viomycin) and capreomycin was shown. Clinical trails of capreomycin revealed its moderate therapeutic efficiency, relatively low toxicity and an allergenizing effect on the host. Transient ventibulopatia without pronounced signs of ototoxic action was observed. The nephrotoxic effect was moderate and transient. It was observed predominantly at the peak of the allergic reactions to the antitubercle drugs. The data obtained during the study allow recommendation of capreomycin use in clinics as reserve drug when the causative agent is not resistant to florimycin. The drug should be used under regular control of the blood picture, electrolyte metabolism, state of the kidneys, auditory and vestibular apparatus.