- Email: [email protected]
XDR tuberculosis
Accepted Manuscript Title: Role of second-line injectable antituberculosis drugs in the treatment of MDR/XDR tuberculosis Author: Fanny Quenard, Pierre Edouard Fournier, Michel Drancourt, Philippe Brouqui PII: DOI: Reference:
S0924-8579(17)30178-4 http://dx.doi.org/doi: 10.1016/j.ijantimicag.2017.01.042 ANTAGE 5124
To appear in:
International Journal of Antimicrobial Agents
Received date: Accepted date:
18-10-2016 28-1-2017
Please cite this article as: Fanny Quenard, Pierre Edouard Fournier, Michel Drancourt, Philippe Brouqui, Role of second-line injectable antituberculosis drugs in the treatment of MDR/XDR tuberculosis, International Journal of Antimicrobial Agents (2017), http://dx.doi.org/doi: 10.1016/j.ijantimicag.2017.01.042. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Role of second-line injectable antituberculosis drugs in the treatment of MDR/XDR tuberculosis
Fanny Quenard a,b, Pierre Edouard Fournier a,b,Michel Drancourt a,b, Philippe Brouqui a,b,*
a
Institut Hospitalo Universitaire Méditerranée Infection, APHM, Marseille, France
b
Aix-Marseille Université, Unité de Recherche sur les Maladies Infectieuses et Tropicales
Emergentes, UM63, CNRS 7278, IRD 198, INSERM 1095, Marseille, France
*
Corresponding author. Address: Institut Hospitalo Universitaire Méditerranée Infection,
APHM, Marseille, France. E-mail address: [email protected] (P. Brouqui).
ARTICLE INFO Received 18 October 2016 Accepted 28 January 2017
Keywords: Tuberculosis Mycobacterium tuberculosis MDR/XDR tuberculosis Adverse events Aminoglycosides Amikacin 1
Page 1 of 11
Second-line injectable antituberculosis drugs Nebulized aminoglycosides
2
Page 2 of 11
1 2 3 4 5 6 7
Highlights
The efficacy of aminoglycosides against multi-drug-resistant (MDR) bacilli is preserved. Aminoglycosides cause frequent adverse events. The average duration of treatment with amikacin is usually reported to be less than the 8 months recommended by the World Health Organization for MDR tuberculosis. The place of amikacin for optimized treatment of MDR/extremely-drug-resistant tuberculosis should be re-evaluated, including its route of administration.
Comment [A1]: AUTHOR: Two different versions of Highlight section were provided and one of the separate file has been used. Please check and confirm that it is correct.
ABSTRACT Second-line injectable antituberculosis drugs (aminoglycosides and capreomycin) are the main drugs used in the management of resistant tuberculosis. Their preserved efficacy in the case of multi-drug-resistant bacillus is counterbalanced by frequent adverse events. Adverse events are linked to the drugs themselves and to the recommended 8-month period of parenteral administration. In numerous countries facing a high incidence of multi-drugresistant tuberculosis, treatment is administered by intramuscular injection. This procedure is painful and restrictive, and therefore treatment adherence is limited. This study reports the follow-up of 11 patients diagnosed with multi-drug- and extensively-resistant tuberculosis and treated with parenteral amikacin, and discusses the role of amikacin in the treatment of resistant tuberculosis.
3
Page 3 of 11
Tuberculosis (an infection due to Mycobacterium tuberculosis) is a major public health problem worldwide, with an estimated 9.6 million new cases and 1.5 million deaths in 2014 [1]. France is a low-incidence country [World Health Organization (WHO) threshold: 20 cases per 105 habitants], with 7.3 cases per 105 habitants; this corresponded to 4827 new cases in 2014. Antibiotic-resistant tuberculosis is defined as tuberculosis caused by an M. tuberculosis strain resistant to at least one first-line treatment drug (pyrazinamide, isoniazid, ethambutol and rifampicin). Multi-drug-resistant (MDR) tuberculosis is defined as tuberculosis caused by an M. tuberculosis strain resistant to isoniazid and rifampicin. Extensively-drug-resistant (XDR) tuberculosis is defined as tuberculosis caused by an M. tuberculosis strain that is also resistant to fluoroquinolones and a second-line injectable drug. The prevalence of resistant tuberculosis is increasing, and 480 000 new cases of MDR tuberculosis were notified in 2014; 9.7% of these cases were XDR tuberculosis. Each year, between 80 and 100 new cases of MDR tuberculosis are diagnosed in France. The treatment success of MDR tuberculosis worldwide is almost 50% [1]. Most second-line antituberculosis drugs [levofloxacin, moxifloxacin, gatifloxacin, amikacin, capreomycin, kanamycin, streptomycin, ethionamide (or prothionamide), cycloserine (or terizidone), linezolid, clofazimine, bedaquiline, delamanid; p-aminosalicylic acid, imipenem-cilastatin, meropenem, amoxicillin-clavulanate, thioacetazone] have poor efficacy, are toxic and require prolonged treatment, compromising patient adherence and therapeutic drug monitoring [2]. Second-line injectable aminoglycosides and capreomycin are major components of MDR and XDR tuberculosis treatment (when susceptibility is preserved), in association with other second-line antituberculosis drugs.
Standard WHO recommendations include a 8-month duration for the ‘intensive phase’, which is the phase when an injectable drug is administered [3]. The efficacy of aminoglycosides on 4
Page 4 of 11
M. tuberculosis has been known for many decades, and resistance is rare, even in cases of MDR tuberculosis [4]. However, aminoglycosides are toxic (ototoxicity, nephrotoxicity) and prolonged administration by the parenteral route has many side effects. The present authors conducted a descriptive, retrospective, monocentric study to determine the number of side effects caused by parenteral amikacin in a cohort of 11 patients treated for MDR or XDR tuberculosis, with conserved amikacin susceptibility. All patients were followed in the Infectious Diseases Unit in the North Hospital of Marseille, France, between 2011 and 2015. Ten patients were treated exclusively with parenteral amikacin, and one patient was treated with parenteral amikacin for a short period followed by nebulized amikacin. There were six cases of ototoxicity, with a mean delay of 2.8 months (range 1–8 months) after amikacin initiation; three cases were definitely due to amikacin and three cases were possibly due to amikacin. There was one case of nephrotoxicity that occurred 3 weeks after the initiation of amikacin (elevation of serum creatinine from 74 to 120 µmol/L), and led to a modification of the route of administration (administration of amikacin by nebulization after this side effect). Renal function subsequently improved in this patient, and remained stable during the 6 months of treatment by nebulization (at the end of treatment, creatinine was 95µmol/L and clearance with MDRD formula was 75 mL/min/1.73 m²). There were no ionic disorders (sodium, potassium, chlorine, magnesium) due to amikacin. Seven side effects were linked to parenteral administration [one intramuscular (IM) and 10 intravenous (IV)]: haematomas on IM injection sites, two lymphangitis on peripheral venous catheter, one thrombus on peripherally inserted central catheter (PICC line), one misuse of PICC line for substance addiction, one colonization of PICC line and one candidaemia on PICC line. Amikacin was definitively stopped in two situations: after a deep vein thrombosis and after misuse of the administration route for substance addiction. Overall, 14 side effects were observed among the 11 patients: seven due to the drug and seven due to the route of 5
Page 5 of 11
administration (Table 1). Amikacin administered parenterally was stopped due to side effects in five cases, and was re-established in one case by nebulization. The average duration of amikacin treatment was 3.6 months (+/- 3.6; range 0.75–10 months), which was much lower than the WHO standard recommendation of 8 months for MDR tuberculosis. The recommended treatment duration was completed in three patients (including the patient who underwent nebulization). The average duration of hospitalization was 4.2 months (+/- 2.6; range 1–9 months). In the literature, the incidence of ototoxicity due to second-line injectable drugs in tuberculosis varied from 10% to 62% (depending on drug used, population studied, sensitivity of diagnostic method of deafness, previous treatment, comorbidities, dose and duration of treatment) [5,6], the incidence of nephrotoxicity varied from 1.2 to 16.8% [7,8], and the incidence of hypomagnesaemia and hypokalaemia was 30% [9]. To the authors’ knowledge, this is the first study to describe side effects due to the route of administration in the treatment of resistant tuberculosis. However, side effects due to prolonged parenteral administration are known in other diseases. The risk of infection associated with use of a peripheral venous catheter was 0.1%, corresponding to 0.5/1000 catheter-days [10]. The risk was greater for PICC lines (2.4%, corresponding to 2.1/1000 catheter-days) [10]. The average onset of PICC line infection was 10 days [11]. For the Port-a-Cath (PAC), a totally implantable venous access device, the infection rate varied between 0.1 and 0.4/1000 catheterdays with a delay of 80–192 days [12]. Another major complication of intravenous catheter use is thromboembolic disease; the incidence rate ranges between 5% and 60% [13]. A prospective study yielded an incidence of PICC line complications in oncology of 24.7% [14]. Moreover, injections with peripheral venous catheters, PICC lines or PACs require nurse care and specific materials. In numerous countries where the incidence of resistant tuberculosis is high and resources are limited, treatment is administered by IM injection, which is painful for patients. WHO has suggested that if toxicity is a limiting factor for the use of second-line 6
Page 6 of 11
injectable drugs and the bacillus is susceptible, aminoglycoside or capreomycin administration could be assessed by nebulization [3]. Inhaled aminoglycosides are commonly used in cystic fibrosis or ventilator-associated pneumonia [15]. Inhaled aminoglycosides are effective in susceptible or MDR tuberculosis, without side effects even if the duration of treatment is long (average duration 58 days) [16–19]. In the authors’ centre, several patients with drug-susceptible tuberculosis received amikacin 500 mg twice per day by nebulization, associated with oral therapy, and were cured without side effects. This study found that one patient with MDR, fluoroquinolone-resistant tuberculosis was treated with inhaled amikacin, following renal failure due to parenteral amikacin associated with oral and adapted antituberculous therapy. Six months after initiation of inhaled amikacin, the M. tuberculosis strain became resistant to amikacin and the tuberculosis was classified as XDR. An optimized treatment for MDR/XDR tuberculosis should have good efficiency, few side effects, per-os administration, and low cost and availability even in unfavourable socio-economic conditions. The present data show that amikacin does not achieve these requirements. There is a need to re-evaluate the duration of treatment with second-line injectable antituberculosis drugs as these are rarely completed. In 2016, WHO recommended the ‘shorter MDR-TB regimen’ (4– 6 months of four second-line drugs including second-line injectable drugs associated with pyrazinamide, ethambutol and isoniazid, followed by 5 months of two second-line drugs associated with pyrazinamide and ethambutol) [18]. WHO may shorten these recommended second-line injectable regimens to a more achievable level. However, this shorter regimen would be unlikely to change the prevalence of adverse events, most of which occur during the first month for adverse events linked to parenteral administration and nephrotoxicity, and during the first 2 months for ototoxicity. Switching IV administration to nebulization merits further investigation, with particular attention and monitoring of the possible emergence of
7
Page 7 of 11
amikacin resistance. The role of amikacin for optimized MDR/XDR treatment should be reevaluated, including its route of administration.
Funding: None.
Competing interests: None declared.
Ethical approval: Written informed consent was obtained from patients.
References [1] Zumla A, George A, Sharma V, Herbert RH, Oxley A, Oliver M. The WHO 2014 global tuberculosis report – further to go. Lancet Glob Health 2015;3:e10–2. [2] Sotgiu G, Tiberi S, D'Ambrosio L, Centis R, Zumla A, Migliori GB. WHO recommendations on shorter treatment of multidrug-resistant tuberculosis. Lancet 2016;387:2486–7. [3] World Health Organization. Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. Geneva: WHO; 2015. [4] Cambau E, Viveiros M, Machado D, Raskine L, Ritter C, Tortoli E, et al. Revisiting susceptibility testing in MDR-TB by a standardized quantitative phenotypic assessment in a European multicentre study. J Antimicrob Chemother 2015;70:686– 96. [5] Seddon JA, Godfrey-Faussett P, Jacobs K, Ebrahim A, Hesseling AC, Schaaf HS. Hearing loss in patients on treatment for drug-resistant tuberculosis. Eur Respir J 2012;40:1277–86.
8
Page 8 of 11
[6] Modongo C, Sobota RS, Kesenogile B, Ncube R, Sirugo G, Williams SM, et al. Successful MDR-TB treatment regimens including amikacin are associated with high rates of hearing loss. BMC Infect Dis 2014;14:542. [7] Shean K, Streicher E, Pieterson E, Symons G, van Zyl SR, Theron G, et al. Drugassociated adverse events and their relationship with outcomes in patients receiving treatment for extensively drug-resistant tuberculosis in South Africa. PLoS One 2013;8:e63057. [8] de JP, van AR. Hearing loss and nephrotoxicity in long-term aminoglycoside treatment in patients with tuberculosis. Int J Tuberc Lung Dis 2002;6:622–7. [9] Shin SS, Pasechnikov AD, Gelmanova IY, Peremitin GG, Strelis AK, Mishustin S, et al. Adverse reactions among patients being treated for MDR-TB in Tomsk, Russia. Int J Tuberc Lung Dis 2007;11:1314–20. [10] Maki DG, Kluger DM, Crnich CJ. The risk of bloodstream infection in adults with different intravascular devices: a systematic review of 200 published prospective studies. Mayo Clin Proc 2006;81:1159–71. [11] Chopra V, Ratz D, Kuhn L, Lopus T, Chenoweth C, Krein S. PICC-associated bloodstream infections: prevalence, patterns, and predictors. Am J Med 2014;127:319–28. [12] Lebeaux D, Fernandez-Hidalgo N, Chauhan A, Lee S, Ghigo JM, Almirante B, et al. Management of infections related to totally implantable venous-access ports: challenges and perspectives. Lancet Infect Dis 2014;14:146–59. [13] Sriskandarajah P, Webb K, Chisholm D, Raobaikady R, Davis K, Pepper N, et al. Retrospective cohort analysis comparing the incidence of deep vein thromboses between peripherally-inserted and long-term skin tunneled venous catheters in hemato-oncology patients. Thromb J 2015;13:21. 9
Page 9 of 11
[14] Bertoglio S, Faccini B, Lalli L, Cafiero F, Bruzzi P. Peripherally inserted central catheters (PICCs) in cancer patients under chemotherapy: a prospective study on the incidence of complications and overall failures. J Surg Oncol 2016;113:708–14. [15] Quon BS, Goss CH, Ramsey BW. Inhaled antibiotics for lower airway infections. Ann Am Thorac Soc 2014;11:425–34. [16] Sacks LV, Pendle S, Orlovic D, Andre M, Popara M, Moore G, et al. Adjunctive salvage therapy with inhaled aminoglycosides for patients with persistent smear-positive pulmonary tuberculosis. Clin Infect Dis 2001;32:44–9. [17] Parola P, Brouqui P. Clinical and microbiological efficacy of adjunctive salvage therapy with inhaled aminoglycosides in a patient with refractory cavitary pulmonary tuberculosis. Clin Infect Dis 2001;33:1439. [18] Berry C, Achar J, du CP. WHO recommendations for multidrug-resistant tuberculosis. Lancet 2016;388:2234. [19] Tsurutani J, Sohda H, Oka M, Kohno S. [A case of multidrug-resistant pulmonary tuberculosis]. Nihon Kokyuki Gakkai Zasshi 2000;38:594–8.
10
Page 10 of 11
Table 1. Fourteen side effects occurred in the 11 patients treated with amikacin for multi-drug- or extremely-drug-resistant tuberculosis between 2011 and 2015. Due to drug
Due to AR
Average delay in occurrence
Consequences
Hearing loss
3 (+3 possibles)
2.8 months
AMK stopped twice
Renal failure
1
3 weeks
Parenteral administration stopped, switched to nebulization
Ionic disorders
0
Haematoma, pain on intramuscular sites of injection
1
1 day
Parenteral AR commenced
Misuse/susbstance addiction
1
21 days
AMK stopped
Veinous thrombus
1
6 days
AMK + anticoagulant treatment stopped
Infection of catheter
4
15 days
- Lymphangitis on PVC
2
6 and 11 days
Local care
- PICC line colonization
1
15 days
PICC line changed
- Candidaemia
1
1 month
PICC line changed and antifungal therapy
AR, administration route; PVC, peripheral venous catheter; PICC, peripherally inserted central catheter; AMK, amikacin.
11
Page 11 of 11
S0924-8579(17)30178-4 http://dx.doi.org/doi: 10.1016/j.ijantimicag.2017.01.042 ANTAGE 5124
To appear in:
International Journal of Antimicrobial Agents
Received date: Accepted date:
18-10-2016 28-1-2017
Please cite this article as: Fanny Quenard, Pierre Edouard Fournier, Michel Drancourt, Philippe Brouqui, Role of second-line injectable antituberculosis drugs in the treatment of MDR/XDR tuberculosis, International Journal of Antimicrobial Agents (2017), http://dx.doi.org/doi: 10.1016/j.ijantimicag.2017.01.042. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Role of second-line injectable antituberculosis drugs in the treatment of MDR/XDR tuberculosis
Fanny Quenard a,b, Pierre Edouard Fournier a,b,Michel Drancourt a,b, Philippe Brouqui a,b,*
a
Institut Hospitalo Universitaire Méditerranée Infection, APHM, Marseille, France
b
Aix-Marseille Université, Unité de Recherche sur les Maladies Infectieuses et Tropicales
Emergentes, UM63, CNRS 7278, IRD 198, INSERM 1095, Marseille, France
*
Corresponding author. Address: Institut Hospitalo Universitaire Méditerranée Infection,
APHM, Marseille, France. E-mail address: [email protected] (P. Brouqui).
ARTICLE INFO Received 18 October 2016 Accepted 28 January 2017
Keywords: Tuberculosis Mycobacterium tuberculosis MDR/XDR tuberculosis Adverse events Aminoglycosides Amikacin 1
Page 1 of 11
Second-line injectable antituberculosis drugs Nebulized aminoglycosides
2
Page 2 of 11
1 2 3 4 5 6 7
Highlights
The efficacy of aminoglycosides against multi-drug-resistant (MDR) bacilli is preserved. Aminoglycosides cause frequent adverse events. The average duration of treatment with amikacin is usually reported to be less than the 8 months recommended by the World Health Organization for MDR tuberculosis. The place of amikacin for optimized treatment of MDR/extremely-drug-resistant tuberculosis should be re-evaluated, including its route of administration.
Comment [A1]: AUTHOR: Two different versions of Highlight section were provided and one of the separate file has been used. Please check and confirm that it is correct.
ABSTRACT Second-line injectable antituberculosis drugs (aminoglycosides and capreomycin) are the main drugs used in the management of resistant tuberculosis. Their preserved efficacy in the case of multi-drug-resistant bacillus is counterbalanced by frequent adverse events. Adverse events are linked to the drugs themselves and to the recommended 8-month period of parenteral administration. In numerous countries facing a high incidence of multi-drugresistant tuberculosis, treatment is administered by intramuscular injection. This procedure is painful and restrictive, and therefore treatment adherence is limited. This study reports the follow-up of 11 patients diagnosed with multi-drug- and extensively-resistant tuberculosis and treated with parenteral amikacin, and discusses the role of amikacin in the treatment of resistant tuberculosis.
3
Page 3 of 11
Tuberculosis (an infection due to Mycobacterium tuberculosis) is a major public health problem worldwide, with an estimated 9.6 million new cases and 1.5 million deaths in 2014 [1]. France is a low-incidence country [World Health Organization (WHO) threshold: 20 cases per 105 habitants], with 7.3 cases per 105 habitants; this corresponded to 4827 new cases in 2014. Antibiotic-resistant tuberculosis is defined as tuberculosis caused by an M. tuberculosis strain resistant to at least one first-line treatment drug (pyrazinamide, isoniazid, ethambutol and rifampicin). Multi-drug-resistant (MDR) tuberculosis is defined as tuberculosis caused by an M. tuberculosis strain resistant to isoniazid and rifampicin. Extensively-drug-resistant (XDR) tuberculosis is defined as tuberculosis caused by an M. tuberculosis strain that is also resistant to fluoroquinolones and a second-line injectable drug. The prevalence of resistant tuberculosis is increasing, and 480 000 new cases of MDR tuberculosis were notified in 2014; 9.7% of these cases were XDR tuberculosis. Each year, between 80 and 100 new cases of MDR tuberculosis are diagnosed in France. The treatment success of MDR tuberculosis worldwide is almost 50% [1]. Most second-line antituberculosis drugs [levofloxacin, moxifloxacin, gatifloxacin, amikacin, capreomycin, kanamycin, streptomycin, ethionamide (or prothionamide), cycloserine (or terizidone), linezolid, clofazimine, bedaquiline, delamanid; p-aminosalicylic acid, imipenem-cilastatin, meropenem, amoxicillin-clavulanate, thioacetazone] have poor efficacy, are toxic and require prolonged treatment, compromising patient adherence and therapeutic drug monitoring [2]. Second-line injectable aminoglycosides and capreomycin are major components of MDR and XDR tuberculosis treatment (when susceptibility is preserved), in association with other second-line antituberculosis drugs.
Standard WHO recommendations include a 8-month duration for the ‘intensive phase’, which is the phase when an injectable drug is administered [3]. The efficacy of aminoglycosides on 4
Page 4 of 11
M. tuberculosis has been known for many decades, and resistance is rare, even in cases of MDR tuberculosis [4]. However, aminoglycosides are toxic (ototoxicity, nephrotoxicity) and prolonged administration by the parenteral route has many side effects. The present authors conducted a descriptive, retrospective, monocentric study to determine the number of side effects caused by parenteral amikacin in a cohort of 11 patients treated for MDR or XDR tuberculosis, with conserved amikacin susceptibility. All patients were followed in the Infectious Diseases Unit in the North Hospital of Marseille, France, between 2011 and 2015. Ten patients were treated exclusively with parenteral amikacin, and one patient was treated with parenteral amikacin for a short period followed by nebulized amikacin. There were six cases of ototoxicity, with a mean delay of 2.8 months (range 1–8 months) after amikacin initiation; three cases were definitely due to amikacin and three cases were possibly due to amikacin. There was one case of nephrotoxicity that occurred 3 weeks after the initiation of amikacin (elevation of serum creatinine from 74 to 120 µmol/L), and led to a modification of the route of administration (administration of amikacin by nebulization after this side effect). Renal function subsequently improved in this patient, and remained stable during the 6 months of treatment by nebulization (at the end of treatment, creatinine was 95µmol/L and clearance with MDRD formula was 75 mL/min/1.73 m²). There were no ionic disorders (sodium, potassium, chlorine, magnesium) due to amikacin. Seven side effects were linked to parenteral administration [one intramuscular (IM) and 10 intravenous (IV)]: haematomas on IM injection sites, two lymphangitis on peripheral venous catheter, one thrombus on peripherally inserted central catheter (PICC line), one misuse of PICC line for substance addiction, one colonization of PICC line and one candidaemia on PICC line. Amikacin was definitively stopped in two situations: after a deep vein thrombosis and after misuse of the administration route for substance addiction. Overall, 14 side effects were observed among the 11 patients: seven due to the drug and seven due to the route of 5
Page 5 of 11
administration (Table 1). Amikacin administered parenterally was stopped due to side effects in five cases, and was re-established in one case by nebulization. The average duration of amikacin treatment was 3.6 months (+/- 3.6; range 0.75–10 months), which was much lower than the WHO standard recommendation of 8 months for MDR tuberculosis. The recommended treatment duration was completed in three patients (including the patient who underwent nebulization). The average duration of hospitalization was 4.2 months (+/- 2.6; range 1–9 months). In the literature, the incidence of ototoxicity due to second-line injectable drugs in tuberculosis varied from 10% to 62% (depending on drug used, population studied, sensitivity of diagnostic method of deafness, previous treatment, comorbidities, dose and duration of treatment) [5,6], the incidence of nephrotoxicity varied from 1.2 to 16.8% [7,8], and the incidence of hypomagnesaemia and hypokalaemia was 30% [9]. To the authors’ knowledge, this is the first study to describe side effects due to the route of administration in the treatment of resistant tuberculosis. However, side effects due to prolonged parenteral administration are known in other diseases. The risk of infection associated with use of a peripheral venous catheter was 0.1%, corresponding to 0.5/1000 catheter-days [10]. The risk was greater for PICC lines (2.4%, corresponding to 2.1/1000 catheter-days) [10]. The average onset of PICC line infection was 10 days [11]. For the Port-a-Cath (PAC), a totally implantable venous access device, the infection rate varied between 0.1 and 0.4/1000 catheterdays with a delay of 80–192 days [12]. Another major complication of intravenous catheter use is thromboembolic disease; the incidence rate ranges between 5% and 60% [13]. A prospective study yielded an incidence of PICC line complications in oncology of 24.7% [14]. Moreover, injections with peripheral venous catheters, PICC lines or PACs require nurse care and specific materials. In numerous countries where the incidence of resistant tuberculosis is high and resources are limited, treatment is administered by IM injection, which is painful for patients. WHO has suggested that if toxicity is a limiting factor for the use of second-line 6
Page 6 of 11
injectable drugs and the bacillus is susceptible, aminoglycoside or capreomycin administration could be assessed by nebulization [3]. Inhaled aminoglycosides are commonly used in cystic fibrosis or ventilator-associated pneumonia [15]. Inhaled aminoglycosides are effective in susceptible or MDR tuberculosis, without side effects even if the duration of treatment is long (average duration 58 days) [16–19]. In the authors’ centre, several patients with drug-susceptible tuberculosis received amikacin 500 mg twice per day by nebulization, associated with oral therapy, and were cured without side effects. This study found that one patient with MDR, fluoroquinolone-resistant tuberculosis was treated with inhaled amikacin, following renal failure due to parenteral amikacin associated with oral and adapted antituberculous therapy. Six months after initiation of inhaled amikacin, the M. tuberculosis strain became resistant to amikacin and the tuberculosis was classified as XDR. An optimized treatment for MDR/XDR tuberculosis should have good efficiency, few side effects, per-os administration, and low cost and availability even in unfavourable socio-economic conditions. The present data show that amikacin does not achieve these requirements. There is a need to re-evaluate the duration of treatment with second-line injectable antituberculosis drugs as these are rarely completed. In 2016, WHO recommended the ‘shorter MDR-TB regimen’ (4– 6 months of four second-line drugs including second-line injectable drugs associated with pyrazinamide, ethambutol and isoniazid, followed by 5 months of two second-line drugs associated with pyrazinamide and ethambutol) [18]. WHO may shorten these recommended second-line injectable regimens to a more achievable level. However, this shorter regimen would be unlikely to change the prevalence of adverse events, most of which occur during the first month for adverse events linked to parenteral administration and nephrotoxicity, and during the first 2 months for ototoxicity. Switching IV administration to nebulization merits further investigation, with particular attention and monitoring of the possible emergence of
7
Page 7 of 11
amikacin resistance. The role of amikacin for optimized MDR/XDR treatment should be reevaluated, including its route of administration.
Funding: None.
Competing interests: None declared.
Ethical approval: Written informed consent was obtained from patients.
References [1] Zumla A, George A, Sharma V, Herbert RH, Oxley A, Oliver M. The WHO 2014 global tuberculosis report – further to go. Lancet Glob Health 2015;3:e10–2. [2] Sotgiu G, Tiberi S, D'Ambrosio L, Centis R, Zumla A, Migliori GB. WHO recommendations on shorter treatment of multidrug-resistant tuberculosis. Lancet 2016;387:2486–7. [3] World Health Organization. Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. Geneva: WHO; 2015. [4] Cambau E, Viveiros M, Machado D, Raskine L, Ritter C, Tortoli E, et al. Revisiting susceptibility testing in MDR-TB by a standardized quantitative phenotypic assessment in a European multicentre study. J Antimicrob Chemother 2015;70:686– 96. [5] Seddon JA, Godfrey-Faussett P, Jacobs K, Ebrahim A, Hesseling AC, Schaaf HS. Hearing loss in patients on treatment for drug-resistant tuberculosis. Eur Respir J 2012;40:1277–86.
8
Page 8 of 11
[6] Modongo C, Sobota RS, Kesenogile B, Ncube R, Sirugo G, Williams SM, et al. Successful MDR-TB treatment regimens including amikacin are associated with high rates of hearing loss. BMC Infect Dis 2014;14:542. [7] Shean K, Streicher E, Pieterson E, Symons G, van Zyl SR, Theron G, et al. Drugassociated adverse events and their relationship with outcomes in patients receiving treatment for extensively drug-resistant tuberculosis in South Africa. PLoS One 2013;8:e63057. [8] de JP, van AR. Hearing loss and nephrotoxicity in long-term aminoglycoside treatment in patients with tuberculosis. Int J Tuberc Lung Dis 2002;6:622–7. [9] Shin SS, Pasechnikov AD, Gelmanova IY, Peremitin GG, Strelis AK, Mishustin S, et al. Adverse reactions among patients being treated for MDR-TB in Tomsk, Russia. Int J Tuberc Lung Dis 2007;11:1314–20. [10] Maki DG, Kluger DM, Crnich CJ. The risk of bloodstream infection in adults with different intravascular devices: a systematic review of 200 published prospective studies. Mayo Clin Proc 2006;81:1159–71. [11] Chopra V, Ratz D, Kuhn L, Lopus T, Chenoweth C, Krein S. PICC-associated bloodstream infections: prevalence, patterns, and predictors. Am J Med 2014;127:319–28. [12] Lebeaux D, Fernandez-Hidalgo N, Chauhan A, Lee S, Ghigo JM, Almirante B, et al. Management of infections related to totally implantable venous-access ports: challenges and perspectives. Lancet Infect Dis 2014;14:146–59. [13] Sriskandarajah P, Webb K, Chisholm D, Raobaikady R, Davis K, Pepper N, et al. Retrospective cohort analysis comparing the incidence of deep vein thromboses between peripherally-inserted and long-term skin tunneled venous catheters in hemato-oncology patients. Thromb J 2015;13:21. 9
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[14] Bertoglio S, Faccini B, Lalli L, Cafiero F, Bruzzi P. Peripherally inserted central catheters (PICCs) in cancer patients under chemotherapy: a prospective study on the incidence of complications and overall failures. J Surg Oncol 2016;113:708–14. [15] Quon BS, Goss CH, Ramsey BW. Inhaled antibiotics for lower airway infections. Ann Am Thorac Soc 2014;11:425–34. [16] Sacks LV, Pendle S, Orlovic D, Andre M, Popara M, Moore G, et al. Adjunctive salvage therapy with inhaled aminoglycosides for patients with persistent smear-positive pulmonary tuberculosis. Clin Infect Dis 2001;32:44–9. [17] Parola P, Brouqui P. Clinical and microbiological efficacy of adjunctive salvage therapy with inhaled aminoglycosides in a patient with refractory cavitary pulmonary tuberculosis. Clin Infect Dis 2001;33:1439. [18] Berry C, Achar J, du CP. WHO recommendations for multidrug-resistant tuberculosis. Lancet 2016;388:2234. [19] Tsurutani J, Sohda H, Oka M, Kohno S. [A case of multidrug-resistant pulmonary tuberculosis]. Nihon Kokyuki Gakkai Zasshi 2000;38:594–8.
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Table 1. Fourteen side effects occurred in the 11 patients treated with amikacin for multi-drug- or extremely-drug-resistant tuberculosis between 2011 and 2015. Due to drug
Due to AR
Average delay in occurrence
Consequences
Hearing loss
3 (+3 possibles)
2.8 months
AMK stopped twice
Renal failure
1
3 weeks
Parenteral administration stopped, switched to nebulization
Ionic disorders
0
Haematoma, pain on intramuscular sites of injection
1
1 day
Parenteral AR commenced
Misuse/susbstance addiction
1
21 days
AMK stopped
Veinous thrombus
1
6 days
AMK + anticoagulant treatment stopped
Infection of catheter
4
15 days
- Lymphangitis on PVC
2
6 and 11 days
Local care
- PICC line colonization
1
15 days
PICC line changed
- Candidaemia
1
1 month
PICC line changed and antifungal therapy
AR, administration route; PVC, peripheral venous catheter; PICC, peripherally inserted central catheter; AMK, amikacin.
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