University of Groningen Therapeutic drug monitoring Pranger, Anna Diewerke

University of Groningen

Therapeutic drug monitoring

Pranger, Anna Diewerke

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Pranger, A. D. (2018). Therapeutic drug monitoring: How to improve moxifloxacin exposure in tuberculosis

patients. Rijksuniversiteit Groningen.

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2B

Chapter

The role of fluoroquinolones

in the treatment of tuberculosis

anno 2018

A.D. Pranger, T.S. van der Werf, J.G.W. Kosterink, and J.W.C. Alffenaar

Chapter 2b Fluoroquinolones for tuberculosis anno 2018

104

Abstract

The inability to use powerful anti-tuberculosis drugs in an increasing number of patients seems to be the biggest threat towards global tuberculosis (TB) elimination. Simplified, shorter and preferably less toxic drug-regimens are investigated for pulmonary TB to counteract emergence of drug-resistance. Intensified regimens, with high-dose anti-TB drugs at the first weeks of treatment, are investigated for TB meningitis to increase the survival rate among these patients. Moxifloxacin (MFX), gatifloxacin (GFX) and levofloxacin (LFX) are

seen as core agents in case of resistance or intolerance against 1st _{line anti-TB drugs.}

However, based on their pharmacokinetics (PK) and pharmacodynamics (PD), these drugs are also promising for TB meningitis and might perhaps have the potential to shorten pulmonary TB treatment if dosing would be optimized. We made a comprehensive summary of clinical trials investigating outcome of TB regimens based on MFX, GFX and LFX in the recent years. In the majority of clinical trials, treatment success was not in favour of these drugs, compared to standard regimens. By discussing these results, we propose that incorporation of extended PK/PD analysis into the armamentarium of drug-development tools is needed to clarify the role of MFX, GFX and LFX for TB, using the right dose. In addition, to prevent failure of treatment or emergence of drug-resistance, PK and PD variability advocates for concentration guided dosing in patients at risk for a too low drug-exposure.

105

Introduction

To end tuberculosis (TB) by 2035, as mentioned in the United Nations Sustainable Development Goals, may be an over-ambitious target as the evidence is emerging that the TB incidence is not declining at all (1,2). According to the latest annual WHO report (2017), 600,000 new TB patients were infected with rifampicin-resistant (RR) M. tuberculosis (MTB)

isolates, resistant against the most important 1st _{line anti-TB agent (3), and in Italy, Iran en}

India, notion has been made of TB cases resistant against (almost) all 2nd _{line anti-TB drugs}

(4-6). The biggest threat towards TB elimination could therefore well be the increase of resistance against powerful anti-TB agents.

Fluoroquinolones (FQs), i.e. moxifloxacin (MFX), gatifloxacin (GFX) and levofloxacin (LFX),

are the most valuable 2nd _{anti-TB agents according to the current WHO guidelines (update}

October 2016) (7). These recommendations were consistent with our forecasts on particularly MFX and GFX based on a review on pharmacokinetics (PK) and pharmacodynamics (PD) of 14 FQs for TB (8). Although MFX was not recommended until the WHO guidelines were updated in 2011, our main finding was that the role of MFX for drug-resistant TB, possibly at a dose of 600 or 800 mg once-daily, based on excellent penetration in alveolar macrophages, epithelial lining fluid, bone and cerebrospinal fluid, the highest bactericidal and sterilizing activity, and bactericidal activity against ofloxacin (OFX)-resistant strains, was underestimated (8). For MFX, GFX and LFX, and for the 4 high potential FQs for TB as defined in 2011 (8), the current marketing and clinical development

status is described in Table 1. The four high-potentials have never been under clinical

development for TB, and the general marketing status of all 7 FQs did not change compared to 2011 (8).

Since rifampicin (R) was authorised for treatment of TB more than half a century ago, the FDA and/or EMA gave only approval to bedaquiline (2012) and delamanid (2014) for TB, as last remedy in case of extensive drug-resistance (9,10). Today’s TB pipeline is working on simplification of regimens (shorter, less toxic, oral) to counteract drug-resistance by promoting drug-adherence (11). Unfortunately, the results of a short-course drug-susceptible TB regimen based on MFX were disappointing (12,13). However, in 2016, the WHO adopted a shorter regimen – still 9 to 12 months – for selected patients with multidrug-resistant TB (MDR-TB) (7). MFX or GFX are preferred components of this shorter regimen, which is

restricted to TB patients with no history of 2nd _{line drugs and no resistance against}

pyrazinamide (Z), FQs or aminoglycosides (7). From 2011 onwards, in TB research and WHO guidelines, FQs (MFX, GFX, LFX) have been given an important share in regimens for

Chapter 2b Fluoroquinolones for tuberculosis anno 2018

Chapter

2

b

104

Abstract

The inability to use powerful anti-tuberculosis drugs in an increasing number of patients seems to be the biggest threat towards global tuberculosis (TB) elimination. Simplified, shorter and preferably less toxic drug-regimens are investigated for pulmonary TB to counteract emergence of drug-resistance. Intensified regimens, with high-dose anti-TB drugs at the first weeks of treatment, are investigated for TB meningitis to increase the survival rate among these patients. Moxifloxacin (MFX), gatifloxacin (GFX) and levofloxacin (LFX) are

seen as core agents in case of resistance or intolerance against 1st _{line anti-TB drugs.}

However, based on their pharmacokinetics (PK) and pharmacodynamics (PD), these drugs are also promising for TB meningitis and might perhaps have the potential to shorten pulmonary TB treatment if dosing would be optimized. We made a comprehensive summary of clinical trials investigating outcome of TB regimens based on MFX, GFX and LFX in the recent years. In the majority of clinical trials, treatment success was not in favour of these drugs, compared to standard regimens. By discussing these results, we propose that incorporation of extended PK/PD analysis into the armamentarium of drug-development tools is needed to clarify the role of MFX, GFX and LFX for TB, using the right dose. In addition, to prevent failure of treatment or emergence of drug-resistance, PK and PD variability advocates for concentration guided dosing in patients at risk for a too low drug-exposure.

105

Introduction

To end tuberculosis (TB) by 2035, as mentioned in the United Nations Sustainable Development Goals, may be an over-ambitious target as the evidence is emerging that the TB incidence is not declining at all (1,2). According to the latest annual WHO report (2017), 600,000 new TB patients were infected with rifampicin-resistant (RR) M. tuberculosis (MTB)

isolates, resistant against the most important 1st _{line anti-TB agent (3), and in Italy, Iran en}

India, notion has been made of TB cases resistant against (almost) all 2nd _{line anti-TB drugs}

(4-6). The biggest threat towards TB elimination could therefore well be the increase of resistance against powerful anti-TB agents.

Fluoroquinolones (FQs), i.e. moxifloxacin (MFX), gatifloxacin (GFX) and levofloxacin (LFX),

are the most valuable 2nd _{anti-TB agents according to the current WHO guidelines (update}

October 2016) (7). These recommendations were consistent with our forecasts on particularly MFX and GFX based on a review on pharmacokinetics (PK) and pharmacodynamics (PD) of 14 FQs for TB (8). Although MFX was not recommended until the WHO guidelines were updated in 2011, our main finding was that the role of MFX for drug-resistant TB, possibly at a dose of 600 or 800 mg once-daily, based on excellent penetration in alveolar macrophages, epithelial lining fluid, bone and cerebrospinal fluid, the highest bactericidal and sterilizing activity, and bactericidal activity against ofloxacin (OFX)-resistant strains, was underestimated (8). For MFX, GFX and LFX, and for the 4 high potential FQs for TB as defined in 2011 (8), the current marketing and clinical development

status is described in Table 1. The four high-potentials have never been under clinical

development for TB, and the general marketing status of all 7 FQs did not change compared to 2011 (8).

Since rifampicin (R) was authorised for treatment of TB more than half a century ago, the FDA and/or EMA gave only approval to bedaquiline (2012) and delamanid (2014) for TB, as last remedy in case of extensive drug-resistance (9,10). Today’s TB pipeline is working on simplification of regimens (shorter, less toxic, oral) to counteract drug-resistance by promoting drug-adherence (11). Unfortunately, the results of a short-course drug-susceptible TB regimen based on MFX were disappointing (12,13). However, in 2016, the WHO adopted a shorter regimen – still 9 to 12 months – for selected patients with multidrug-resistant TB (MDR-TB) (7). MFX or GFX are preferred components of this shorter regimen, which is

restricted to TB patients with no history of 2nd _{line drugs and no resistance against}

pyrazinamide (Z), FQs or aminoglycosides (7). From 2011 onwards, in TB research and WHO guidelines, FQs (MFX, GFX, LFX) have been given an important share in regimens for

Chapter 2b Fluoroquinolones for tuberculosis anno 2018

106

drug-susceptible and drug-resistant TB. This role seems justified based on its PK and PD (8). The aim of this review was to update, summarize and discuss treatment outcome of regimens based on MFX, GFX or LFX for TB.

Table 1. State of Clinical Development in TB treatment and General Marketing Status anno 2018 Marketing status other

than TB 1,2

Registered strength (mg)

Clinical Development Phase for TB (2011-2018) 3, 4 WHO recommended FQs (2018)

GFX None - III

LFX Approved (US)$ _{250, 500 and 750 IV*,II,III}

MFX Approved (US)$ _{400 II*,III}

High-potential FQs based on PK/PD

SFX Discontinued (US) - None

STX None - None

TFX Discontinued (US/EU) - None

DC None - None

Searches were conducted in March 2018. Table format partly adopted from Pranger et al. Current Pharmaceutical Design 2011. Oral formulation unless indicated otherwise. 1_{Marketing status is indicated as the state of the FQ on}

the market of the United States (US) and/or European Union (EU). 2_{Marketing status “none”: registered data was}

not available on fda.gov or ema.europa.eu. 3_{Clinical development status “none”: no registered trial (Phase I to IV)}

on clinicaltrials.gov or available as literature on PubMed. 4_{Pulmonary TB unless otherwise indicated.} $_Intravenous

and oral formulation. *For pulmonary TB as well as TB meningitis. DC, DC-159a; FQ, fluoroquinolone; GFX, gatifloxacin; LFX, levofloxacin; MFX, moxifloxacin; PK/PD, pharmacokinetics/pharmacodynamics; SFX, sparfloxacin; STX, sitafloxacin; TFX, trovafloxacin.

Methods

A PubMed search was preformed, using the keywords “moxifloxacin” OR “levofloxacin” OR “gatifloxacin” AND “tuberculosis”. The limitations “human”, “English” and a publication date of the last “5 years”, and article types “clinical trial”, “randomized controlled trial”, “controlled clinical trial” and “comparative study” were added to the searches. We included articles reporting bacteriological and/or clinical treatment outcome. Publications reporting only pharmacokinetic outcome and/or early bactericidal results were excluded. Trials were included regardless of the extent of drug-resistance and regardless of the localization of TB. All searches were conducted in June 2017. A second search in March 2018 revealed no new articles.

107

Results

Pulmonary tuberculosis

Five clinical trials investigated treatment outcome of MFX, GFX and/or LFX for pulmonary TB

(Table 2). In one clinical trial (14), MFX was compared with LFX as part of an MDR-TB

regimen. In the remaining 4 clinical trials (12,13,15,16), results of seven FQ-based regimens (MFX: 5, GFX: 2) compared to a standard WHO-recommended daily (5 times) or thrice-weekly (2 times, MFX: 1, GFX: 1) drug-susceptible (DS) TB treatment, were published. A thrice-weekly DS-TB regimen is no longer recommended in the recently (2017) updated WHO guidelines (17).

Four-month FQ containing regimens

A two-month shorter regimen was investigated in 6-out-of-7 FQ-regimens for DS-TB, but none of these regimens demonstrated a favourable outcome after a follow-up period of at

least six months, compared to the standard DS-TB regimen (Table 2, S). A remarkably

higher TB recurrence rate was observed in the experimental compared to the control arms (12,13,16), leading to premature termination of both the MFX and GFX containing arm in one clinical trial (16). Additionally, in one of the other clinical trials, non-inferiority was not observed after 12-months of follow-up, but was observed at the end of treatment for two MFX containing regimens (12). Moreover, in the preliminary terminated study (16), with the only thrice-weekly control and experimental regimens, a higher TB recurrence rate was observed

for GFX (16%) compared to MFX (10%), and almost all recurrences occurred before the 6th

month post-treatment. A minimal increase in unfavourable outcome was observed at the end of treatment (16). Finally, one clinical trial suggested that standard HRZE might even benefit specific patient populations, like DS-TB patients with a HIV-negative status, if a daily 4-month GFX regimen is the alternative treatment option (15).

Moxifloxacin

The treatment-shortening potential of MFX was the most studied subject in the recent years,

regarding FQ’s for pulmonary TB (Table 2). Contrary to the results of these 4-month

regimens, the efficacy, including the relapse rate after treatment, of a 6-month course that included four months of once-a-week dosing of MFX and rifapentine was similar to that of the standard DS-TB regimen (13). For MDR-TB treatment success, MFX and LFX (750mg/day) were equally effective in one clinical trial (14).

Chapter 2b Fluoroquinolones for tuberculosis anno 2018

Chapter

2

b

106

drug-susceptible and drug-resistant TB. This role seems justified based on its PK and PD (8). The aim of this review was to update, summarize and discuss treatment outcome of regimens based on MFX, GFX or LFX for TB.

Table 1. State of Clinical Development in TB treatment and General Marketing Status anno 2018 Marketing status other

than TB 1,2

Registered strength (mg)

Clinical Development Phase for TB (2011-2018) 3, 4 WHO recommended FQs (2018)

GFX None - III

LFX Approved (US)$ _{250, 500 and 750 IV*,II,III}

MFX Approved (US)$ _{400 II*,III}

High-potential FQs based on PK/PD

SFX Discontinued (US) - None

STX None - None

TFX Discontinued (US/EU) - None

DC None - None

Searches were conducted in March 2018. Table format partly adopted from Pranger et al. Current Pharmaceutical Design 2011. Oral formulation unless indicated otherwise. 1_{Marketing status is indicated as the state of the FQ on}

the market of the United States (US) and/or European Union (EU). 2_{Marketing status “none”: registered data was}

not available on fda.gov or ema.europa.eu. 3_{Clinical development status “none”: no registered trial (Phase I to IV)}

on clinicaltrials.gov or available as literature on PubMed. 4_{Pulmonary TB unless otherwise indicated.} $_Intravenous

and oral formulation. *For pulmonary TB as well as TB meningitis. DC, DC-159a; FQ, fluoroquinolone; GFX, gatifloxacin; LFX, levofloxacin; MFX, moxifloxacin; PK/PD, pharmacokinetics/pharmacodynamics; SFX, sparfloxacin; STX, sitafloxacin; TFX, trovafloxacin.

Methods

A PubMed search was preformed, using the keywords “moxifloxacin” OR “levofloxacin” OR “gatifloxacin” AND “tuberculosis”. The limitations “human”, “English” and a publication date of the last “5 years”, and article types “clinical trial”, “randomized controlled trial”, “controlled clinical trial” and “comparative study” were added to the searches. We included articles reporting bacteriological and/or clinical treatment outcome. Publications reporting only pharmacokinetic outcome and/or early bactericidal results were excluded. Trials were included regardless of the extent of drug-resistance and regardless of the localization of TB. All searches were conducted in June 2017. A second search in March 2018 revealed no new articles.

107

Results

Pulmonary tuberculosis

Five clinical trials investigated treatment outcome of MFX, GFX and/or LFX for pulmonary TB

(Table 2). In one clinical trial (14), MFX was compared with LFX as part of an MDR-TB

regimen. In the remaining 4 clinical trials (12,13,15,16), results of seven FQ-based regimens (MFX: 5, GFX: 2) compared to a standard WHO-recommended daily (5 times) or thrice-weekly (2 times, MFX: 1, GFX: 1) drug-susceptible (DS) TB treatment, were published. A thrice-weekly DS-TB regimen is no longer recommended in the recently (2017) updated WHO guidelines (17).

Four-month FQ containing regimens

A two-month shorter regimen was investigated in 6-out-of-7 FQ-regimens for DS-TB, but none of these regimens demonstrated a favourable outcome after a follow-up period of at

least six months, compared to the standard DS-TB regimen (Table 2, S). A remarkably

higher TB recurrence rate was observed in the experimental compared to the control arms (12,13,16), leading to premature termination of both the MFX and GFX containing arm in one clinical trial (16). Additionally, in one of the other clinical trials, non-inferiority was not observed after 12-months of follow-up, but was observed at the end of treatment for two MFX containing regimens (12). Moreover, in the preliminary terminated study (16), with the only thrice-weekly control and experimental regimens, a higher TB recurrence rate was observed

for GFX (16%) compared to MFX (10%), and almost all recurrences occurred before the 6th

month post-treatment. A minimal increase in unfavourable outcome was observed at the end of treatment (16). Finally, one clinical trial suggested that standard HRZE might even benefit specific patient populations, like DS-TB patients with a HIV-negative status, if a daily 4-month GFX regimen is the alternative treatment option (15).

Moxifloxacin

The treatment-shortening potential of MFX was the most studied subject in the recent years,

regarding FQ’s for pulmonary TB (Table 2). Contrary to the results of these 4-month

regimens, the efficacy, including the relapse rate after treatment, of a 6-month course that included four months of once-a-week dosing of MFX and rifapentine was similar to that of the standard DS-TB regimen (13). For MDR-TB treatment success, MFX and LFX (750mg/day) were equally effective in one clinical trial (14).

Table 2 (I) . T rea tm en t o utc om es o f FQ -c on tai ni ng re gi m en s for pul m on ar y T B . Tre atm ent reg im en^ Stud y Tre atm ent o utc om e FQ (m g) FQ (m ont hs ) Con tro l (m ont hs ) Ty pe No. $ Pa tie nt Pri m ary e nd po in t(s ) En d-point # En d-point FQ $ En d-point Con tro l $ FQ m in us Con tro l $* FQ n on -in fe rio r ¥ Ref. M 400 S M RZE(2 ) MR i900m g (2 ) 1 H RZE(2 ) HR (4 ) Non -in fe rio rity , RCT 193( M ) 188( C ) Drug -se nsi tiv e 2 , sme ar -pos iti ve U nfav or abl e o ut co m e (c ul tu re -p os iti ve, or dea th , or cl in ic al n eed t o c han ge tre at m ent , or inc om pl et e tre at m ent w ith p os iti ve c ul tur e at th e end o f f ol low -up) 3 ≥6 27% 4 14% 13. 1 ( 5. 6 t o 20 .6 )% No 13 M 400 M RZE(2 ) MR i1200m g (4 ) 5 H RZE(2 ) HR (4 ) Non -in fe rio rity , RCT 212( M ) 188( C ) Drug -se nsi tiv e 2, sme ar -pos iti ve U nfav or abl e o ut co m e (c ul tu re -p os iti ve, or dea th , or cl in ic al n eed t o c han ge tre at m ent , or inc om pl et e tre atm en t w ith p os iti ve c ul tur e at th e end o f f ol low -up) 3 ≥6 14% 14% 0.4 (-5. 7 to 6.6 )% Ye s 13 M 400 S HRZ M (2 ) HR M (2 ) HRZ E (2 ) HR (4 ) P lac ebo -cont rol led, doub le -bl in d, non -in fe rio rity , RCT 568( M ) 555( C ) R - and FQ - se nsi tiv e, sme ar -pos iti ve U nfav or abl e o ut co m e (b ac te rio lo gic ally o r c lin ic ally def in ed f ai lur e o r r el aps e) 12 23% 6 16% 7. 8 ( 2. 7 to 13. 0) 0.4 8 ( -2. 16 to 3 .1 1) 7 No 12 M 400 S M RZE(2 ) R M (2 ) H RZE(2 ) H R(4) P lac ebo -cont rol led, doub le -bl in d, non -in fe rio rity , RCT 551( M ) 555( C ) R - and FQ - se nsi tiv e, sme ar -pos iti ve U nfav or abl e o ut co m e (b ac te rio lo gic ally o r c lin ic ally def in ed f ai lur e o r r el aps e) 12 24% 6 16% 9. 0 ( 3. 8 to 14. 2) 1.9 6 ( -0. 90 to 4 .8 3) 7 No 12 ^D ai ly re gi m en u nl es s i ndi cat ed o th er w is e. ¥(M odi fie d) int ent ion -to -tr eat a nd p er -pr ot oc ol p opul at ion unl es s i ndi cat ed o ther w is e. $(M odi fied) int ent io n-to -tr eat po pul at ion u nl es s indi cat ed o ther w is e. # M ont hs a fter th e e nd o f c on tro l t re at m ent . * Poi nt -di ffer en ce ( 95% or 9 7. 5%C I). 1 Adm ini st er ed tw ic e-w eek ly . 2 R, H a nd M s en si tiv e T B. M os t p ati en ts w ith unf av or ab le D S T r es ul ts w er e e xc luded a fte r r ando m iz at ion ( lat e ex cl us io ns , ex cl uded fro m m od ifi ed i nt ent ion -to -tre at a na ly si s). 3 Pa tie nt s w ith re -inf ec tio n a nd pr eg nant p at ient s w er e e xc luded . 4R em ar kabl e h igh r el ap se r at e co m par ed to cont ro l. 5A dm in is ter ed onc e-w eek ly . 6Appr ox . 10 per cen t r el aps e-ra te a fte r t he e nd o f tr ea tm ent . 7S en sit iv ity anal ys es : non -in fe rio r s ta tus at the e nd o f t re at m ent . C , c ont rol ; E , et ha m bu to l; FQ , fl uor oq ui nol one; H , i soni az id, M , m ox ifl ox ac in; R C T, random iz ed cont rol le d tri al ; R i, rifa pe nti ne ; R, r ifa m pi ci n; S , s ho rt-co ur se ; Z , p yr az in am ide. Table 2 (II) . T rea tm en t o utc om es o f FQ -c on tai ni ng re gi m en s for pul m on ar y T B . Tre atm ent re gi m en^ Stud y Tre atm ent o utc om e FQ (mg ) FQ (m ont hs ) Con tro l (m ont hs ) Ty pe No. $ Pa tie nt Pri m ary e nd po in t(s ) En d-point ¶ En d-point FQ $ En d-point Con tro l $ FQ m in us Con tro l $* FQ non -in fe rio r ¥ Ref. G 400 S G HR Z(2 ) G HR (2 ) HRZ E (2 ) HR (4 ) Non -in fe rio rity , open -labe l, RCT 1356 R -se nsi tiv e, sme ar -pos iti ve unf av or ab le out com e (c ul tu re -p os iti ve a t th e end o f tr ea tm ent , rel ap se or re -in fe cti on , or d ea th , or s tudy d rop -out ) 24 21% 17% 3.5 (-0. 7 to 7. 7) % 1 No 15 G 400 S G HR Z(2 ) 2 G HR (2 ) 2 HRZ E (2 ) 2 HR (4 ) 2 O pen -la be l, RC T 136 ( G ) 3 165 ( C ) 3 Cul tu re -pos iti ve unf av or ab le out com e (c ul tu re -p os iti ve , o r deat h, o r c lini cal need to c hang e tr ea tm ent ) re cu rre nc e 0 24 5% 4 16% 4,5 3% 4 6% 4 - N/a 16 L M 750 400 LB(3 +) 6 M B(3 +) 6 - O pen -labe l, RCT 77 ( L) 7 74 ( M ) 7 M DR , cul tur e-pos iti ve tre atm en t s uc ce ss (s um of c ur e and com pl et ion) 8 tre atm en t f ai lu re (s um of d eat h and fa ilur e) 0 0 84% ( L) 80% ( M ) 8% ( L) 7% ( M ) - M -L: -4 .7 (-17 .0 to 7 .6 )% M -L: -1 .0 (-10 .1 to 8 .1 )% N/a 14 M 400 S M HR Z(2 ) 2 M HR (2 ) 2 HRZ E (2 ) 2 HR (4 ) 2 O pen -la be l, RC T 115 (M) 3 165 ( C ) 3 Cul tu re -pos iti ve unf av or ab le out com e (c ul tu re -p os iti ve , o r deat h, o r c lini cal need to c hang e tr ea tm ent ) re cu rre nc e 0 ₂₄ 2% 4 10% 4 3% 4 6% 4 - N/a 16 ^D ai ly re gi m en u nl es s i ndi cat ed o th er w is e. ¥ (M odi fie d) int ent ion -to -tr eat a nd p er -pr ot oc ol p opul at ion unl es s i ndi cat ed o ther w is e. $ (M odi fied) int ent io n-to -tr eat po pul at ion u nl es s indi cat ed o ther w is e. ¶ M ont hs af ter the e nd o f tr ea tm ent . *Poi nt -di ffer en ce ( 95%C I). 1Su bg ro up s HIV -nega tiv e, c av ita tion, B M I ≥16 : 9 5% CI in fa vo r o f C on tro l. 2th ric e-w ee kl y. 3Prem at ur e ter m inat ion due t o t he ex te nt of T B re cur re nc e i n t he G - an d M -a rm . 4Drug -s us ce pti bl e (DS) T B p at ie nt s (t es te d d ru gs : H,R,E,O ): 94 % (G ), 97 % (M ) a nd 8 4% (C). DS -TB p at ient s: e qui val ent fr equ enc ie s f or p rim ar y e ndpo int s c om par ed to th e to ta l g ro up. 5FQ v s. Con tro l: p < 0 .0 5. 63 m on th s tri al -m edi cat ion, ther eaf te r a cc or di ng t o W H O gui del ines . 7Pre m at ur e ter m in at ion d ue to d rop of pa tie nt enr ol lm ent . 8Fo llo w -up a nal ys is c om par ing a ll W H O d ef ini tion s of tr ea tm ent o ut co m e. Ini tia l s tudy had pr im ar y out com e = s put um c ul tur e con ver si on. B , b ac kgr ound r egi m en a cc or di ng to W H O g ui del in es . C , c ont rol ; E , et ham but ol ; F Q , fl uo roqui nol one; G , g at ifl ox ac in; H , i soni az id; L, lev of lox ac in; M , m ox ifl ox ac in; M D R , m ul ti-dr ug res is ta nc e; O , of lox ac in; R C T, rand om iz ed c on tro lle d tri al ; R, rifa m pi ci n; S , s ho rt-cour se; Z , py raz inam ide. 108

Chapter

2

b Table 2 (I) . T rea tm en t o utc om es o f FQ -c on tai ni ng re gi m en s for pul m on ar y T B . Tre atm ent reg im en^ Stud y Tre atm ent o utc om e FQ (m g) FQ (m ont hs ) Con tro l (m ont hs ) Ty pe No. $ Pa tie nt Pri m ary e nd po in t(s ) En d-point # En d-point FQ $ En d-point Con tro l $ FQ m in us Con tro l $* FQ n on -in fe rio r ¥ Ref. M 400 S M RZE(2 ) MR i900m g (2 ) 1 H RZE(2 ) HR (4 ) Non -in fe rio rity , RCT 193( M ) 188( C ) Drug -se nsi tiv e 2 , sme ar -pos iti ve U nfav or abl e o ut co m e (c ul tu re -p os iti ve, or dea th , or cl in ic al n eed t o c han ge tre at m ent , or inc om pl et e tre at m ent w ith p os iti ve c ul tur e at th e end o f f ol low -up) 3 ≥6 27% 4 14% 13. 1 ( 5. 6 t o 20 .6 )% No 13 M 400 M RZE(2 ) MR i1200m g (4 ) 5 H RZE(2 ) HR (4 ) Non -in fe rio rity , RCT 212( M ) 188( C ) Drug -se nsi tiv e 2 , sme ar -pos iti ve U nfav or abl e o ut co m e (c ul tu re -p os iti ve, or dea th , or cl in ic al n eed t o c han ge tre at m ent , or inc om pl et e tre atm en t w ith p os iti ve c ul tur e at th e end o f f ol low -up) 3 ≥6 14% 14% 0.4 (-5. 7 to 6.6 )% Ye s 13 M 400 S HRZ M (2 ) HR M (2 ) HRZ E (2 ) HR (4 ) P lac ebo -cont rol led, doub le -bl in d, non -in fe rio rity , RCT 568( M ) 555( C ) R - and FQ - se nsi tiv e, sme ar -pos iti ve U nfav or abl e o ut co m e (b ac te rio lo gic ally o r c lin ic ally def in ed f ai lur e o r r el aps e) 12 23% 6 16% 7. 8 ( 2. 7 to 13. 0) 0.4 8 ( -2. 16 to 3 .1 1) 7 No 12 M 400 S M RZE(2 ) R M (2 ) H RZE(2 ) H R(4) P lac ebo -cont rol led, doub le -bl in d, non -in fe rio rity , RCT 551( M ) 555( C ) R - and FQ - se nsi tiv e, sme ar -pos iti ve U nfav or abl e o ut co m e (b ac te rio lo gic ally o r c lin ic ally def in ed f ai lur e o r r el aps e) 12 24% 6 16% 9. 0 ( 3. 8 to 14. 2) 1.9 6 ( -0. 90 to 4 .8 3) 7 No 12 ^D ai ly re gi m en u nl es s i ndi cat ed o th er w is e. ¥(M odi fie d) int ent ion -to -tr eat a nd p er -pr ot oc ol p opul at ion unl es s i ndi cat ed o ther w is e. $(M odi fied) int ent io n-to -tr eat po pul at ion u nl es s indi cat ed o ther w is e. # M ont hs a fter th e e nd o f c on tro l t re at m ent . * Poi nt -di ffer en ce ( 95% or 9 7. 5%C I). 1 Adm ini st er ed tw ic e-w eek ly . 2 R, H a nd M s en si tiv e T B. M os t p ati en ts w ith unf av or ab le D S T r es ul ts w er e e xc luded a fte r r ando m iz at ion ( lat e ex cl us io ns , ex cl uded fro m m od ifi ed i nt ent ion -to -tre at a na ly si s). 3Pa tie nt s w ith re -inf ec tio n a nd pr eg nant p at ient s w er e e xc luded . 4R em ar kabl e h igh r el ap se r at e co m par ed to cont ro l. 5A dm in is ter ed onc e-w eek ly . 6Appr ox . 10 per cen t r el aps e-ra te a fte r t he e nd o f tr ea tm ent . 7S en sit iv ity anal ys es : non -in fe rio r s ta tus at the e nd o f t re at m ent . C , c ont rol ; E , et ha m bu to l; FQ , fl uor oq ui nol one; H , i soni az id, M , m ox ifl ox ac in; R C T, random iz ed cont rol le d tri al ; R i, rifa pe nti ne ; R, r ifa m pi ci n; S , s ho rt-co ur se ; Z , p yr az in am ide. Table 2 (II) . T rea tm en t o utc om es o f FQ -c on tai ni ng re gi m en s for pul m on ar y T B . Tre atm ent re gi m en^ Stud y Tre atm ent o utc om e FQ (mg ) FQ (m ont hs ) Con tro l (m ont hs ) Ty pe No. $ Pa tie nt Pri m ary e nd po in t(s ) En d-point ¶ En d-point FQ $ En d-point Con tro l $ FQ m in us Con tro l $* FQ non -in fe rio r ¥ Ref. G 400 S G HR Z(2 ) G HR (2 ) HRZ E (2 ) HR (4 ) Non -in fe rio rity , open -labe l, RCT 1356 R -se nsi tiv e, sme ar -pos iti ve unf av or ab le out com e (c ul tu re -p os iti ve a t th e end o f tr ea tm ent , rel ap se or re -in fe cti on , or d ea th , or s tudy d rop -out ) 24 21% 17% 3.5 (-0. 7 to 7. 7) % 1 No 15 G 400 S G HR Z(2 ) 2 G HR (2 ) 2 HRZ E (2 ) 2 HR (4 ) 2 O pen -la be l, RC T 136 ( G ) 3 165 ( C ) 3 Cul tu re -pos iti ve unf av or ab le out com e (c ul tu re -p os iti ve , o r deat h, o r c lini cal need to c hang e tr ea tm ent ) re cu rre nc e 0 24 5% 4 16% 4,5 3% 4 6% 4 - N/a 16 L M 750 400 LB(3 +) 6 M B(3 +) 6 - O pen -labe l, RCT 77 ( L) 7 74 ( M ) 7 M DR , cul tur e-pos iti ve tre atm en t s uc ce ss (s um of c ur e and com pl et ion) 8 tre atm en t f ai lu re (s um of d eat h and fa ilur e) 0 0 84% ( L) 80% ( M ) 8% ( L) 7% ( M ) - M -L: -4 .7 (-17 .0 to 7 .6 )% M -L: -1 .0 (-10 .1 to 8 .1 )% N/a 14 M 400 S M HR Z(2 ) 2 M HR (2 ) 2 HRZ E (2 ) 2 HR (4 ) 2 O pen -la be l, RC T 115 (M) 3 165 ( C ) 3 Cul tu re -pos iti ve unf av or ab le out com e (c ul tu re -p os iti ve , o r deat h, o r c lini cal need to c hang e tr ea tm ent ) re cu rre nc e 0 ₂₄ 2% 4 10% 4 3% 4 6% 4 - N/a 16 ^D ai ly re gi m en u nl es s i ndi cat ed o th er w is e. ¥ (M odi fie d) int ent ion -to -tr eat a nd p er -pr ot oc ol p opul at ion unl es s i ndi cat ed o ther w is e. $ (M odi fied) int ent io n-to -tr eat po pul at ion u nl es s indi cat ed o ther w is e. ¶ M ont hs af ter the e nd o f tr ea tm ent . *Poi nt -di ffer en ce ( 95%C I). 1Su bg ro up s HIV -nega tiv e, c av ita tion, B M I ≥16 : 9 5% CI in fa vo r o f C on tro l. 2th ric e-w ee kl y. 3Prem at ur e ter m inat ion due t o t he ex te nt of T B re cur re nc e i n t he G - an d M -a rm . 4Drug -s us ce pti bl e (DS) T B p at ie nt s (t es te d d ru gs : H,R,E,O ): 94 % (G ), 97 % (M ) a nd 8 4% (C). DS -TB p at ient s: e qui val ent fr equ enc ie s f or p rim ar y e ndpo int s c om par ed to th e to ta l g ro up. 5FQ v s. Con tro l: p < 0 .0 5. 63 m on th s tri al -m edi cat ion, ther eaf te r a cc or di ng t o W H O gui del ines . 7Pre m at ur e ter m in at ion d ue to d rop of pa tie nt enr ol lm ent . 8Fo llo w -up a nal ys is c om par ing a ll W H O d ef ini tion s of tr ea tm ent o ut co m e. Ini tia l s tudy had pr im ar y out com e = s put um c ul tur e con ver si on. B , b ac kgr ound r egi m en a cc or di ng to W H O g ui del in es . C , c ont rol ; E , et ham but ol ; F Q , fl uo roqui nol one; G , g at ifl ox ac in; H , i soni az id; L, lev of lox ac in; M , m ox ifl ox ac in; M D R , m ul ti-dr ug res is ta nc e; O , of lox ac in; R C T, rand om iz ed c on tro lle d tri al ; R, rifa m pi ci n; S , s ho rt-cour se; Z , py raz inam ide. 109

Chapter 2b

110

Tuberculosis meningitis

Three clinical trials investigated survival benefit of a FQ added to, or replacing a drug of the

standard regimen for the treatment of TB meningitis (TBM) (Table 3). A significant survival

benefit (Hazard Ratio: 2.13, 95% CI: 1.04 - 4.34, P = 0.04) was observed for TBM patients, regardless of stage of TBM, treated with LFX (10mg/kg/day, max. 500mg/day) instead of R, next to isoniazid (H), Z and ethambutol (E). Although the proportion of patients with an unfavourable outcome did not change in the per-protocol analysis (excluding patients with serious adverse events) for both treatment groups, it was striking that LFX had to be discontinued in 16 of 60 patients mainly due to seizures (18). In the remaining two clinical trials (19,20), intensified TBM regimens for DS-TB were investigated that included a high-dose FQ (LFX or MFX) and/or high-high-dose R during the first weeks of treatment. Adding LFX

(20mg/kg/day) plus R (5mg/kg/day) to the standard HRZE combination during the 1st ₈

weeks of treatment did not contribute in reducing death after 9 months of treatment (19). Although the sample size was small and the study was exploratory, replacing E by MFX (400

or 800mg) in the 1st _{2 weeks of standard DS-TB treatment was also not associated with any}

survival benefit (20). On the other hand, in this study high-dose R (600mg iv.) in the 1st ₂

weeks of treatment was associated with a lower six-month mortality compared to the standard R dose (450mg oral) (20).

Table 3 . T rea tm en t ou tc om es of FQ -c on tai ni ng re gi m en s f or T B m en ing iti s. Tre atm ent re gi m en^ Stud y Tre atm ent o utc om e Surv iv al FQ/Control FQ (mg ) FQ (m ont hs ) Con tro l (m ont hs ) Ty pe No. $ Pa tie nt Pri m ary endpo int E ndpo int m ont hs ¶ E ndpo int FQ $ E ndpo int Con tro l $ Haz ard ra tio (9 5% CI) $ P -val ue Ref. L 20/ kg LR (8 w ks )+ HR ZE(3 ) 1 HR (6 ) HR ZE(3 ) HR (6 ) Dou bl e-bl in d, pl ac ebo -cont rol led, RCT 817 Cli ni ca l di ag nos is , no M D R 2 Dea th 0 28% 28% Dea th : 0. 94 ( 0. 73 -1. 22) 0.6 6 19 L 10/ kg (m ax . 500) H LZE(6 ) H R ZE(6 ) O pen -la bel , RCT 120 Cli ni ca l di ag nos is Dea th 0 22% 4 38% 4 Su rv iv al : 2. 13 ( 1. 04 -4. 34) 3 0.0 4 18 M 0 400 800 HRZ E (2 w ks) 5 HRZ M (2 w ks) 5 HRZ M (2 w ks) 5 A ll ar ms > 2w ks: HR ZE(2 m th s-2w ks) HR (4 ) - O pen -la bel , RC T, fa cto ria l des ign +R 450m g 12 10 9 +R 600m g 10 9 10 Cli ni ca l di ag nos is Dea th 6 0 +R450m g 58% 60% 78% _+R600m g 30% 22% 50% - Dea th : 0. 76 ( 0. 30 -1. 94) 7,8 1. 27 ( 0. 53 -3. 02) 7,8 0.5 5 8 20 ^Dai ly re gi m en . $(M odi fied ) i nt ent io n-to -tr eat popu lat ion. ¶ M ont hs af ter th e end of tr eat m ent . 1+5 m g/ kg/ day ri fa m pi ci n ( tot al 1 5 m g/ kg/ day ) i n the fir st 8 w eek s. S tre pt om yc in w as a dded fo r th e fi rs t 3 m ont hs in tr eat m ent -ex per ien ced p at ien ts . 2 M D R p rov en b y s put um c ul tur e o r s us pe ct ed. 3 Adj us te d f or c ov ar iat es of s ur vi val s uc h as s tage of d is eas e. 4Lev of lox ax in w as w ith dr aw n i n 1 6 p at ient s d ue to S A E’ s. D eat h i n the p er -pr ot oc ol a na ly si s ( pat ient s w ith S A E ’s ex cl uded ): 25% ( L) v s. 4 1% ( R ). 56 a rm s: 1 st rand om iz at ion or al R45 0m g (s ta ndar d) o r i nt ra venou s R 600m g (hi gh -dos e) , 2 nd rando m iz at ion M 400m g , M 800 m g o r E. 6 S ec ond ar y e ndp oi nt . N o sam pl e s iz e c al cul at ion b ec au se o f t he e xpl or at or y nat ur e o f t he s tu dy . S am pl e s iz e w as a ss um ed to b e s uf fic ie nt to e xpl or e phar m ac ok ine tic s a nd saf et y o f i nt en si fied r egi m ens bas ed o n M a nd/ or R . 7Adj us te d for R600m g , HIV st at us , a nd G las gow c om a sc al e a t bas el ine. 8 M (4 00m g, 800 m g) ver su s E . E, et ham but ol ; F Q , f luor oqui nol one; H , i soni az id; L, lev of lox ac in ; M D R , m ul ti-dru g re si sta nc e; M , m ox ifl ox ac in; R C T, rando m iz ed co nt ro lled tri al ; R , r ifa m pi ci n; Z, py raz ina m id e.

Chapter 2b

Chapter

2

b

110

Tuberculosis meningitis

Three clinical trials investigated survival benefit of a FQ added to, or replacing a drug of the

standard regimen for the treatment of TB meningitis (TBM) (Table 3). A significant survival

benefit (Hazard Ratio: 2.13, 95% CI: 1.04 - 4.34, P = 0.04) was observed for TBM patients, regardless of stage of TBM, treated with LFX (10mg/kg/day, max. 500mg/day) instead of R, next to isoniazid (H), Z and ethambutol (E). Although the proportion of patients with an unfavourable outcome did not change in the per-protocol analysis (excluding patients with serious adverse events) for both treatment groups, it was striking that LFX had to be discontinued in 16 of 60 patients mainly due to seizures (18). In the remaining two clinical trials (19,20), intensified TBM regimens for DS-TB were investigated that included a high-dose FQ (LFX or MFX) and/or high-high-dose R during the first weeks of treatment. Adding LFX

(20mg/kg/day) plus R (5mg/kg/day) to the standard HRZE combination during the 1st ₈

weeks of treatment did not contribute in reducing death after 9 months of treatment (19). Although the sample size was small and the study was exploratory, replacing E by MFX (400

or 800mg) in the 1st _{2 weeks of standard DS-TB treatment was also not associated with any}

survival benefit (20). On the other hand, in this study high-dose R (600mg iv.) in the 1st ₂

weeks of treatment was associated with a lower six-month mortality compared to the standard R dose (450mg oral) (20).

Table 3 . T rea tm en t ou tc om es of FQ -c on tai ni ng re gi m en s f or T B m en ing iti s. Tre atm ent re gi m en^ Stud y Tre atm ent o utc om e Surv iv al FQ/Control FQ (mg ) FQ (m ont hs ) Con tro l (m ont hs ) Ty pe No. $ Pa tie nt Pri m ary endpo int E ndpo int m ont hs ¶ E ndpo int FQ $ E ndpo int Con tro l $ Haz ard ra tio (9 5% CI) $ P -val ue Ref. L 20/ kg LR (8 w ks )+ HR ZE(3 ) 1 HR (6 ) HR ZE(3 ) HR (6 ) Dou bl e-bl in d, pl ac ebo -cont rol led, RCT 817 Cli ni ca l di ag nos is , no M D R 2 Dea th 0 28% 28% Dea th : 0. 94 ( 0. 73 -1. 22) 0.6 6 19 L 10/ kg (m ax . 500) H LZE(6 ) H R ZE(6 ) O pen -la bel , RCT 120 Cli ni ca l di ag nos is Dea th 0 22% 4 38% 4 Su rv iv al : 2. 13 ( 1. 04 -4. 34) 3 0.0 4 18 M 0 400 800 HRZ E (2 w ks) 5 HRZ M (2 w ks) 5 HRZ M (2 w ks) 5 A ll ar ms > 2w ks: HR ZE(2 m th s-2w ks) HR (4 ) - O pen -la bel , RC T, fa cto ria l des ign +R 450m g 12 10 9 +R 600m g 10 9 10 Cli ni ca l di ag nos is Dea th 6 0 +R450m g 58% 60% 78% _+R600m g 30% 22% 50% - Dea th : 0. 76 ( 0. 30 -1. 94) 7,8 1. 27 ( 0. 53 -3. 02) 7,8 0.5 5 8 20 ^Dai ly re gi m en . $ (M odi fied ) i nt ent io n-to -tr eat popu lat ion. ¶ M ont hs af ter th e end of tr eat m ent . 1 +5 m g/ kg/ day ri fa m pi ci n ( tot al 1 5 m g/ kg/ day ) i n the fir st 8 w eek s. S tre pt om yc in w as a dded fo r th e fi rs t 3 m ont hs in tr eat m ent -ex per ien ced p at ien ts . 2 M D R p rov en b y s put um c ul tur e o r s us pe ct ed. 3 Adj us te d f or c ov ar iat es of s ur vi val s uc h as s tage of d is eas e. 4 Lev of lox ax in w as w ith dr aw n i n 1 6 p at ient s d ue to S A E’ s. D eat h i n the p er -pr ot oc ol a na ly si s ( pat ient s w ith S A E ’s ex cl uded ): 25% ( L) v s. 4 1% ( R ). 5 6 a rm s: 1 st rand om iz at ion or al R45 0m g (s ta ndar d) o r i nt ra venou s R 600m g (hi gh -dos e) , 2 nd rando m iz at ion M 400m g , M 800 m g o r E. 6 S ec ond ar y e ndp oi nt . N o sam pl e s iz e c al cul at ion b ec au se o f t he e xpl or at or y nat ur e o f t he s tu dy . S am pl e s iz e w as a ss um ed to b e s uf fic ie nt to e xpl or e phar m ac ok ine tic s a nd saf et y o f i nt en si fied r egi m ens bas ed o n M a nd/ or R . 7Adj us te d for R600m g , HIV st at us , a nd G las gow c om a sc al e a t bas el ine. 8 M (4 00m g, 800 m g) ver su s E . E, et ham but ol ; F Q , f luor oqui nol one; H , i soni az id; L, lev of lox ac in ; M D R , m ul ti-dru g re si sta nc e; M , m ox ifl ox ac in; R C T, rando m iz ed co nt ro lled tri al ; R , r ifa m pi ci n; Z, py raz ina m id e. 111

Chapter 2b Fluoroquinolones for tuberculosis anno 2018

112

Discussion

Pulmonary tuberculosis

Main finding of this review is that the 4-month MFX or GFX containing regimens successfully treated 75-90% of pulmonary TB patients, but none of them demonstrated a favourable outcome after a follow-up period of at least six months, compared to the standard DS-TB

regimen (Table 2). Particularly, the TB relapse rate after treatment was remarkable.

MTB has the capacity to survive in a hypoxic environment by switching to a low-replicating and low-metabolic rate, resulting in a difficult-to-treat sub-population of persistent TB bacilli in pulmonary TB lesions (21) and thus several months of treatment are needed to attain sterilising treatment. The indication that MFX or GFX had the potential to shorten DS-TB treatment was based on the in vitro bactericidal activity of MFX and GFX against anaerobic, non-replicating TB bacilli, a stable cure in BALB/c mice after 4 instead of 6 months of treatment with H replaced by MFX, and a similar or higher proportion of TB patients with negative sputum culture after 8 weeks of treatment with MFX or GFX instead of H or E (22-27). A poor predictive value of the pre-clinical study designs used and a sub-optimal exposure of anti-TB drugs at the side of infection might explain the unfavourable results of these shorter-course regimens.

First, the standard BALB/c mouse does not exhibit the TB lesion heterogeneity as seen in humans, making this mouse model possibly unsuitable to study in vivo activity of drugs against non-replicating TB bacilli (28). The C3HeB/FeJ mouse, on the other hand, may be more suitable (28). In addition, the two 4-month MFX containing regimens of the REMoxTB Phase III study were retrospectively evaluated in a pre-clinical model with C3HeB/FeJ mice (29). In accordance with the results of the Phase III trial, a stable cure was also not expected after 4 months of treatment based on this murine model (29). Second, using in vitro PK/PD modelling and Monte Carlo simulations, it has been suggested that a daily dose of 800mg MFX or more is needed for optimal kill of MTB and to suppress drug-resistant mutants in log-phase growth (30,31). The optimal sterilizing dose is thus unknown, but 400mg/day is likely not the optimal dosage of MFX for TB. In addition, combination therapy with R might be synergistic for suppression of drug-resistance (MTB in log-phase growth), but antagonistic for the time needed to kill the non-growing mycobacterial population (31). Given the possible paradoxical effect of R on MFX, the predictive performance for sterilizing activity of Phase IIB studies, investigating culture conversion at 2-months of MFX substituted for H or E in a standard DS-TB regimen, is at least questioned. Also, PD interactions (synergistic, antagonistic or additive) might be concentration dependent. An in vitro hollow fiber system

113 (HFS) has the ability to study both the bactericidal and sterilizing effects for drug-combinations using a variety of concentrations over time (28,32). Therefore, the HFS might be a useful model to study potentially sterilizing drugs like MFX and GFX, as part of a standard or new TB-regimen. Recently, the HFS was used to select the optimal sterilizing dose of both linezolid and ertapenem-clavulanate for TB (33,34).

Furthermore, in our TB patients treated under direct observation (DOT), MFX PK-variability in plasma was found to be 9-fold on 400mg/day (35). The PK of all anti-tuberculosis drugs could be affected by TB disease activity (wasting, loss of lean body mass, fat and serum proteins), HIV, diabetes or drug-drug interactions (36,37). The PK interaction between R and MFX is well known (38,39), but also male gender might be a risk factor for reduced MFX exposure in the early phase of treatment, which is probably due to disease-related intestinal dysfunction (publication to be submitted). In healthy volunteers, MFX has a high penetration into alveolar macrophages and epithelial lining fluid (8). However, based on MALDI mass spectrometry imaging, the penetration of MFX into the hypoxic sites of pulmonary lesions of TB patients is marginal compared to the oxygen-rich sites, and compared to R (40). All together, the optimal sterilizing dose appears to differ from one patient to another probably due to PK variability, and this advocates for sub-group analyses in pre-clinical animal models (e.g. extent of cavitation) and clinical trials (e.g. low BMI), and also for drug concentration monitoring in patients at risk for low drug exposure during treatment. In addition, despite limited data on GFX PK, in one of the Phase III trials (OFLOTUB), the 4-month GFX containing regimen was not associated with treatment success for the total group of patients, but was in favour of treatment success for patients without cavitation, for patients with HIV co-infection, and for patients with a low BMI, compared to the standard DS-TB regimen (15). In the recent years, one clinical trial compared two conventional MDR-TB regimens (Table 2). In accordance with the results of this study (14), LFX and MFX are both core agents for RR/MDR-TB treatment in the WHO guidelines (7). Next to reclassification of anti-TB drugs into core and add-on agents, the recently updated WHO guidelines (October 2016) proposed a shorter course – still 9 to 12 months – regimen for RR/MDR-TB patients (7). This largely standardized GFX (or MFX) containing regimen is based on three observational studies of cohorts from Bangladesh, Niger and Cameroon, supplemented with individual patient data (7,41-43). Although the number of patients in follow up was limited, MDR/RR-TB patients

without previous use of 2nd _{line drugs, and without resistance against FQs and injectable}

agents, were found likely enough to benefit from this shorter regimen (7). An important note is that the short-course Bangladesh regimen included high-dose GFX (600mg for bodyweight 33-50kg, 800mg for >50kg) (41,43). As earlier suggested for DS-TB, and as was proposed

Chapter 2b Fluoroquinolones for tuberculosis anno 2018 Chapter

2

b 112 Discussion Pulmonary tuberculosis

Main finding of this review is that the 4-month MFX or GFX containing regimens successfully treated 75-90% of pulmonary TB patients, but none of them demonstrated a favourable outcome after a follow-up period of at least six months, compared to the standard DS-TB

regimen (Table 2). Particularly, the TB relapse rate after treatment was remarkable.

MTB has the capacity to survive in a hypoxic environment by switching to a low-replicating and low-metabolic rate, resulting in a difficult-to-treat sub-population of persistent TB bacilli in pulmonary TB lesions (21) and thus several months of treatment are needed to attain sterilising treatment. The indication that MFX or GFX had the potential to shorten DS-TB treatment was based on the in vitro bactericidal activity of MFX and GFX against anaerobic, non-replicating TB bacilli, a stable cure in BALB/c mice after 4 instead of 6 months of treatment with H replaced by MFX, and a similar or higher proportion of TB patients with negative sputum culture after 8 weeks of treatment with MFX or GFX instead of H or E (22-27). A poor predictive value of the pre-clinical study designs used and a sub-optimal exposure of anti-TB drugs at the side of infection might explain the unfavourable results of these shorter-course regimens.

First, the standard BALB/c mouse does not exhibit the TB lesion heterogeneity as seen in humans, making this mouse model possibly unsuitable to study in vivo activity of drugs against non-replicating TB bacilli (28). The C3HeB/FeJ mouse, on the other hand, may be more suitable (28). In addition, the two 4-month MFX containing regimens of the REMoxTB Phase III study were retrospectively evaluated in a pre-clinical model with C3HeB/FeJ mice (29). In accordance with the results of the Phase III trial, a stable cure was also not expected after 4 months of treatment based on this murine model (29). Second, using in vitro PK/PD modelling and Monte Carlo simulations, it has been suggested that a daily dose of 800mg MFX or more is needed for optimal kill of MTB and to suppress drug-resistant mutants in log-phase growth (30,31). The optimal sterilizing dose is thus unknown, but 400mg/day is likely not the optimal dosage of MFX for TB. In addition, combination therapy with R might be synergistic for suppression of drug-resistance (MTB in log-phase growth), but antagonistic for the time needed to kill the non-growing mycobacterial population (31). Given the possible paradoxical effect of R on MFX, the predictive performance for sterilizing activity of Phase IIB studies, investigating culture conversion at 2-months of MFX substituted for H or E in a standard DS-TB regimen, is at least questioned. Also, PD interactions (synergistic, antagonistic or additive) might be concentration dependent. An in vitro hollow fiber system

113 (HFS) has the ability to study both the bactericidal and sterilizing effects for drug-combinations using a variety of concentrations over time (28,32). Therefore, the HFS might be a useful model to study potentially sterilizing drugs like MFX and GFX, as part of a standard or new TB-regimen. Recently, the HFS was used to select the optimal sterilizing dose of both linezolid and ertapenem-clavulanate for TB (33,34).

Furthermore, in our TB patients treated under direct observation (DOT), MFX PK-variability in plasma was found to be 9-fold on 400mg/day (35). The PK of all anti-tuberculosis drugs could be affected by TB disease activity (wasting, loss of lean body mass, fat and serum proteins), HIV, diabetes or drug-drug interactions (36,37). The PK interaction between R and MFX is well known (38,39), but also male gender might be a risk factor for reduced MFX exposure in the early phase of treatment, which is probably due to disease-related intestinal dysfunction (publication to be submitted). In healthy volunteers, MFX has a high penetration into alveolar macrophages and epithelial lining fluid (8). However, based on MALDI mass spectrometry imaging, the penetration of MFX into the hypoxic sites of pulmonary lesions of TB patients is marginal compared to the oxygen-rich sites, and compared to R (40). All together, the optimal sterilizing dose appears to differ from one patient to another probably due to PK variability, and this advocates for sub-group analyses in pre-clinical animal models (e.g. extent of cavitation) and clinical trials (e.g. low BMI), and also for drug concentration monitoring in patients at risk for low drug exposure during treatment. In addition, despite limited data on GFX PK, in one of the Phase III trials (OFLOTUB), the 4-month GFX containing regimen was not associated with treatment success for the total group of patients, but was in favour of treatment success for patients without cavitation, for patients with HIV co-infection, and for patients with a low BMI, compared to the standard DS-TB regimen (15). In the recent years, one clinical trial compared two conventional MDR-TB regimens (Table 2). In accordance with the results of this study (14), LFX and MFX are both core agents for RR/MDR-TB treatment in the WHO guidelines (7). Next to reclassification of anti-TB drugs into core and add-on agents, the recently updated WHO guidelines (October 2016) proposed a shorter course – still 9 to 12 months – regimen for RR/MDR-TB patients (7). This largely standardized GFX (or MFX) containing regimen is based on three observational studies of cohorts from Bangladesh, Niger and Cameroon, supplemented with individual patient data (7,41-43). Although the number of patients in follow up was limited, MDR/RR-TB patients

without previous use of 2nd _{line drugs, and without resistance against FQs and injectable}

agents, were found likely enough to benefit from this shorter regimen (7). An important note is that the short-course Bangladesh regimen included high-dose GFX (600mg for bodyweight 33-50kg, 800mg for >50kg) (41,43). As earlier suggested for DS-TB, and as was proposed

Chapter 2b Fluoroquinolones for tuberculosis anno 2018

114

for ertapenem-clavulanate (34), we propose a combination of studies in a HFS and Monte Carlo simulations, using RR/MDR-TB patient data, to select the sterilizing FQ dose most suitable to be tested in controlled Phase III trials as part of RR/MDR-TB regimens.

Tuberculosis meningitis

A significant survival benefit for TBM patients treated with a FQ containing regimen was

observed in one of the three published clinical trials (Table 3). The idea to use MFX and LFX

for improvement of TBM survival is based on favourable penetration into cerebrospinal fluid (CSF) (8). Because an evidence-based regimen is lacking, TBM patients are often treated (for a pragmatic longer period) with the standardized pulmonary TB regimen, as recommended by the WHO despite the fact that R only marginally penetrates into CSF (17,44). In the only RCT with favourable results for the patients treated with an FQ (18), LFX was compared to R, both using a standard dose, next to H, Z and E. The improved outcome for TBM patients treated with LFX might be explained by the much better penetration of LFX into CSF compared to R (8,44).

As adequate early-phase treatment is important to prevent patients suffering from TBM to deteriorate, the two remaining clinical studies investigated intensified, high-dose, therapies at the early phase of TBM treatment (19,20). Although the trial with MFX was not powered for survival analysis, not the high-dose MFX (800mg), but rather the ‘high-dose’ R (600mg iv.) in

the 1st _{two weeks, given in an attempt to increase CSF drug-exposure, was associated with}

survival benefit (20). In this study, the MFX dose was escalated because of the well-known drug-drug interaction with R. An additional PK/PD analysis was done to investigate the extent to which exposure was related to outcome (45). Despite the small sample size, MFX AUC was not, but the AUC of R was related to TBM survival, and therefore the authors concluded that increasing the R dose above 600mg might be the way forward to further optimize TBM treatment. However, there was a trend to a higher MFX peak-plasma concentration for patients who survived at least two weeks. We therefore agree with the authors that an extended cumulative PK/PD analysis of the TBM regimen is needed to clarify the (long-term)

role of MFX for TBM (46,47). The same might be true for the 3rd _{study (19), including}

high-dosages of LFX and R in the 1st _{8 weeks added to HRZE, which did not result in a cumulative}

survival benefit. Remarkably, the head-to-head comparison of standard dosages of LFX and

R in the 1st _{study was in favour of LFX (18), which might support further investigating the}

relationship between drug-exposure and outcome in a multiple drug-regimen.

Finally, considering that the (protein-unbound) drug-exposure in plasma is closely linked to drug-exposure in CSF, like for plasma, CSF PK variability might play an important role.

115 Therefore, the identification of sub-groups at risk for inadequate CSF exposure might be important for clinical research and clinical practice. Inadequate drug-exposure may result in drug-resistance and high drug-exposure in toxicity, and, as CSF penetration has to be

sufficiently high, 2nd _{line treatment options are even more limited for TBM compared to the}

2nd _{line drug-options for pulmonary TB. Aminoglycosides belong to the core RR/MDR-TB}

agents; these drugs have however marginal penetration into CSF (44). In addition, a recent sub-group analysis showed that in H-mono-resistant TB, an intensified combination of LFX and R in the early phase of treatment was associated with a lower 9-month mortality although an overall survival benefit was not observed. LFX combined with R might therefore provide a survival benefit for H-resistant TBM patients (19,48). Concerning safety of high-dose FQs, data is limited, but no increase of serious adverse events was reported for LFX or MFX in TBM patients (19,20,49). However, high-dose MFX was always combined with R in these studies and a high-incidence of seizures was observed by using the standard dose of LFX (18,20,49). The authors of the standard-dose LFX study discussed that there could have been a relatively high seizure-potential amongst their patients due to inter alia severe meningitis (18). However, as long as there is no drug-exposure breakpoint for safety, ECG monitoring is still recommended for high-dose MFX and one should be aware of seizures by using (high-dose) LFX.

Conclusion

We provide a comprehensive summary of clinical trials investigating outcome of FQ containing regimens for TB in the recent years. In general, the results of these trials were not

in favour of FQs for TB. MFX, LFX and GFX are important 2nd _{line anti-TB agents, but we}

advise extended PK/PD analysis to measure drug-exposure, and identify suitable dosing, for

clarification of the role of FQs as sterilizing agent for pulmonary TB and as 1st _{line agent for}

TBM. PK variability calls for sub-group analysis or strict inclusion criteria in clinical trials, and for therapeutic drug monitoring in patients at risk for inadequately low exposure. Therefore, to prevent failure of treatment and emergence of drug-resistance, a strategy for concentration guided dosing, including point-of-care tools, is the proposed way forward (50,51).

Chapter 2b Fluoroquinolones for tuberculosis anno 2018

Chapter

2

b

114

for ertapenem-clavulanate (34), we propose a combination of studies in a HFS and Monte Carlo simulations, using RR/MDR-TB patient data, to select the sterilizing FQ dose most suitable to be tested in controlled Phase III trials as part of RR/MDR-TB regimens.

Tuberculosis meningitis

A significant survival benefit for TBM patients treated with a FQ containing regimen was

observed in one of the three published clinical trials (Table 3). The idea to use MFX and LFX

for improvement of TBM survival is based on favourable penetration into cerebrospinal fluid (CSF) (8). Because an evidence-based regimen is lacking, TBM patients are often treated (for a pragmatic longer period) with the standardized pulmonary TB regimen, as recommended by the WHO despite the fact that R only marginally penetrates into CSF (17,44). In the only RCT with favourable results for the patients treated with an FQ (18), LFX was compared to R, both using a standard dose, next to H, Z and E. The improved outcome for TBM patients treated with LFX might be explained by the much better penetration of LFX into CSF compared to R (8,44).

As adequate early-phase treatment is important to prevent patients suffering from TBM to deteriorate, the two remaining clinical studies investigated intensified, high-dose, therapies at the early phase of TBM treatment (19,20). Although the trial with MFX was not powered for survival analysis, not the high-dose MFX (800mg), but rather the ‘high-dose’ R (600mg iv.) in

the 1st _{two weeks, given in an attempt to increase CSF drug-exposure, was associated with}

survival benefit (20). In this study, the MFX dose was escalated because of the well-known drug-drug interaction with R. An additional PK/PD analysis was done to investigate the extent to which exposure was related to outcome (45). Despite the small sample size, MFX AUC was not, but the AUC of R was related to TBM survival, and therefore the authors concluded that increasing the R dose above 600mg might be the way forward to further optimize TBM treatment. However, there was a trend to a higher MFX peak-plasma concentration for patients who survived at least two weeks. We therefore agree with the authors that an extended cumulative PK/PD analysis of the TBM regimen is needed to clarify the (long-term)

role of MFX for TBM (46,47). The same might be true for the 3rd _{study (19), including}

high-dosages of LFX and R in the 1st _{8 weeks added to HRZE, which did not result in a cumulative}

survival benefit. Remarkably, the head-to-head comparison of standard dosages of LFX and

R in the 1st _{study was in favour of LFX (18), which might support further investigating the}

relationship between drug-exposure and outcome in a multiple drug-regimen.

Finally, considering that the (protein-unbound) drug-exposure in plasma is closely linked to drug-exposure in CSF, like for plasma, CSF PK variability might play an important role.

115 Therefore, the identification of sub-groups at risk for inadequate CSF exposure might be important for clinical research and clinical practice. Inadequate drug-exposure may result in drug-resistance and high drug-exposure in toxicity, and, as CSF penetration has to be

sufficiently high, 2nd _{line treatment options are even more limited for TBM compared to the}

2nd _{line drug-options for pulmonary TB. Aminoglycosides belong to the core RR/MDR-TB}

agents; these drugs have however marginal penetration into CSF (44). In addition, a recent sub-group analysis showed that in H-mono-resistant TB, an intensified combination of LFX and R in the early phase of treatment was associated with a lower 9-month mortality although an overall survival benefit was not observed. LFX combined with R might therefore provide a survival benefit for H-resistant TBM patients (19,48). Concerning safety of high-dose FQs, data is limited, but no increase of serious adverse events was reported for LFX or MFX in TBM patients (19,20,49). However, high-dose MFX was always combined with R in these studies and a high-incidence of seizures was observed by using the standard dose of LFX (18,20,49). The authors of the standard-dose LFX study discussed that there could have been a relatively high seizure-potential amongst their patients due to inter alia severe meningitis (18). However, as long as there is no drug-exposure breakpoint for safety, ECG monitoring is still recommended for high-dose MFX and one should be aware of seizures by using (high-dose) LFX.

Conclusion

We provide a comprehensive summary of clinical trials investigating outcome of FQ containing regimens for TB in the recent years. In general, the results of these trials were not

in favour of FQs for TB. MFX, LFX and GFX are important 2nd _{line anti-TB agents, but we}

advise extended PK/PD analysis to measure drug-exposure, and identify suitable dosing, for

clarification of the role of FQs as sterilizing agent for pulmonary TB and as 1st _{line agent for}

TBM. PK variability calls for sub-group analysis or strict inclusion criteria in clinical trials, and for therapeutic drug monitoring in patients at risk for inadequately low exposure. Therefore, to prevent failure of treatment and emergence of drug-resistance, a strategy for concentration guided dosing, including point-of-care tools, is the proposed way forward (50,51).

Chapter 2b Fluoroquinolones for tuberculosis anno 2018

116

References

1. Murray C.J., Ortblad K.F., and Guinovart C. et al. 2014. Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systemic analysis for the Global Burden of Disease study 2013. Lancet. 384(9947):1005-70.

2. World Health Organization (WHO) (ed.). 2014. The end TB strategy: Global strategy and targets for tuberculosis prevention, care, and control after 2015. World Health Organization, Geneva, Switzerland.

3. World Health Organization (WHO) (ed.). 2017. Global tuberculosis report 2017. World Health Organization, Geneva, Switzerland.

4. Migliori G.B., De laco G., Besozzi G., Centis R., and Cirillo D.M. 2007. First tuberculosis cases in Italy resistant to all tested drugs. Eurosurveillance. 12(5):E070517.1.

5. Velyati A.A., Masjedi M.R., Farnia P., Tabarsi P., Ghanavi J., Ziazarifi A.H., and Hoffner S.E. 2009. Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in iran. Chest. 136(2):420-5. 6. Udwadia Z.F., Amale R.A., Ajbani K.K., and Rodrigues C. 2012. Totally drug-resistant

tuberculosis in India. Clin. Infect. Dis. 54(4):579-81.

7. World Health Organization (WHO) (ed.). 2016. WHO treatment guidelines for drug-resistant tuberculosis. 2016 update. World Health Organization, Geneva, Switzerland.

8. Pranger A.D., Alffenaar J.W., and Aarnoutse R.E. 2011. Fluoroquinolones, the cornerstone of treatment of drug-resistant tuberculosis: a pharmacokinetic and pharmacodynamics approach. Curr Pharm Des. 17(27):2900-30.

9. U.S. Food & Drug Administration (FDA) (ed.). Drugs@FDA: FDA Approved Drug Products. U.S. Department of Health and Human Services, Washington D.C., United States of America. Accessed: March 17th _{2018 via www.fda.gov.}

10. European Medicines Agency (EMA) (ed.). European public assessment reports. European Union, London, United Kingdom. Accessed: March 17th _{2018 via www.ema.europe.eu.} 11. Working Group on New Drugs (ed.). Clinical pipeline. Stop TB Partnership. Accessed: March

17th _{2018 via www.newtbdrugs.org.}

12. Gillespie S.H., Crook A.M., McHugh T.D., Mendel C.M., Meredith S.K., Murray S.R., Pappas F., Phillips P.P., Nunn. A.J; REMoxTB Consortium. 2014. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med. 371(17):1577-87.

13. Jindani A., Harrison T.S., Nunn A.J., Phillips P.P., Churchyard G.J., Charalambous S., Hatherill M., Geldenhuys H., Mcllleron H.M., Zvada S.P., Mungofa S., Shah N.A., Zizhou S., Magweta L., Shepard J., Nyirenda S., van Dijk J.H., Clouting H.E., Coleman D., Bateson A.L., McHugh T.D., Butcher P.D., Mitchison D.A; RIFAQUIN Trial Team. 2014. High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. N Engl J Med. 371(17):1599-608. 14. Kang Y.A., Shim T.S., Koh W.J., Lee S.H., Lee C.H., Choi J.C., Lee J.H., Jang S.H., Yoo

K.H., Jung K.H., Kim K.U., Choi S.B., Ryu Y.J., Kim K.C., Um S., Kwon Y.S., Kim Y.H., Choi W.I., Jeon K., Hwang Y.I., Kim S.J., Lee H.K., Heo E., and Yim J.J. 2016. Choice between

117

levofloxacin and moxifloxacin and multidrug-resistant tuberculosis treatment outcomes. Ann Am Thorac Soc. 13(3):364-70.

15. Merle C.S., Fielding K., Sow O.B., Gninafon M., Lo M.B., Mthiyane T., Odhiambo J., Amukoye E., Bah B., Kassa F., N’Diaye A., Rustomjee R., de Jong B.C., Horton J., Perronne C., Sismanidis C., Lapujade O., Olliaro P.L., Lienhardt C; OFLOTUB/Gatifloxacin for Tuberculosis Project. 2014. A four-month gatifloxacin-containing regimen for treating tuberculosis. N Engl J Med. 371(17):1588-98.

16. Jawahar M.S., Banurekha V.V., Paramasivan C.N., Rahman F., Ramachandran R., Venkatesan P., Balasubramanian R., Selvakumar N., Ponnuraja C., Iliayas A.S., Gangadevi N.P., Raman B., Baskaran D., Kumar S.R., Kumar M.M., Mohan V., Ganapathy S., Kumar V., Shanmugam G., Charles N., Sakthivel M.R., Jaqannath K., Chandrasekar C., Parthasarathy R.T., and Narayanan P.R. 2013. Randomized clinical trial of thrice-weekly 4-month moxifloxacin or gatifloxacin containing regimens in the treatment of new sputum positive pulmonary tuberculosis patients. PLoS One. 8(7):e67030.

17. World Health Organization (WHO) (ed.). 2017. Guidelines for treatment of drug-susceptible tuberculosis and patient care (2017 update). World Health Organization, Geneva, Switzerland. 18. Kalita J., Misra U.K., Prasad S., and Bhoi S.K. 2014. Safety and efficacy of levofloxacin versus rifampicin in tuberculosis meningitis: an open-label randomized controlled trial. J Antimicrob Chemother. 69(8):2246-51.

19. Heemskerk A.D., Bang N.D., Mai N.T., Chau T.T., Phu N.H., Loc P.P., Chau N.V., Hien T.T., Dung N.H., Lan N.T., Lan N.H., Lan N.N., Phong le T., Vien N.N., Hien N.Q., Yen N.T., Ha D.T., Day J.N., Caws M., Merson L., Thinh T.T., Wolbers M., Thwaites G.E., and Farrar J.J. 2016. Intensified antituberculosis therapy in adults with tuberculous meningitis. N Engl J Med. 374(2):124-34.

20. Ruslami R., Ganiem A.R., Dian S., Apriani L., Achmad T.H., van der Ven A.J., Borm G., Aarnoutse R.E., and van Crevel R. 2013. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label randomised controlled phase 2 trial. Lancet Infect Dis. 13(1):27-35.

21. Boon C. and Dick T. 2012. How Mycobacterium tuberculosis goes to sleep: the dormancy survival regulator DosR a decade later. Future Microbiol. 7(4):513-8.

22. Lakshminarayana S.B., Huat T.B., Ho P.C., Manjunatha U.H., Dartois V., Dick T, and Rao S.P. 2015. Comprehensive physiochemical, pharmacokinetic and activity profiling of anti-TB agents. J Antimicrob. Chemother. 70(3):857-67.

23. Nuermberger E.L., Yoshimatsu T., Tyagi S., Williams K., Rosenthal I., O’Brien R.J., Vernon A.A., Chaisson R.E., Bishai W.R., and Grosset J.H. 2004. Moxifloxacin-containing regimen of reduced duration produce a stable cure in murine tuberculosis. Am J Respir Crit Care Med. 170(10):1131-4.

24. Dorman S.E., Johnson J.L, Goldberg S., Muzanye G., Padayatchi N., Bozeman L., Heilig C.M., Bernardo J., Choudhri S., Grosset J.H., Guy E., Guyadeen P., Leus M.C., Maltas G., Menzies D., Nuermberger E.L., Villarino M., Vernon A., and Chaisson R.E.; Tuberculosis