an ibio ics
A icle
Eu opean Regis y on Helicobac e pylo i Managemen :
E ec i eness o Fi s and Second-Line T ea men in Spain
Ma ía Caldas 1,Ángeles Pé ez-Aisa 2, Manuel Cas o-Fe nández 3, Luis Bujanda 4, Al edo J. Lucendo 5,
Luis Rod igo 6, Jose M. Hugue 7, Jo ge Pé ez-Lasala 8, Ja ie Molina-In an e 9, Jesús Ba io 10,
Luis Fe nández-Salaza 11,Ángel Lanas 12, Mónica Pe ona 13, Manuel Domínguez-Cajal 14, Juan O uño 15,
Blas JoséGómez-Rod íguez 16, Ped o Almela 17, Josep Ma ía Bo a gués18,Ósca Núñez 19, Inés Modolell 20,
Judi h Gómez 21, Ra ael Ruiz-Zo illa 22, C is óbal De la Coba 23, Alain Hue a 24, Edua do Iyo 25, Liliana Pozza i 26,
Rosa io An ón27, Me céBa enys 28, Te esa Anguei a 5, Miguel Fe nández-Be mejo 29, Ana Campillo 30,
Ja ie Alcedo 31 , Ramón Paja es-Villa oya 32, Ma ianela Mego 33, Fe nando Be mejo 34,
JoséLuis Dominguez-Jiménez 35, Llúcia Ti ó36, Nu ia Fe nández 2, Manuel Pabón-Ca asco 37 ,Ángel Cosme 4,
Pila Ma a-Rome o 9, Noelia Alcaide 11, Inés A iño 12, Tommaso Di Mai a 15 , Ana Ga e 1, Ignasi Puig 38 ,
Olga P. Nyssen 1, F ancis Meg aud 39 , Colm O’Mo ain 40, Ja ie P. Gisbe 1,* and on behal o he
Hp-EuReg In es iga o s
Ci a ion: Caldas, M.; Pé ez-Aisa, Á.;
Cas o-Fe nández, M.; Bujanda, L.;
Lucendo, A.J.; Rod igo, L.; Hugue ,
J.M.; Pé ez-Lasala, J.; Molina-In an e,
J.; Ba io, J.; e al. Eu opean Regis y
on Helicobac e pylo i Managemen :
E ec i eness o Fi s and Second-Line
T ea men in Spain. An ibio ics 2021,
10, 13. h ps://dx.doi.o g/
an ibio ics10010013
Recei ed: 1 Decembe 2020
Accep ed: 21 Decembe 2020
Published: 25 Decembe 2020
Publishe ’s No e: MDPI s ays neu-
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in published maps and ins i u ional
a ilia ions.
Copy igh : © 2020 by he au ho s. Li-
censee MDPI, Basel, Swi ze land. This
a icleisan open accessa icledis ibu ed
unde he e ms and condi ions o he
C ea i e Commons A ibu ion(CC BY)
license(h ps://c ea i ecommons.o g/
licenses/by/4.0/).
1Gas oen e ology Uni , Hospi al Uni e si a io de La P incesa, Ins i u o de In es igación Sani a ia
P incesa (IIS-IP), Uni e sidad Au ónoma de Mad id (UAM) and Cen o de In es igación Biomédica en Red
de En e medades Hepá icas y Diges i as (CIBERehd), 28006 Mad id, Spain;
[email p o ec ed] (M.C.); anaga [email p o ec ed] (A.G.);
opn.aeg edcap@aegas o.es (O.P.N.)
2
Diges i e Uni , Agencia Sani a ia Cos a del Sol, Red de In es igación en Se icios de Salud en En e medades
C ónicas (REDISSEC), 29651 Ma bella, Spain; [email p o ec ed] (Á.P.-A.); [email p o ec ed] (N.F.)
3Depa men o Gas oen e ology, Hospi al de Valme, 41014 Se illa, Spain;
[email p o ec ed]
4Depa men o Gas oen e ology, Hospi al Donos ia/Ins i u o Biodonos ia and CIBERehd, Uni e sidad del
País Vasco (UPV/EHU), 20014 San Sebas ián, Spain; [email p o ec ed] (L.B.);
[email p o ec ed] (Á.C.)
5Depa men o Gas oen e ology, Hospi al Gene al de Tomelloso and CIBERehd, 13700 Ciudad Real, Spain;
[email p o ec ed] (A.J.L.); [email p o ec ed] (T.A.)
6Gas oen e ology Uni , Hospi al Cen al de As u ias, 33011 O iedo, Spain; [email p o ec ed]
7Gas oen e ology Uni , Conso cio Hospi al Gene al Uni e si a io de Valencia, 46014 Valencia, Spain;
[email p o ec ed]
8Diges i e Se ice, HM Sanchina o, 28050 Mad id, Spain; jpe [email p o ec ed]
9Depa men o Gas oen e ology, Hospi al San Ped o de Alcán a a and CIBERehd, 10003 Cáce es, Spain;
ja ie [email p o ec ed] (J.M.-I.); pila [email p o ec ed] (P.M.-R.)
10 Depa men o Gas oen e ology, Hospi al Uni e si a io Río Ho ega, 47012 Valladolid, Spain;
[email p o ec ed]
11 Diges i e Se ice, Hospi al Clínico Uni e si a io de Valladolid, 47003 Valladolid, Spain;
[email p o ec ed] (L.F.-S.); [email p o ec ed] (N.A.)
12 Diges i e Se ice, Hospi al Clínico Uni e si a io Lozano Blesa and CIBERehd, 50009 Za agoza, Spain;
alanas@uniza .es (Á.L.); [email p o ec ed] (I.A.)
13 Gas oen e ology Uni , Hospi al Qui ón Ma bella, 29603 Málaga, Spain; monica.pe ona@qui on.es
14 Diges i e Se ice, Hospi al Gene al San Jo ge, 22004 Huesca, Spain; [email p o ec ed]
15
Diges i e Se ice, Hospi al Uni e si a i y Poli ècnic La Fe de Valencia and CIBERehd, 46026 Valencia, Spain;
jo unoc@com .es (J.O.); [email p o ec ed] (T.D.M.)
16 Diges i e Se ice, Hospi al Uni e si a io Vi gen Maca ena, 41009 Se illa, Spain; [email p o ec ed]
17 Diges i e Se ice, Hospi al Uni e si a i Gene al de Cas elló, 12004 Cas ellón, Spain; [email p o ec ed]
18
Diges i e Se ice, Hospi al Uni e si a i de Bell i ge, 08907 Ba celona, Spain; jbo a [email p o ec ed]
19 Diges i e Se ice, Hospi al Uni e si a io Sani as La Mo aleja, 28050 Mad id, Spain; [email p o ec ed]
20 Diges i e Se ice, Conso ci Sani a i de Te assa, 08191 Ba celona, Spain; [email p o ec ed]
21 Diges i e Se ice, Complejo Asis encial Uni e si a io de Bu gos, 09006 Bu gos, Spain;
[email p o ec ed]
22 Diges i e Se ice, Hospi al Sie allana, 39300 Can ab ia, Spain; [email p o ec ed]
23 Diges i e Se ice, Hospi al de Cabueñes, 33394 As u ias, Spain; [email p o ec ed]
24 Diges i e Se ice, Hospi al de Galdakao-Usansolo, 48960 Vizcaya, Spain;
ALAIN.HUERT[email p o ec ed]
An ibio ics 2021,10, 13. h ps://dx.doi.o g/10.3390/an ibio ics10010013 h ps://www.mdpi.com/jou nal/an ibio ics
An ibio ics 2021,10, 13 2 o 15
25 Diges i e Se ice, Hospi al Coma cal de Inca, 07300 Mallo ca, Spain; edua doy[email p o ec ed]
26 Diges i e Se ice, Hospi al de Mé ida, 06800 Badajoz, Spain; [email p o ec ed]
27 Diges i e Medicine Depa men , Hospi al Clínic Uni e si a i de Vàlencia, 46010 Valencia, Spain;
M.Rosa io.An on@u .es
28 Diges i e Se ice, Hospi al de Viladecans, 08840 Ba celona, Spain; mba [email p o ec ed]
29 Diges i e Se ice, Clínica San F ancisco, 10002 Cáce es, Spain; [email p o ec ed]
30 Diges i e Se ice, Hospi al Reina So ía, Tudela, 31500 Na a a, Spain; [email p o ec ed]
31 Diges i e Se ice, Hospi al de Ba bas o, 22300 Huesca, Spain; [email p o ec ed]
32 Diges i e Se ice, Hospi al In an a So ía, 28703 Mad id, Spain; [email p o ec ed]g
33 Diges i e Se ice, Hospi al Uni e si a io Gene al de Ca alunya, 08195 Ba celona, Spain;
[email p o ec ed]
34 Diges i e Se ice, Hospi al Uni e si a io de Fuenlab ada, idiPAZ, 28942 Mad id, Spain;
[email p o ec ed]
35 Diges i e Se ice, Hospi al Al o del Guadalqui i , 23740 Jaén, Spain; [email p o ec ed]
36 Diges i e Se ice, Hospi al de Ma a ó, 08304 Ba celona, Spain; [email p o ec ed]
37 Diges i e Se ice, Cen o Uni e si a io de C uz Roja, Uni e sidad de Se illa, 41004 Se illa, Spain;
mpabon@c uz oja.es
38 Diges i e Se ice, Al haia Xa xa Assis encial Uni e si à ia de Man esa and Uni e si a de Vic-Uni e si a
Cen al de Ca alunya (UVicUCC), 08242 Man esa, Spain; [email p o ec ed]
39 Labo a oi e de Bac é iologie, Hôpi al Pelleg in, Bo deaux & INSERM U1053 BaRITOn, Uni e si éde
Bo deaux, 33076 Bo deaux, F ance; [email p o ec ed]
40
Depa men o Clinical Medicine, T ini y College Dublin, D24 NR0A Dublin, I eland; ColmOMo ain@ cpi.ie
*Co espondence: ja ie [email p o ec ed]; Tel.: +34-913093911; Fax: 34-915204013
Abs ac :
The managemen o Helicobac e pylo i in ec ion has o ely on p e ious local e ec i e-
ness due o he geog aphical a iabili y o an ibio ic esis ance. The aim o his s udy was o
e alua e he e ec i eness o i s and second-line H. pylo i ea men in Spain, whe e he empi -
ical p esc ip ion is ecommended. A mul icen e p ospec i e non-in e en ional egis y o he
clinical p ac ice o Eu opean gas oen e ologis s conce ning H. pylo i in ec ion (Hp-EuReg) was
de eloped, including pa ien s om 2013 un il June 2019. E ec i eness was e alua ed desc ip i ely
and h ough a mul i a ia e analysis conce ning age, gende , p esence o ulce , p o on-pump in-
hibi o (PPI) dose, he apy du a ion and compliance. O e all, 53 Spanish hospi als we e included,
and 10,267 pa ien s ecei ed a i s -line he apy. The bes esul s we e ob ained wi h he 10-day
bismu h single-capsule he apy (95% cu e a e by in en ion- o- ea ) and wi h bo h he 14-day
bismu h-cla i h omycin quad uple (PPI-bismu h-cla i h omycin-amoxicillin, 91%) and he 14-day
non-bismu h quad uple concomi an (PPI-cla i h omycin-amoxicillin-me onidazole, 92%) he apies.
Second-line he apies we e p esc ibed o 2448 pa ien s, wi h mos -e ec i e he apies being he iple
quinolone (PPI-amoxicillin-le o loxacin/moxi loxacin) and he bismu h-le o loxacin quad uple
schemes (PPI-bismu h-le o loxacin-amoxicillin) p esc ibed o 14 days (92%, 89% and 90% e ec i e-
ness, espec i ely), and he bismu h single-capsule (10 days, 88.5%). Compliance, longe du a ion
and highe acid inhibi ion we e associa ed wi h highe e ec i eness. “Op imized” H. pylo i he apies
achie e o e 90% success in Spain.
Keywo ds: Helicobac e pylo i; ea men ; i s -line; second-line; Spain
1. In oduc ion
Helicobac e pylo i (H. pylo i) is a g am-nega i e bac e ium wi h an es ima ed p e alence
in sou he n Eu ope o 50%, in ol ed in se e al impo an diseases such as ch onic gas i is,
pep ic ulce disease and gas ic cance , as well as in some impo an ex a-gas ic diseases
such as i on de iciency anaemia o idiopa hic h ombocy openic pu pu a, among o he s [
1
–
5
].
These wo ac o s a e enough o explain he impo ance o inding a success ul he apy
able o elimina e he bac e ium wi h he leas amoun o an ibio ic ea men a emp s. This
is especially impo an conside ing he e ec o an ibio ics on he pa ien ’s gu mic obio a
and he eme gence o mul i- esis an bac e ial s ains wo ldwide [6–8].
An ibio ics 2021,10, 13 3 o 15
Howe e , an e ec i e global ea men has no been ound. Al hough se e al ac o s
migh be conside ed, he geog aphical a iabili y o an ibio ic esis ance among di e en
H. pylo i s ains (due o p e ious an ibio ic exposu e o bo h he pa ien and he communi y)
ep esen s an impo an obs acle, especially conside ing he ex ended ecommenda ion
o using empi ical p esc ip ions [
1
,
9
,
10
]. In his sense, cla i h omycin, me onidazole and
le o loxacin, an ibio ics equen ly used agains H. pylo i, ha e shown a leas mode a e
esis ance a es in sou he n Eu ope and speci ically in Spain, which has jus i ied he
eme gence o nume ous and a ied op imiza ion s a egies [9,11,12].
Wi h he aim o ob aining upda ed in o ma ion on H. pylo i ea men in Spain and o
ind s a egies o imp o e he apies in his a ea, we designed his long- e m p ospec i e
clinical p ac ice s udy.
2. Resul s
2.1. Baseline Cha ac e is ics
In o al, 53 Spanish hospi als we e selec ed (Supplemen a y Ma e ials Figu e S1) and
14,128 pa ien s we e included o he desc ip i e demog aphic analysis (Table 1).
Table 1. Baseline cha ac e is ics o i s - and second-line ea men s.
Va iables O e all N (%) 1s Line N (%) 2nd Line N (%)
14,128 10,633 2481
Gende Female 8795 (62) 6477 (61) 1632 (66)
Male 5320 (38) 4146 (39) 847 (34)
Age, mean (s anda d de ia ion) 50 ±15 51 ±14.7 50 ±14.5
Penicillin alle gy P esence 644 (4.6) 435 (4.1) 151 (6.1)
Indica ion
Dyspepsia 9152 (65) 6823 (64) 1656 (67)
Ulce disease 2103 (15) 1554 (15) 393 (16)
O he s 2868 (20) 2251 (21) 432 (17)
Diagnos ic es s Requi ed endoscopy 8180 (58) 6672 (63) 1061 (43)
Cul u e
Pe o med
NA
366 (3.4)
NA
No esis ance 199 (54)
Cla i h omycin R 52 (14)
Me onidazole R 93 (25)
Cla i h omycin and
me onidazole R 18 (4.9)
Le o loxacin R 63 (17)
T ea men leng h
7 days 182 (1.3) 160 (1.5) 17 (0.7)
10 days 8615 (61) 6670 (63) 1382 (56)
14 days 5273 (37) 3764 (35) 1074 (43)
O he s 58 (0.4) 39 (0.4) 8 (0.3)
P o on pump inhibi o dose
Low 5110 (37) 4063 (39) 751 (31)
S anda d 3290 (24) 2605 (25) 458 (19)
High 5496 (39) 3834 (36) 1239 (50)
Compliance
No (<90% d ug in ake) 415 (2.9) 304 (3) 69 (2.8)
Yes (
≥
90% d ug in ake)
13,159 (93) 9932 (93) 2302 (92.8)
Unknown 554 (3.9) 397 (4) 110 (4.4)
N, o al o pa ien s included; %, p opo ion o pa ien s included; R, esis ance; NA, no applicable; Low,
≈
20 mg omep azole equi alen s
b.i.d.; S anda d, ≈40 mg omep azole equi alen s b.i.d.; High, ≈60 mg omep azole equi alen s b.i.d.
2.2. T ea men Use and E ec i eness
2.2.1. Fi s -Line T ea men
A o al o 10,267 pa ien s ecei ed an empi ical i s -line ea men . The mos e-
quen ly p esc ibed egimens we e: non-bismu h quad uple concomi an he apy (PPI-
cla i h omycin-amoxicillin-me onidazole, all ou d ugs adminis e ed concomi an ly,
An ibio ics 2021,10, 13 4 o 15
n= 4051, 40%), s anda d iple egimen (PPI-cla i h omycin-amoxicillin, n= 2712, 26%),
bismu h quad uple he apy (bismu h single-capsule, ma ke ed as Pyle a
®
(Alle gan, Inc
Dublin, IE) con aining e acycline-me onidazole-bismu h sal s adminis e ed oge he
wi h a PPI, n= 1660, 16%), bismu h-cla i h omycin quad uple he apy (PPI-cla i h omycin-
amoxicillin-bismu h, n= 1055, 10%), non-bismu h sequen ial quad uple egimen (PPI-
amoxicillin du ing i e days, ollowed by PPI-cla i h omycin-me onidazole du ing he
i e emaining days, n= 230, 2.2%) and cla i h omycin-me onidazole iple he apy (PPI-
cla i h omycin-me onidazole, n= 124, 1.2%). The p esc ip ion ends o e ime, as shown
in Figu e 1.
An ibio ics 2021, 10, x FOR PEER REVIEW 4 o 16
wi h a PPI, n = 1660, 16%), bismu h-cla i h omycin quad uple he apy (PPI-cla i h omy-
cin-amoxicillin-bismu h, n = 1055, 10%), non-bismu h sequen ial quad uple egimen (PPI-
amoxicillin du ing i e days, ollowed by PPI-cla i h omycin-me onidazole du ing he
i e emaining days, n = 230, 2.2%) and cla i h omycin-me onidazole iple he apy (PPI-
cla i h omycin-me onidazole, n = 124, 1.2%). The p esc ip ion ends o e ime, as shown
in Figu e 1.
Figu e 1. P esc ip ion ends in i s - (A) Type o he apy; (B) Du a ion o he apy; (C) Dose o PPI and second-line (D)
Type o he apy; (E) Du a ion o he apy; (F) Dose o PPI ea men . PPI: p o on-pump inhibi o , C: cla i h omycin, A:
amoxicillin, M: me onidazole, Single-capsule: h ee-in-one single capsule, Bi: bismu h, Conc: concomi an adminis a ion,
Seq: sequen ial adminis a ion, L: le o loxacin, Mx: Moxi loxacin, Low: ≈20 mg omep azole equi alen s b.i.d., S anda d:
≈40 mg omep azole equi alen s b.i.d., High: ≈60 mg omep azole equi alen s b.i.d.
O e all e ec i eness o he i s -line he apies eached 88% on he mITT analysis. The
highes e ec i eness was ob ained wi h he bismu h single-capsule (95%), he bismu h-
cla i h omycin he apy (91%) and he concomi an he apy (90%) (Table 2). Ad e se
e en s (AE) appea ed in 25% o he pa ien s; howe e , mos o hem we e o mild in ensi y
(62%) and only 0.2% o he pa ien s p esen ed a se ious AE. Compliance was highe han
97% (see Table S1 and File S2 o a de ailed analysis o sa e y).
Figu e 1.
P esc ip ion ends in i s - (
A
) Type o he apy; (
B
) Du a ion o he apy; (
C
) Dose o PPI and second-line (
D
)
Type o he apy; (
E
) Du a ion o he apy; (
F
) Dose o PPI ea men . PPI: p o on-pump inhibi o , C: cla i h omycin, A:
amoxicillin, M: me onidazole, Single-capsule: h ee-in-one single capsule, Bi: bismu h, Conc: concomi an adminis a ion,
Seq: sequen ial adminis a ion, L: le o loxacin, Mx: Moxi loxacin, Low:
≈
20 mg omep azole equi alen s b.i.d., S anda d:
≈40 mg omep azole equi alen s b.i.d., High: ≈60 mg omep azole equi alen s b.i.d.
O e all e ec i eness o he i s -line he apies eached 88% on he mITT analysis. The
highes e ec i eness was ob ained wi h he bismu h single-capsule (95%), he bismu h-
cla i h omycin he apy (91%) and he concomi an he apy (90%) (Table 2). Ad e se e en s
(AE) appea ed in 25% o he pa ien s; howe e , mos o hem we e o mild in ensi y (62%)
and only 0.2% o he pa ien s p esen ed a se ious AE. Compliance was highe han 97%
(see Table S1 and File S1 o a de ailed analysis o sa e y).
The o e all mul i a ia e analysis pe o med wi h he i s -line ea men showed ha
highe e ec i eness was associa ed wi h good compliance (OR = 4.1; 95% CI: 3.0–5.5),
ex ended he apies (10 days (OR = 4.5; 95% CI: 3.2–6.2) o 14 days leng h (OR = 4.1; 95% CI:
2.9–5.9)), highe gas ic acid inhibi ion (s anda d (OR = 1.4; 95% CI: 1.2–1.7) o high PPI
doses (OR = 2.1; 95% CI: 1.7–2.4)), p esence o pep ic ulce (OR = 1.2; 95% CI: 1.0–1.5) and
male gende (OR = 1.2; 95% CI: 1.1–1.4) (see Table 3 o he analysis o each he apy).
An ibio ics 2021,10, 13 5 o 15
Table 2. E ec i eness, sa e y and compliance o he mos equen he apies p esc ibed in he i s - and second-line ea men s.
E ec i eness Ad e se E en s Compliance
T ea men ITT mITT PP
N (%) 95% CI N (%) 95% CI N (%) 95% CI N (%) 95% CI N (%) 95% CI
1s line 10,101 (83.5) 83–84 9726 (88) 88–89 9497 (89) 88–89 9937 (25) 25–26 9886 (97) 96–97
PPI + C + A + M (Conc) 3996 (86) 85–87 3880 (90) 89–91 3781 (90) 89–91 3963 (28) 26–29 3942 (97) 96–97
PPI + C + A 2712 (78) 76–80 2544 (83) 82–85 2498 (84) 82–85 2617 (15) 13–16 2598 (98) 97–98
PPI + Single–capsule 1574 (88) 86–89 1540 (95) 94–96 1514 (96) 95–97 1566 (25) 23–27 1562 (97) 96–98
PPI + Bi + C + A 1034 (88) 86–90 1015 (91) 89–93 1002 (91) 89–93 1019 (40) 37–44 1021 (98) 98–99
PPI + C + A + M (Seq) 230 (79) 73–84 222 (81.5) 76–86 192 (84) 79–89 230 (49) 42–55 222 (86.5) 81–91
PPI + C + M 124 (59) 50–68 113 (65) 55–73 112 (65) 65–74 119 (16) 10–24 118 (97.5) 93–99
2nd line 2420 (79) 77–80 2295 (84) 82–85 2247 (84) 82–86 2348 (28) 27–30 2342 (97) 96–98
PPI + L + A 944 (74) 71–77 893 (78.5) 76–81 881 (79) 76–82 919 (26) 23–29 908 (99) 98–99
PPI + Bi + L + A 463 (86) 83–89 451 (89) 86–92 435 (90) 87–93 454 (33) 28–37 459 (95) 93–97
PPI + Single–capsule 443 (80) 76–84 409 (88) 85–91 398 (89) 85–92 422 (31) 27–36 420 (96) 94–98
PPI + Mx + A 135 (87) 80–92 129 (91) 84–95 129 (91) 84–95 134 (19) 13–27 133 (99) 96–100
PPI + C + A + M (Conc) 120 (74) 65–82 110 (82) 73–89 109 (82) 73–88 112 (24) 17–33 112 (98) 94–100
ITT, in en ion- o- ea ; mITT, modi ied in en ion- o- ea ; PP, pe p o ocol; N, o al o pa ien s included; %, p opo ion o pa ien s p esen ing e ec i eness/ad e se e en s/compliance; CI, con idence in e al; PPI,
p o on pump inhibi o ; C, cla i h omycin; A, amoxicillin; M, me onidazole; Single-capsule, h ee-in-one single capsule; Bi, bismu h; L: le o loxacin; Mx, moxi loxacin; Conc, concomi an adminis a ion; Seq,
sequen ial adminis a ion.
An ibio ics 2021,10, 13 6 o 15
Table 3. Mul i a ia e analysis o pa ien s ea ed wi h a i s -line he apy.
Va iables O e all PPI+C+A+M
(Conc) PPI + C + A PPI + Single-Capsule PPI + Bi + C + A PPI + C + A + M (Seq)
OR (95%
CI) p-Values OR (95%
CI) p-Values OR (95%
CI) p-Values OR (95%
CI) p-Values OR (95%
CI) p-Values OR (95%
CI) p-Values
Gende [R: Female] 1 1 1 1 1 1
Male 1.22
(1.07–1.40) 0.004 1.39
(1.11–1.75) 0.004 1.26
(1.00–1.59) 0.050 0.83
(0.51–1.34) 0.442 1.10
(0.79–1.74) 0.690 1.85
(0.84–4.04) 0.125
Age (yea s)
[R: 18–30] 1 1 1 1 1 1
31–50 1.15
(0.92–1.44) 0.232 1.32
(0.92–1.90) 0.136 1.13
(0.77–1.65) 0.530 0.73
(0.24–2.18) 0.568 0.86
(0.38–1.95) 0.723 0.33
(0.07–1.57) 0.163
51–70 1.08
(0.86–1.35) 0.514 1.23
(0.86–1.77) 0.265 1.10
(0.75–1.61) 0.615 0.72
(0.24–2.12) 0.547 0.82
(0.37–1.85) 0.634 0.32
(0.07–1.62) 0.170
≥71 1.18
(0.87–1.59) 0.289 1.29
(0.78–2.12) 0.327 1.26
(0.76–2.08) 0.369 0.70
(0.20–2.47) 0.575 0.65
(0.24–1.79) 0.406 0.23
(0.03–1.53) 0.128
P esence o ulce [R: No] 1 1 1 1 1 1
Yes 1.23
(1.01–1.49) 0.042 1.15
(0.83–1.60) 0.389 1.48
(1.07–2.04) 0.019 1.02
(0.50–2.10) 0.950 3.12
(0.96–10.2) 0.059 0.93
(0.36–2.41) 0.875
Leng h (days)
[R: 7] 1 NA 1
NA †
NA
NA ‡
10 4.46
(3.20–6.23) 0.000 1 2.78
(1.92–4.04) 0.000 1
14 4.11
(2.88–5.87) 0.000 1.28
(0.98–1.66) 0.068 2.46
(1.60–3.77) 0.000 0.71
(0.06–8.54) 0.790
PPI dose o OE
[R: Low] 1 1 1 1 1 1
S anda d 1.42
(1.21–1.66) 0.000 0.98
(0.75–1.29) 0.888 2.14
(1.67–2.74) 0.000 1.50
(0.84–2.69) 0.168 6.69
(1.35–33.3) 0.020 1.99
(0.24–16.4) 0.521
High 2.05
(1.72–2.44) 0.000 1.59
(1.24–2.03) 0.000 3.54
(2.49–5.03) 0.000 1.97
(1.08–3.59) 0.027 2.26
(0.63–8.08) 0.211 0.56
(0.22–1.49) 0.244
Compliance [R: <90% DI] 1 1 1 1 1 1
≥90% DI 4.07
(3.04–5.45) 0.000 3.41
(2.14–5.43) 0.000 7.12
(3.69–13.7) 0.000 16
(6.99–36.6) 0.000 1.78
(0.37–8.45) 0.469 2.98
(1.28–6.94) 0.011
O e all, he popula ion ecei ing a i s -line he apy; PPI, p o on pump inhibi o ; C, cla i h omycin; A, amoxicillin; M, me onidazole; Single-capsule, h ee-in-one single capsule; Bi, bismu h; Conc, concomi an
adminis a ion; Seq, sequen ial adminis a ion; OR, odds a io; CI, con idence in e al; R, ca ego y o e e ence used o he logis ic eg ession; OE, omep azole equi alen ; DI, d ug in ake; NA, no applicable;
†
99.7% o he pa ien s ecei ed 10-days o he apy so compa ison in leng h e ms was no possible; ‡ 99.6% o he pa ien s ecei ed 10-days o ea men so compa ison in e ms o leng h was no possible.
An ibio ics 2021,10, 13 7 o 15
2.2.2. Second-Line T ea men
A o al o 2448 pa ien s ecei ed an empi ical second-line he apy. Fi e he apies
we e mos equen ly used: he le o loxacin-amoxicillin iple he apy (PPI-amoxicillin-
le o loxacin, n= 944, 39%), he bismu h-le o loxacin quad uple he apy (PPI-amoxicillin-
le o loxacin-bismu h, n= 475, 19.4%), he bismu h single-capsule (n= 454, 18.6%), he
moxi loxacin-amoxicillin he apy (PPI-amoxicillin-moxi loxacin, n= 136, 5.6%) and he
concomi an he apy (n= 121, 4.9%). T ea men p esc ip ions o e ime a e depic ed in
Figu e 1.
O e all e ec i eness o second-line he apies eached 84% on he mITT analysis.
Highes e ec i eness was ob ained wi h he bismu h-le o loxacin he apy (89%) and he
bismu h single-capsule (88%) (Table 2). AE we e epo ed in 28% o he cases (49% and 47%
o hem being o mode a e and mild in ensi y, espec i ely, and only one pa ien showing
a se ious AE). Compliance was highe han 95% (see Table S1 and File S1 o a de ailed
analysis o sa e y).
The o e all mul i a ia e analysis pe o med wi h second-line ea men showed ha
highe e ec i eness was associa ed wi h good compliance (OR = 3.4; 95% CI: 1.7–6.9), high
PPI dose (OR = 1.9; 95% CI: 1.4–2.6) and 14-day he apy (OR = 1.5; 95% CI: 1.1–2.1) (See
Table 4 o he analysis o sepa a ed he apies conside ing only he h ee he apies mo e
equen ly used in second-line in Spain).
E ec i eness by ea men du a ion and PPI doses in i s - and second- line egimens
a e shown in Tables S2 and S3.
An ibio ics 2021,10, 13 8 o 15
Table 4. Mul i a ia e analysis o pa ien s ea ed wi h a second-line he apy.
Va iables O e all PPI + L + A PPI + Bi + L + A PPI + Single-Capsule
OR
(95% CI) p-Values OR
(95% CI) p-Values OR
(95% CI) p-Values OR
(95% CI) p-Values
Gende [R: Female] 1 1 1 1
Male 1.39 (1.07–1.81) 0.014 1.03 (0.70–1.50) 0.898 2.83 (1.33–6.05) 0.007 0.96 (0.47–1.93) 0.898
Age
[R: 18–30] 1 1 1 1
31–50 0.60 (0.36–0.99) 0.045 0.81 (0.39–1.70) 0.582 0.64 (0.17–2.34) 0.506 0.33 (0.07–1.52) 0.156
51–70 0.44 (0.27–0.73) 0.001 0.47 (0.23–0.97) 0.041 0.36 (0.10–1.29) 0.118 0.38 (0.08–1.73) 0.211
≥71 0.37 (0.20–0.69) 0.002 0.43 (0.18–1.03) 0.059 0.24 (0.05–1.09) 0.064 0.73 (0.09–5.82) 0.766
P esence o
ulce
[R: No] 1 1 1 1
Yes 1.07 (0.74–1.54) 0.729 1.04 (0.63–1.73) 0.869 1.97 (0.44–8.76) 0.374 0.79 (0.32–1.94) 0.600
P e ious C [R: No] 1 1 1 NA †
Yes 0.63 (0.33–1.21) 0.167 0.82 (0.16–4.12) 0.809 0.21 (0.03–1.79) 0.155
Leng h [R: 10] 1 1 1
14 1.51 (1.11–2.05) 0.009 3.88 (2.24–6.71) 0.000 3.12 (0.35–27.6) 0.307 0.64 (0.07–5.93) 0.692
PPI dose o OE
[R: Low] 1 1 1 1
S anda d 1.21 (0.88–1.65) 0.241 1.20 (0.81–1.79) 0.360 2.50 (0.40–15.5) 0.325 1.45 (0.56–3.77) 0.443
High 1.88 (1.37–2.59) 0.000 1.66 (0.99–2.77) 0.055 3.24 (1.09–9.59) 0.034 1.43 (0.72–2.87) 0.310
Compliance [R: <90% DI] 1 1 1 1
≥90% DI 3.43 (1.71–6.88) 0.001 5.47 (1.27–23.5) 0.023 3.01 (0.91–9.99) 0.071 4.46 (1.02–19.5) 0.047
O e all, he popula ion ecei ing a second-line he apy; PPI, p o on pump inhibi o . L, le o loxacin; A, amoxicillin; Bi, bismu h; Single-capsule, h ee-in-one single capsule; OR, odds a io; CI, con idence in e al;
R, ca ego y o e e ence used o he logis ic eg ession; C, cla i h omycin; OE, omep azole equi alen ; DI, d ug in ake; NA, no applicable;
†
96% o he pa ien s had p e iously ecei ed cla i h omycin so
compa ison be ween bo h g oups was no possible.
An ibio ics 2021,10, 13 9 o 15
2.3. Penicillin Alle gic Pa ien s
A o al o 411 pa ien s alle gic o penicillin ecei ed an empi ical i s -line he apy,
being he mos equen , he bismu h single-capsule (n= 154, 37.5%) and he cla i h omycin-
me onidazole he apy (n= 117, 28.5%). The o e all e ec i eness was 81% in i s -line,
al hough he bismu h single-capsule eached 94% mITT e ec i eness. A second-line
a emp was empi ically used in 137 pa ien s alle gic o penicillin, being he bismu h
single-capsule (n= 34, 24.8%), he mos equen ly used.
Resul s on e ec i eness, sa e y and compliance as well as e ec i eness s a i ied by
leng h and PPI dose, a e shown in Tables S4–S6.
3. Discussion
T ea men o H. pylo i in ec ion in Spain in i s - and second- line, in which he empi i-
cal app oach is gene ally ecommended, s ill emains a challenge, especially conside ing
he mo e demanding h eshold o e ec i eness equi ed la ely (90%) [
6
]. This has led
o he p og essi e complexi y o he egimens p esc ibed, which in ol e an inc easing
use o quad uple egimens, longe p esc ip ions (10–14 days) and highe PPI doses o e
ime [1,9].
Conce ning i s -line ea men , we ound an o e all e ec i eness o 88% in ou coho ,
close o he op imal h eshold equi ed, combined wi h an op imal sa e y p o ile [6,13].
Analysis o each speci ic he apy e ealed ha he s anda d iple he apy con aining
cla i h omycin and amoxicillin, ecommended h oughou se e al yea s in Spain, only
eached app oxima ely 80% success, in line wi h p e ious e idence [
14
]. I s low e ec i e-
ness, oge he wi h he inc easing cla i h omycin esis ance a es o e ime (up o 20%
ecen ly no i ied) led o he discon inua ion o i s use in ou a ea [
6
,
9
,
12
]. This d op in
p esc ip ions o e ime in ou coho b ough wi h i he inc ease o use o quad uple he a-
pies, such as he concomi an , he bismu h single-capsule and he bismu h-cla i h omycin
he apies, which also we e, p ecisely, he he apies showing he highes e ec i eness
(≥90%).
Concomi an ea men was he he apy mos equen ly used in i s -line, in ag ee-
men wi h ecommenda ions p o ided by na ional guidelines [
9
]. This he apy showed
90% e ec i eness, simila o p e ious epo s, and was mos ly due o he ela i ely low
dual esis ance a es o bo h cla i h omycin and me onidazole documen ed in ou coun-
y [
9
,
12
,
15
–
17
]. Wi h ega d o he bismu h-cla i h omycin quad uple he apy, a p og es-
si e ise on i s p esc ip ion was seen o e ime, and i showed a e y high e ec i eness
(91%), simila o p e ious e idence [
18
]. In ac , da a coming om a eas wi h highe
cla i h omycin esis ance han Spain such as China s ill show high success o his he apy,
which is hough o be a leas pa ially compensa ed by he use o bismu h [
19
]. This is
encou aging, assuming a hypo he ical inc ease o cla i h omycin esis ance in Spain in he
ollowing yea s. The use o a bismu h quad uple he apy ha con ains e acycline and
me onidazole also a oids he p oblem o cla i h omycin esis ance due o he absence
o his an ibio ic and he low p obabili y o de eloping esis ance o componen s such
as bismu h o e acycline by H. pylo i [
9
,
20
]. Mo eo e , he comme cializa ion o a pill
con aining he h ee a o emen ioned d ugs acili a ed he access o e acycline, which used
o be ha dly a ailable in his a ea [
9
,
21
]. This he apy showed an e adica ion a e o 95% in
ou coho , simila o wha was desc ibed in a ecen ly published me a-analysis [22].
When we analysed he a iables associa ed wi h he inc ease o e ec i eness, good
compliance (
≥
90% o d ug in ake) showed he highes associa ion o o e all ea men
and also o nea ly all he he apies analysed indi idually. O he au ho s had p e iously
epo ed his associa ion [
17
,
18
,
23
,
24
]. The e o e, s a egies designed o pu sue he bes
compliance possible a e needed.
The use o s anda d PPI doses (
≈
40 mg omep azole equi alen s b.i.d.) o high PPI
doses (
≈
60 mg omep azole equi alen s b.i.d.) showed highe e ec i eness in ou coho in
he o e all analysis and in he concomi an , bismu h-cla i h omycin and bismu h single-
capsule he apies. P e ious epo s had al eady shown a bene icial e ec o highe g ades
