Ci a ion: Es adé, O.; Vozmediano, V.;
Ca al, N.; Isla, A.; González, M.;
Poole, R.; Sua ez, E. Key Fac o s in
E ec i e Pa ien -Tailo ed Dosing o
Fluo oquinolones in U ological
In ec ions: In e indi idual
Pha macokine ic and
Pha macodynamic Va iabili y.
An ibio ics 2022,11, 641. h ps://
doi.o g/10.3390/an ibio ics11050641
Academic Edi o s: F ançoise
Van Bambeke, Sebas ian Wicha,
Ma kus Zei linge and Paul
M. Tulkens
Recei ed: 27 Ap il 2022
Accep ed: 9 May 2022
Published: 11 May 2022
Publishe ’s No e: MDPI s ays neu al
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an ibio ics
Re iew
Key Fac o s in E ec i e Pa ien -Tailo ed Dosing o
Fluo oquinolones in U ological In ec ions: In e indi idual
Pha macokine ic and Pha macodynamic Va iabili y
Oska Es adé1, Val ane a Vozmediano 2, Ne ea Ca al 3,4, A an xa Isla 5,6 , Ma ga i a González 2, Rachel Poole 2
and Elena Sua ez 3,4,*
1Depa men o U ology, C uces Uni e si y Hospi al, 48903 Ba akaldo, Spain; [email p o ec ed]
2
Cen e o Pha macome ics and Sys ems Pha macology, Depa men o Pha maceu ics, Uni e si y o Flo ida,
Gaines ille, FL 32612, USA; [email p o ec ed] (V.V.); [email p o ec ed] (M.G.); [email p o ec ed] (R.P.)
3Depa men o Pha macology, Facul y o Medicine and Nu sey, Uni e si y o Basque Coun y UPV/EHU,
48940 Leioa, Spain; [email p o ec ed]
4Bioc uces Heal h Resea ch Ins i u e, 48903 Ba akaldo, Spain
5Pha macokine ic, Nano echnology and Gene The apy G oup (Pha maNanoGene), Facul y o Pha macy,
Cen o de In es igación Lasca ay Ike gunea, Uni e si y o he Basque Coun y UPV/EHU,
01006 Vi o ia-Gas eiz, Spain; [email p o ec ed]
6Ins i u o de In es igación Sani a ia Bioa aba, Mic obiology, In ec ious Disease, An imic obial Agen s, and
Gene The apy, 01006 Vi o ia-Gas eiz, Spain
*Co espondence: elena.sua [email p o ec ed]
Abs ac :
Fluo oquinolones (FQs) a e a c i ical g oup o an imic obials p esc ibed in u ological
in ec ions as hey ha e a b oad an imic obial spec um o ac i i y and a a o able issue pene a ion
a he si e o in ec ion. Howe e , hei clinical p ac ice is no p oblem- ee o ea men ailu e, isk o
eme gence o esis ance, and a e bu impo an ad e se e ec s. Due o hei c i ical ole in clinical
imp o emen , unde s anding he dose- esponse ela ion is necessa y o op imize he e ec i eness
o FQs he apy, as i is essen ial o selec he igh an ibio ic a he igh dose o he igh du a ion
in u ological in ec ions. The aim o his s udy was o e iew he published li e a u e abou in e -
indi idual a iabili y in pha macological p ocesses ha can be esponsible o he clinical esponse
a e empi ic dose o he mos commonly p esc ibed u ological FQs: cip o loxacin, le o loxacin,
and moxi loxacin. In e indi idual pha macokine ic (PK) a iabili y, pa icula ly in elimina ion,
may con ibu e o ea men ailu e. Clea ance ela ed o c ea inine clea ance should be speci ically
conside ed o cip o loxacin and le o loxacin. Likewise, oday, undesi ed in e egional a iabili y in
FQs an imic obial ac i i y agains ce ain mic oo ganisms exis s. FQs pha macology, pa ien -speci ic
cha ac e is ics, and he iden i y o he local in ec ing o ganism a e key ac o s in de e mining clinical
ou comes in FQs use.
Keywo ds: luo oquinolone; in e indi idual a iabili y; pha macokine ic; pha macodynamic
1. In oduc ion
Fluo oquinolones (FQs) a e conside ed a c i ically impo an an imic obial class o
human medicine [
1
]. They ha e a b oad spec um o ac i i y agains nume ous G am
(+) and G am (-) bac e ia and exhibi a o able pha macokine ic p ope ies ha acili a e
adequa e d ug disposi ion a he si e o in ec ion. Due o hese p ope ies, FQs ha e been
used o ea di e en ypes o sys emic in ec ions bo h in he ou pa ien and inpa ien
se ing [
2
,
3
], and also a a ie y o u ological in ec ions, such as pyeloneph i is, u e h i is,
and bac e ial p os a i is [
4
]. Especially in he la e , hei ole is essen ial o sa ing li es.
Howe e , wo clea p oblems cu en ly exis in clinical p ac ice in he managemen o
u ological in ec ions wi h FQs: he eme gence o u opa hogen esis ance [
5
,
6
] and he wide
An ibio ics 2022,11, 641. h ps://doi.o g/10.3390/an ibio ics11050641 h ps://www.mdpi.com/jou nal/an ibio ics
An ibio ics 2022,11, 641 2 o 19
a ay o epo ed ad e se e ec s [
7
,
8
]. Consequen ly, hei use has been limi ed o s ic ly
necessa y si ua ions in clinical p ac ice [7–9].
The mos commonly used FQs in u ological p ac ice in he Uni ed S a es and Eu ope
a e cip o loxacin (CIP), le o loxacin (LEV), and moxi loxacin (MOX) [
2
,
3
,
10
]. The ecom-
mended doses a e 250 o 500 mg o ally o 400 mg in a enously o CIP, 500 o 750 mg
o ally o in a enously o LEV, and 400 mg o ally o in a enously o MOX [
2
–
4
]. In
gene al, hese dosing egimens allow adequa e d ug dis ibu ion a he si e o in ec ion o
achie e su icien an ibio ic exposu e and ea men e icacy. Howe e , he use o s anda d
empi ical doses may lead o unnecessa y o e exposu e and a highe incidence o ad e se
e ec s in some pa ien s and, consequen ly, non-compliance o discon inua ion o d ug
ea men . In con as , some pa ien s could expe ience unde exposu e, isking ea men
ailu e and he de elopmen o bac e ial esis ance [11–13].
Op imally dosing FQs is dependen on se e al ac o s, such as pa hophysiological
cha ac e is ics o he pa ien , he in ec ing o ganism, he si e o in ec ion, and he pha ma-
cokine ic/pha macodynamic (PK/PD) p ope ies o he d ug (Figu e 1). PK p ope ies
include he ac o s a ec ing d ug abso p ion, dis ibu ion, me abolism, and elimina ion,
which de e mine i s concen a ion in he body. Physiopa hological ac o s associa ed wi h
he pa ien may be esponsible o he in e indi idual a iabili y o he PK p ocesses. PD
desc ibe he mechanism by which he d ug exe s i s an imic obial e ec [
14
,
15
]. In e e-
gional and ime-dependen di e ences in MIC dis ibu ion alues a e esponsible o he
PD a iabili y o he an ibio ic. Ca e ul conside a ion o he ac o s a ec ing PK/PD should
allow o selec ion o he mos app op ia e an ibio ic when ea ing u ological in ec ions
and es ablishing he dosage wi h a be e isk/bene i a io in e ms o e icacy, sa e y,
and de elopmen o esis ances [
8
,
13
,
16
,
17
]. The in e indi idual a iabili y in PK/PD
p ocesses is likely o be one o he main con ibu o s o he a iabili y in he an ibac e ial
dose-exposu e esponse ela ion [18,19].
An ibio ics 2022, 11, x FOR PEER REVIEW 2 o 20
u ological in ec ions wi h FQs: he eme gence o u opa hogen esis ance [5,6] and he
wide a ay o epo ed ad e se e ec s [7,8]. Consequen ly, hei use has been limi ed o
s ic ly necessa y si ua ions in clinical p ac ice [7–9].
The mos commonly used FQs in u ological p ac ice in he Uni ed S a es and Eu ope
a e cip o loxacin (CIP), le o loxacin (LEV), and moxi loxacin (MOX) [2,3,10]. The
ecommended doses a e 250 o 500 mg o ally o 400 mg in a enously o CIP, 500 o 750
mg o ally o in a enously o LEV, and 400 mg o ally o in a enously o MOX [2–4]. In
gene al, hese dosing egimens allow adequa e d ug dis ibu ion a he si e o in ec ion o
achie e su icien an ibio ic exposu e and ea men e icacy. Howe e , he use o
s anda d empi ical doses may lead o unnecessa y o e exposu e and a highe incidence
o ad e se e ec s in some pa ien s and, consequen ly, non-compliance o discon inua ion
o d ug ea men . In con as , some pa ien s could expe ience unde exposu e, isking
ea men ailu e and he de elopmen o bac e ial esis ance [11–13].
Op imally dosing FQs is dependen on se e al ac o s, such as pa hophysiological
cha ac e is ics o he pa ien , he in ec ing o ganism, he si e o in ec ion, and he
pha macokine ic/pha macodynamic (PK/PD) p ope ies o he d ug (Figu e 1). PK
p ope ies include he ac o s a ec ing d ug abso p ion, dis ibu ion, me abolism, and
elimina ion, which de e mine i s concen a ion in he body. Physiopa hological ac o s
associa ed wi h he pa ien may be esponsible o he in e indi idual a iabili y o he
PK p ocesses. PD desc ibe he mechanism by which he d ug exe s i s an imic obial e ec
[14,15]. In e egional and ime-dependen di e ences in MIC dis ibu ion alues a e
esponsible o he PD a iabili y o he an ibio ic. Ca e ul conside a ion o he ac o s
a ec ing PK/PD should allow o selec ion o he mos app op ia e an ibio ic when
ea ing u ological in ec ions and es ablishing he dosage wi h a be e isk/bene i a io
in e ms o e icacy, sa e y, and de elopmen o esis ances [8,13,16,17]. The
in e indi idual a iabili y in PK/PD p ocesses is likely o be one o he main con ibu o s
o he a iabili y in he an ibac e ial dose-exposu e esponse ela ion [18,19].
Figu e 1. Pha macokine ic/Pha macodynamic ac o s a ec ing he dose-an imic obial esponse
ela ion. Cmax: peak plasma concen a ion, AUC: a ea unde he plasma d ug concen a ion- ime
cu e om ime, MIC: minimum inhibi o y concen a ion o an an ibio ic agains a bac e ial
pa hogen.
Figu e 1.
Pha macokine ic/Pha macodynamic ac o s a ec ing he dose-an imic obial esponse
ela ion. Cmax: peak plasma concen a ion, AUC: a ea unde he plasma d ug concen a ion- ime
cu e om ime, MIC: minimum inhibi o y concen a ion o an an ibio ic agains a bac e ial pa hogen.
The objec i e o he cu en e iew is o iden i y sou ces o in e indi idual a iabili y
in PK/PD p ope ies o he mos commonly FQs used in u ological p ac ice–CIP, LEV and
An ibio ics 2022,11, 641 3 o 19
MOX–which could in luence he an ibac e ial dose-exposu e esponse ela ion. E alua ion
o hei e ec on FQs clinical ou comes would allow he de elopmen o pa ien - ailo ed
dosing s a egies, leading o educed ea men ailu e, especially in c i ical in ec ions
as p os a i is.
2. Conce ns abou he Clinical E icacy o Fluo oquinolone Dosing: The Role o
PK/PD Index as a Tool
Selec ing a dose o gua an ee an imic obial e icacy while minimizing he isk o
esis ance eme gence wi h minimum ad e se e ec s should be based on he FQ’s PK
p ope ies, PD p ope ies, and he p obabili y o a ain he PK/PD index associa ed wi h
clinical e icacy wi h he adminis e ed dose [
14
,
16
,
20
,
21
]. PK p ope ies e e o d ugs’
abso p ion, dis ibu ion, me abolism, and exc e ion, while PD p ope ies a e ela ed o he
po en ial ac i i y o an an ibio ic agains a bac e ial pa hogen, measu ed as he minimum
inhibi o y concen a ion (MIC), and pos an ibio ic e ec . The PK/PD a ge is he key alue
associa ed wi h an imic obial e icacy and a ies acco ding o a chosen endpoin such as
s asis, maximal kill, o esis ance supp ession o p eclinical s udies, and mic obiological
o clinical cu e o clinical s udies [
15
,
16
,
22
]. To a ain a a o able PK/PD a ge o
FQ, pa hogens mus ha e adequa e an imic obial exposu e based on hei MIC. This
exposu e, measu ed as peak plasma concen a ion (Cmax) and a ea unde he plasma d ug
concen a ion- ime cu e om ime 0–24 h (AUC
0–24h
), is dependen on he dose used and
he PK p ope ies o he d ug. Only he unbound d ug concen a ions a e mic obiologically
ac i e, and he e o e, he PK/PD index should be based on ee d ug concen a ions [21].
A subs an ial numbe o s udies ha e been pe o med o iden i y he PK/PD index
ela ion associa ed wi h he bac e icidal ac i i y and clinical e icacy o FQs. An imic obial
ac i i y o FQs exhibi s concen a ion-dependen killing along wi h p olonged pe sis-
en e ec s. Mul iple clinical and p eclinical da a sugges ha he a io o ee AUC
0–24h
( AUC
0–24h
) o MIC ( AUC
0–24h
/MIC) is he bes PK/PD index o link an imic obial dispo-
si ion, he MIC alue, and he clinical e icacy o FQs [
15
,
23
,
24
]. While he a io Cmax/MIC
ou weighs he a io AUC
0–24h
/MIC as an indica o o esis ance supp ession, ewe s udies
exis wi h he aim o iden i y d i e s o esis ance supp ession [11].
Based on he abo e concep s, Mon e Ca lo simula ions (MCS) can be un o compu a-
ionally es ima e he likelihood o a gi en d ug dose o a ain a p ede ined alue o a PK/PD
a ge p e iously de ined o u ological FQs [
19
,
21
]. The p obabili y o a ge a ainmen
(PTA)–de ined as he p obabili y ha a speci ic alue o he PK/PD index associa ed wi h
he e icacy o he an ibio ic is achie ed a a ce ain MIC [
20
]–can he e o e be calcula ed
o di e en MIC alues agains a a ie y o pa hogens. Thus, PK/PD indexes can be used
as a ool o selec dosing egimens wi h PTA >90% in he s udied popula ion, inc easing
he p obabili y o selec ing clinically success ul ea men s, iden i ying clinical b eakpoin s,
and p e en ing he eme gence o esis ance [14,19].
The use o hese me ics is he e o e essen ial o s eamline FQs ea men and adjus
dosing egimens in clinical p ac ice. In addi ion, he indi idual s a us o he pa ien and
he suspec ed in ec ing o ganism should be accoun ed o in dose decision-making. In an
exposu e– esponse model based on clinical da a om pa ien s wi h communi y-acqui ed
pneumonia associa ed wi h S. pneumoniae, G am (+) mic oo ganism, and ea ed wi h a
500 mg o al dose daily o LEV, he p obabili y o success ul clinical esponse was 95% in
pa ien s who achie ed a a ge o AUC
0–24h
/MIC > 33.8, and was 67% in pa ien s who did
no achie e ha a ge [
23
]. Fo in ec ions caused by G am (-) bac e ia, he h eshold o
he a io AUC
0–24h
/MIC was ound o be a signi ican b eakpoin o p obabili ies o bo h
clinical and mic obiologic cu es, bu he equi ed alue o ea men success was highe
han ha equi ed o G am (+) bac e ial in ec ions. In hospi alized pa ien s ea ed wi h a
400 mg in a enous dose o CIP, a AUC
0–24h
/MIC > 125, he p obabili ies o clinical and
mic obiological cu e we e 80% and 82%, espec i ely, o G am (-) bac e ia [
25
]. Simila
esul s we e ob ained o pa ien s wi h nosocomial pneumonia and G am (-) isola es ea ed
wi h a 750 mg in a enous dose o LEV [
24
]. The Uni ed S a es Commi ee on An imic obial
An ibio ics 2022,11, 641 4 o 19
Suscep ibili y Tes ing (USCAST) epo p o ides an ex ensi e in eg a i e e alua ion o
he
in i o
suscep ibili y es ing, PK/PD b eakpoin s (i.e., AUC
0–24h
/MIC a io a ge s o
En e ococcus spp., Esche ichia coli, and o he En e obac e iaceae spp., Pseudomonas ae uginosa,
and S ep ococcus au eus), and clinical b eakpoin s by in ec ion ype [
26
]. Howe e , simila
s udies in pa ien s wi h u ological in ec ions a e s ill sca ce.
Published PK/PD s udies ha e aised conce ns abou pa ien clinical ou comes wi h
he use o FQs, pa icula ly wi h ega ds o ea men ailu e a e empi ic dosing ela ed
o a iabili y in PK and bac e ia suscep ibili y, as MIC alue. Ra anaumpawan e al. [
27
]
examined he impac o PD a iabili y associa ed wi h MIC alue on FQs’ clinical ou -
comes in adul emale pa ien s wi h complica ed u ina y ac in ec ions caused by E. coli.
T ea men ailu e a es o 0.8% and 6.9% we e obse ed when hey compa ed isola es wi h
low and high MIC alues, espec i ely. Peloquin e al. [
28
] ound ha esis ance o CIP
occu ed in pa ien s a e ea ing nosocomial lowe espi a o y ac in ec ions caused
by G am (-) bac e ia, such as P. ae uginosa. The au ho s explained ha he Cmax/MIC
a io was a g ea e wi h isola es ha we e e adica ed han wi h hose ha pe sis ed,
a ibu ing a iabili y in MIC alues as he de e mining ac o in ea men esolu ion. In
pa ien s wi h nosocomial pneumonia, measu ing CIP and LEV concen a ions, de e mining
pa hogen MIC, and subsequen ly pe o ming dose adjus men s signi ican ly imp o ed
he p obabili y o success ul clinical ou comes and pa hogen e adica ion [
29
]. Fo pa ien s
diagnosed wi h Mycoplasma geni alium, a pa hogen ansmi ed h ough sexual con ac , he
inc eased use o 400 mg o MOX caused an eme gence o cases wi h ea men ailu e. The
MIC o MOX in he mu an s ains inc eased 4- old as compa ed wi h ha o he pa en
s ain [30].
No eddin e al. [
31
] de e mined ha age plays an impo an ole in explaining he
in e indi idual a iabili y in he PK o hospi alized pa ien s wi h communi y-acqui ed
pneumonia ea ed wi h LEV. This ac o in luenced he abili y o achie e he a ge a -
ainmen ela ed wi h clinical esponse. Va ia ions in clinical esponse o S. pneumoniae
we e obse ed when compa ing elde ly and younge pa ien s. Elde ly pa ien s showed
highe AUC
0–24h
alues leading o a highe AUC
0–24h
/MIC a io and imp o ed bac e i-
ological ou come compa ed o younge adul s. In ano he s udy analyzing CIP use in
hospi alized pa ien s wi h u ina y ac , abdominal, and a ious o he in ec ions p oduced
by G am (-) mic oo ganisms, 21–75% o he pa ien s did no achie e he e icacy a ge o
AUC
0–24h
/MIC a io
≥
125 wi h MICs o 0.25 and 0.5 mg/L, espec i ely. The AUC
0–24h
achie ed wi h s anda d dosing was ela ed o he high in e indi idual a iabili y o CIP
clea ance, associa ed wi h age and se um c ea inine. This pha macokine ic a iable and he
ele a ed MIC alues obse ed in his s udy highligh he need o indi idualizing dosing
egimens o maximize e icacy, minimize ad e se e ec s, and p e en he appea ance o
esis ance [32].
Ongoing e o s a e s ill need o iden i y op imal FQs dosing s a egies o achie e he
e icacy a ge o AUC
0–24h
/MIC du ing u ological clinical use due o he c i ical ole ha
he managemen o hese d ugs plays in his ype o in ec ions [
2
,
12
,
21
]. In e indi idual
a iabili y in FQs PK and u ological mic oo ganism MIC needs o be known and conside ed
du ing dose adjus men in pa ien s, as i s a iabili y can nega i ely in luence he p obabili y
o eaching he e icacy PK/PD index and achie emen o success ul clinical ou comes [
33
,
34
].
3. In e indi idual Pha macokine ic Va iabili y and Thei Causes
An imic obial exposu e ela ed o d ug disposi ion, gi en as AUC
0–24h
and Cmax, is
subjec o in e indi idual a iabili y in PK p ope ies, such as d ug abso p ion, dis ibu ion,
and elimina ion. Tables 1–3summa ize he PK pa ame e s and hei impo an in e indi-
idual a iabili y o CIP, LEVO, and MOX, espec i ely, in di e en pa ien popula ions
ex ac ed om li e a u e. I is impo an o conside ha he es ima ion o indi idual PK
pa ame e s o each pa ien allows he es ima ion o indi idual exposu es o he d ug;
he e o e, popula ion PK s udies a e essen ial o achie e his objec i e [
18
,
19
,
33
,
34
]. In
An ibio ics 2022,11, 641 5 o 19
he ollowing sec ions, he ac o s iden i ied as po en ial sou ces o a iabili y in he PK
p ocesses o FQs a e discussed (abso p ion, dis ibu ion, and elimina ion).
3.1. Abso p ion P ocess: Role o Food
Abso p ion e e s o he amoun o d ug eaching he bloods eam om he si e o
adminis a ion. FQs a e well abso bed a e o al adminis a ion wi h bioa ailabili y (F)
alues o 70% o CIP [
35
], 99% o LEV [
36
], and 86% o MOX [
37
]. Concomi an o al
adminis a ion o an acids con aining mul i alen ca ions, such as calcium, aluminum, o
magnesium, calcium o i on supplemen s, and suc al a e, dec ease FQs abso p ion due o
he o ma ion o insoluble quinolone-mul i alen ca ion chela es in he gas oin es inal ac .
Fo example, o CIP, F dec eases o 15% wi h concomi an aluminum and magnesium
an acid use wi hin 5 o 10 min o d ug adminis a ion [
38
]. Simila e ec s ha e been
epo ed o milk, o he dai y p oduc s, and supplemen s con aining mul i alen ca ions.
The ex en o he in e ac ion diminishes when he in e ac ing d ug is adminis e ed a leas 2
o 4 h be o e o 6 o 8 h a e he FQs [
39
]. Mul i alen ca ions p esen in ood, supplemen s,
o o he d ug p oduc s can lead o clinically ele an in e ac ions wi h FQs, con ibu ing o
a iabili y in d ug abso p ion, educing he o e all exposu e, and inc easing he isk o
he apeu ic ailu e. Con e sely, ood no con aining mul i alen ca ions is no expec ed o
modi y FQs abso p ion [39,40].
Acco ding o he Food and D ug Adminis a ion’s Biopha maceu ics Classi ica ion
Sys em (BCS), CIP is ca ego ized as class III, hough his is somewha con o e sial, wi h
some au ho s classi ying CIP as class II/IV. Unlike LEV o MOX, CIP p esen s a pH-
dependen solubili y. I is highly soluble a an acidic pH, howe e , a an in es inal pH o 6.8
o 7.5, i s solubili y is much lowe [
41
]. Any meals o be e ages able o signi ican ly a ec
he pH may hus a ec CIP o al bioa ailabili y [42].
3.2. Dis ibu ion P ocess: Role o Pa ien ’s Pa hophysiological Cha ac e is ics
A e en e ing sys emic ci cula ion, he d ug mus dis ibu e h oughou he body
ia he bloods eam o he issues. The ex en o d ug dis ibu ion depends on a a ie y
o ac o s, including he physicochemical p ope ies o he d ug, he a e o blood low
o he issue, and he abili y o he d ug o bind o plasma p o eins and issue. Gi en
ha only unbound o ee d ugs can access he si e o in ec ion [
43
,
44
], he in luence o
plasma p o ein binding on he dis ibu ion o FQs was e alua ed. The pe cen o plasma
p o ein binding is low o FQs (30% o CIP [
45
], 31% o LEV [
46
], and 48% o MOX) [
37
].
Mo eo e , i has no been es ablished ha a iabili y in plasma p o ein binding has any
signi ican di ec o indi ec impac on he he apeu ic e ec i eness o FQs [
47
]. Rega ding
he issue dis ibu ion, he physicochemical p ope ies o FQs pe mi apid pene a ion
in o ex a ascula and in acellula si es, wi h a apid equilib ium es ablished be ween
compa men s. CIP, LEV, and MOX a e widely dis ibu ed h oughou he body and
each high concen a ions in a a ie y o issues, such as he u ina y ac (e.g., u ine,
p os a e) [
48
,
49
], and o he a eas such as he lungs, pa anasal sinuses, in lamed lesions,
and bones [50,51].
Speci ically, FQs a e e ec i e in he ea men o many ypes o u ological in ec ions
and o he sys emic in ec ions due o hei abili y o achie e high concen a ions in issues
and body luids and hei wide an ibac e ial spec um. Howe e , se e al complex mech-
anisms a e in ol ed in he pene a ion o special issues, such as p os a e. In addi ion o
passi e di usion [
52
], condi ioned by he d ug’s acidic o alkaline na u e, i s pKa, and he
pH o p os a ic luid, he e is e idence o he in ol emen o e lux anspo e s–p ima ily
P-glycop o ein–on FQs issue pene a ion (Figu e 2).
The esul s o Zimme mann e al. s ongly suppo he ole o e lux anspo e s on
he p os a ic issue pene a ion o LEV [
53
], bu no o CIP [
54
]. Due o his complexi y,
in e indi idual a iabili y in d ug pene a ion in o issues could esul in a iabili y o con-
cen a ions a he si e o in ec ion and condi ion he e ec i eness o he ea men o a ec o
he eme gence o bac e ial esis ance. Whole body physiologically based pha macokine ic
An ibio ics 2022,11, 641 6 o 19
(PBPK) models p o ide a aluable ool o inco po a e d ug disposi ion cha ac e is ics–
including he ole o anspo e s–and p edic unbound issue dis ibu ion in di e en
o gans. The applica ion o PBPK modeling has inc eased o e he pas decade o imp o e
he mechanis ic unde s anding o d ug PK and suppo dosing ecommenda ions [
55
].
PBPK models can also inco po a e ele an disease-speci ic changes in he physiology,
allowing he p edic ion o d ug PK unde di e en ch onic condi ions, as o example enal
o hepa ic disease, hea ailu e, o obesi y [56–58].
An ibio ics 2022, 11, x FOR PEER REVIEW 6 o 20
Figu e 2. Dis ibu ion mechanisms o luo oquinolone om he blood o he p os a e gland. F:
unbound luo oquinolone; FP: p o ein-bound luo oquinolone.
The esul s o Zimme mann e al. s ongly suppo he ole o e lux anspo e s on
he p os a ic issue pene a ion o LEV [53], bu no o CIP [54]. Due o his complexi y,
in e indi idual a iabili y in d ug pene a ion in o issues could esul in a iabili y o
concen a ions a he si e o in ec ion and condi ion he e ec i eness o he ea men o
a ec o he eme gence o bac e ial esis ance. Whole body physiologically based
pha macokine ic (PBPK) models p o ide a aluable ool o inco po a e d ug disposi ion
cha ac e is ics–including he ole o anspo e s–and p edic unbound issue dis ibu ion
in di e en o gans. The applica ion o PBPK modeling has inc eased o e he pas decade
o imp o e he mechanis ic unde s anding o d ug PK and suppo dosing
ecommenda ions [55]. PBPK models can also inco po a e ele an disease-speci ic
changes in he physiology, allowing he p edic ion o d ug PK unde di e en ch onic
condi ions, as o example enal o hepa ic disease, hea ailu e, o obesi y [56–58].
Dis ibu ion s udies use cen al blood/plasma concen a ions as a su oga e o issue
dis ibu ion as hey a e easily accessible o measu e. Volume o dis ibu ion (Vd) is he PK
pa ame e ha ep esen s he deg ee o which a d ug is able o dis ibu e h oughou he
body o he issues [59]. Body weigh and i s changes in obese pa ien s, age, and
pa hological condi ion o pa ien s can explain he in e indi idual a iabili y o
dis ibu ion seen wi h FQs o a ce ain deg ee. As can be obse ed in Table 1, when CIP
was in used o a g oup o obese, he Vd was ound o be 23% la ge in he obese g oup
han in he non-obese g oup. Howe e , when he Vd was adjus ed o he o al body
weigh , he obese exhibi ed lowe Vd/kg han he non-obese subjec s. These indings
indica e ha CIP is no highly dis ibu ed in o adipose issue [60]. Addi ional popula ion
PK analysis s udies conduc ed in elde ly pa ien s [61–63] and in adul pa ien s wi h sep ic
shock [64] e ealed ha o al body weigh is a signi ican co a ia e on he Vd o CIP. No
signi ican changes in Vd ha e been ound in pa ien s wi h hepa ic o enal impai men
[65–67]. A high a iabili y in his pa ame e was obse ed in pa ien s wi h c i ical illness,
bu no co a ia es we e associa ed wi h his a iabili y due he complex o he pa hology
[62,64,68,69]. Fo LEV, pa ien -speci ic ac o s such as age, sex, and ace [70], bu no
Figu e 2.
Dis ibu ion mechanisms o luo oquinolone om he blood o he p os a e gland. F: un-
bound luo oquinolone; FP: p o ein-bound luo oquinolone.
Dis ibu ion s udies use cen al blood/plasma concen a ions as a su oga e o issue
dis ibu ion as hey a e easily accessible o measu e. Volume o dis ibu ion (Vd) is he
PK pa ame e ha ep esen s he deg ee o which a d ug is able o dis ibu e h oughou
he body o he issues [
59
]. Body weigh and i s changes in obese pa ien s, age, and
pa hological condi ion o pa ien s can explain he in e indi idual a iabili y o dis ibu ion
seen wi h FQs o a ce ain deg ee. As can be obse ed in Table 1, when CIP was in used o a
g oup o obese, he Vd was ound o be 23% la ge in he obese g oup han in he non-obese
g oup. Howe e , when he Vd was adjus ed o he o al body weigh , he obese exhibi ed
lowe Vd/kg han he non-obese subjec s. These indings indica e ha CIP is no highly
dis ibu ed in o adipose issue [
60
]. Addi ional popula ion PK analysis s udies conduc ed
in elde ly pa ien s [
61
–
63
] and in adul pa ien s wi h sep ic shock [
64
] e ealed ha o al
body weigh is a signi ican co a ia e on he Vd o CIP. No signi ican changes in Vd ha e
been ound in pa ien s wi h hepa ic o enal impai men [
65
–
67
]. A high a iabili y in his
pa ame e was obse ed in pa ien s wi h c i ical illness, bu no co a ia es we e associa ed
wi h his a iabili y due he complex o he pa hology [
62
,
64
,
68
,
69
]. Fo LEV, pa ien -
An ibio ics 2022,11, 641 7 o 19
speci ic ac o s such as age, sex, and ace [
70
], bu no obesi y–e en conside ing obese
pa ien s and se e ely mo bidly obese [
71
,
72
]–con ibu ed o a iabili y in Vd (Table 2). The
Vd o MOX, howe e , was no signi ican ly a ec ed by age o sex [
73
], bu was ound o be
co ela ed wi h lean body weigh o bo h no mal weigh [
74
] and obese pa ien s [
75
], as
has been published in he a icles e e enced in Table 3.
3.3. Elimina ion P ocess: Role o Renal and Hepa ic Func ion
FQs a e elimina ed om he body ia wo main mechanisms: bio ans o ma ion–o
hepa ic me abolism–and enal exc e ion. Once he an ibio ic eaches he sys emic ci cula-
ion, hese elimina ion p ocesses unc ion o dec ease he blood concen a ion o FQs and
consequen ly dec ease an ibio ic exposu e a he si e o in ec ion [
21
,
34
]. Clea ance (CL) is
de ined as he olume o body luid, usually plasma, om which he d ug is comple ely
emo ed pe uni o ime. This PK pa ame e e lec s he a e o d ug elimina ion om
he body and is p opo ional o he blood concen a ion o he d ug. Fo e e y d ug, each
o gan o elimina ion has i s own clea ance (e.g., hepa ic clea ance o enal clea ance). The
o al body clea ance o he d ug is he e o e he sum o he clea ances om all elimina ing
o gans (CL = CL
Renal
+ CL
Hepa ic
+ CL
O he
) [
59
]. Clea ance is he ac o de e mining he
a e age concen a ion o FQs a e con inuous in a enous in usion. A e o al adminis a-
ion, howe e , he elimina ion p ocess is de e mined by bo h he clea ance and abso p ion
p ocess and unde lying bioa ailabili y (CL/F).
Di e en ac o s con ibu e o he in e indi idual a iabili y in he CL o he u ological
FQs unde e iew. Fi s , Table 1summa izes he changes in PK pa ame e s ela ed o CIP
elimina ion p ocesses (T
1/2
and CL) and di e en pa ien subpopula ions. Fo CIP, se e al
mechanisms and ac o s may con ibu e o he in e indi idual a iabili y in CL. Non-
enal mechanisms o elimina ion–mainly hepa ic me abolism–accoun o app oxima ely
one- hi d o CIP elimina ion. Fou me aboli es o CIP– dese hylenecip o loxacin, sul o-
cip o loxacin, oxo-cip o loxacin, and N-ace ylcip o loxacin–ha e been eco e ed in he
u ine and eces. Due o changes in chemical s uc u e, hese me aboli es ha e some
an ibac e ial ac i i y, bu less han ha o he pa en compound [
46
]. App oxima ely 15% o
a 100 mg in a enous dose o CIP is exc e ed in he eces, likely due o elimina ion di ec ly
h ough he in es inal mucosa and bilia y exc e ion. The emaining wo- hi ds o he CIP
dose is elimina ed ia he kidneys, due o a combina ion o glome ula il a ion and ubula
sec e ion [
76
]. As a esul o unde going CL h ough bo h non- enal and enal pa hways,
CIP has a ela i ely sho hal -li e when compa ed o o he FQs and equi es wice daily
dosing [
39
,
46
]. Popula ion PK modeling has been used in se e al s udies o es ima e he
e ec o indi idual PK pa ame e alues in a a ie y o pa ien popula ions and bac e ial
in ec ions [
61
,
62
,
64
,
68
,
69
,
77
–
80
], showed in Table 1. Fac o s a ec ing enal and hepa ic
unc ion could also be esponsible o he in e indi idual a iabili y in he CL o CIP, and
hei e ec may be di icul o p edic . Hepa ic dys unc ion appea s o ha e minimal e ec
on he elimina ion o CIP, wi h no changes in CL ound in ch onic ci ho ic pa ien s [
65
].
C ea inine clea ance (CL
CR
), howe e , has been iden i ied in mul iple popula ion PK
s udies as one o he main co a ia es esponsible o in e indi idual a iabili y in he
sys emic CL o CIP. In pa ien s wi h a ying deg ees o enal dys unc ion, CIP CL has
been shown o dec ease as CL
CR
dec eases [
66
,
67
,
77
]. Consequen ly, age- ela ed decline
in enal unc ion could also lead o a educ ion in CIP elimina ion in olde adul s [
61
–
63
].
In addi ion, an inc ease in CL has been epo ed in obese pa ien s when compa ed o
pa ien s o no mal weigh , which could be ela ed o he inc ease in glome ula il a ion
and ubula sec e ion known o occu in obese adul s [
60
]. Las ly, c i ically ill pa ien s
exhibi highe in e indi idual a iabili y in CL associa ed wi h pa hophysiological changes
d i en by al e ed enal unc ion [
62
,
64
,
68
,
69
,
80
]. Non- enal mechanisms, such as bilia y
clea ance, may e ec i ely compensa e o he educ ion in enal CL in hese pa ien s, and
could u he con ibu e o he inc ease in in e indi idual a iabili y [64,80].
App oxima ely 83% o LEV is exc e ed in he u ine as an unchanged d ug, indica ing
ha i p ima ily unde goes enal elimina ion [
36
,
39
]. Simila ly o CIP, popula ion PK
An ibio ics 2022,11, 641 8 o 19
modeling has been used in se e al s udies wi h LEV o es ima e he e ec o indi idual
PK pa ame e alues in a a ie y o pa ien popula ions and bac e ial in ec ions [
70
,
81
–
93
]
(Table 2). In se e al s udies, CL
CR
[
71
,
82
–
85
,
91
–
93
], age [
70
], and ace [
70
] we e ound o
be co a ia es ha in luenced he CL o LEV. In hospi alized elde ly pa ien s wi h a ying
deg ees o enal unc ion, CL
CR
was again shown o be he main co a ia e associa ed wi h
in e indi idual a iabili y in LEV CL [90]. A p ospec i e popula ion PK s udy conduc ed
in pa ien s wi h bone and join in ec ions demons a ed ha age and glome ula il a ion
a e we e co a ia es ela ed o in e indi idual a iabili y o CL/F [
81
]. C i ical illness was
no a signi ican a iable in al e ing LEV CL pe se, wi h al e ed enal unc ion being he
de e mining ac o [
77
,
93
–
96
]. Obesi y may be ano he ac o a ec ing he in e indi idual
a iabili y o LEV PK. Howe e , mos s udies wi h LEV ha e been pe o med in no mal
weigh pa ien s, and only a ew published s udies pe o med in o e weigh and obese
pa ien s. One such s udy epo ed a highe CL o LEV in mo bidly obese pa ien s and
sugges ed ha CL was ela ed o CL
CR
es ima ed by he Cockc o –Gaul equa ion and
ideal body weigh [72].
MOX p ima ily unde goes hepa ic me abolism and ecal exc e ion. Despi e he la ge
pe cen age o me abolism by he li e , moxi loxacin does no appea o be ans o med
by he cy och ome P450 (CYP) isoenzyme sys em, making i less suscep ible o d ug–
d ug in e ac ions. Moxi loxacin has wo me aboli es, M1 (sulpho-compound) and M2
(glucu onide) [
96
–
98
]. To al clea ance is modi ied only by lean body weigh in heal hy
adul s [
37
,
73
]. As shown Table 3, he PK a e a single and mul iple in a enous doses o
MOX di e ed only ma ginally in pa ien s wi h se e e hepa ic impai men compa ed o
heal hy pa ien s, and demons a ed no accumula ion [
99
]. Only 20% o MOX is exc e ed
unchanged by he kidneys, condi ioned by he p ocesses o glome ula il a ion and
ubula eabso p ion. As a esul , enal impai men has li le clinically ele an e ec on
he PK o MOX, including CL, and does no equi e dose adjus men s [
96
]. MOX PK in
c i ically ill pa ien s wi h acu e enal ailu e unde going ex ended daily dialysis a e simila
o heal hy pa ien s wi hou enal impai men [
96
,
100
,
101
]. O he pa ien -speci ic ac o s
such as age [
74
], ace [
102
], and obesi y [
75
] ha e no been shown o be esponsible o he
in e indi idual a iabili y in he CL o MOX.
FQs exhibi dose-independen PK, meaning ha F, CL, and Vd a e cons an o e he
ange o doses encoun e ed clinically [
39
]. Se e al pa hophysiological ac o s, ha may be
p esen in pa ien s wi h u ological in ec ions, could in luence in e indi idual a iabili y in
FQs PK and po en ially a ec clinical esponse and ou comes. Gi en hei la ge Vd and
abili y o accumula e in issues, in e indi idual a iabili y in he Vd o FQs could a ec he
deg ee ha FQs a e able o pene a e he si e o in ec ion. Addi ional issue dis ibu ion
s udies could he e o e help o be e unde s and a iabili y in he Vd o FQs, especially
associa ed wi h pa ien s’ pa hophysiological cha ac e is ics. Howe e , he impo ance o
CL is a mo e e iden [
103
]. Gi en FQs’ concen a ion-dependen an ibac e ial ac i i y,
unde s anding he in e indi idual a iabili y o CL a e in a enous adminis a ion and
F a iabili y a e o al adminis a ion is c ucial o ensu ing adequa e an ibio ic exposu e–
AUC–is achie ed and main ained when ea ing u ological in ec ions. CL, especially o
CIP and LEV, dec eases undamen ally wi h dec ease in enal unc ion. This dec ease
in CL ansla es o a highe AUC in pa ien s and, as a esul , a highe p obabili y o
expe iencing concen a ion-dependen ad e se e ec s [
104
,
105
]. Ano he impo an aspec
o conside is he impac o d ug–d ug in e ac ions (DDIs) on d ug exposu e. PBPK
modeling and simula ion can be used as a ool o de e mine he impac o disease- ela ed
physiological changes and DDIs on he sys emic exposu e o FQs, and he possible need o
dose adjus men in speci ic diseases and/o due o co-medica ions [
106
]. As an example,
al e a ions in blood low o main o gans and dec ease in clea ance obse ed in ch onic
kidney disease o ch onic hea ailu e can be inco po a ed in he model o p edic changes
in he ADME p ope ies o FQs. In addi ion, mechanis ic modeling can be used o explo e
possible disease e ec s, es hypo heses, and gene a e suppo ing e idences when no
enough clinical da a a e a ailable [107].
An ibio ics 2022,11, 641 9 o 19
Table 1.
S eady-s a e pha macokine ic pa ame e s o
cip o loxacin
in pa ien s wi h se e al
physiopa hology condi ions a e in a enous o o al adminis a ion ( alues exp essed as mean
(s anda d de ia ion)).
Cip o loxacin
S udy Cha ac e is ic Vd (L) Cl (L/h) T1/2(h) Re e ence
Heal hy, non-obese
200 mg In usion IV
21–30 yea s
199.1 (34.2) 26.8 (5.7) 4.2 (0.8)
Plaisance e al., 1987 [
35
]
219.0 (35.8) 44.6 (7.2) 4.0 (0.3) Alla d e al., 1993 [60]
146.0 (27.4) 25.2 (5.8) 4. 4(0.9) D usano e al., 1986 [77]
750 mg O al
21–29 yea s 256.0 (80.0) 129.5 (5.9) 15.2 (0.7)
Plaisance e al., 1987 [
35
]
46–68 yea s 217.0 (45.0) 150.4 (14.4) 13.7 (0.4) D usano e al.,1986 [77]
Heal hy, obese
400 mg In usion IV
29 ±7 yea s
BMI = 36 ±4 kg/m2
269.1 (51.6) 53.8 (9.5) 4.3 (0.6) Alla d e al., 1993 [60]
Pa ien s wi h ci hosis
750 mg O al
52 ±6 yea s 218.1 (45.4) 145.9 (14.1) 13.7 (0.4) F os e al., 1989 [65]
Pa ien s wi h enal disease
200 mg In usion IV
22–62 yea s
CLCR ≥100 mL/min 191.7 (35.4) 26.8 (5.7) 4.3 (0.8)
D usano e al., 1987 [66]
CLCR = 86–60 mL/min 243.0 (97.1) 26.3 (10.3) 6.1 (1.6)
CLCR = 11–57 mL/min 183.2 (47.7) 15.0 (3.8) 7.7 (1.2)
CLCR = 0 mL/min 210.2 (70.8) 15.4 (4.3) 8.5 (3.3)
750 mg O al
48–90 yea s
CLCR ≥50 mL/min 158.0 (46.5) 170.4 (48.9) 13.5 (1.2) Gasse e al., 1987 [67]
CLCR < 50 mL/min 113.8 (34.2) 129.4 (6.4) 16.3 (3.2)
Elde ly pa ien s
200 mg In usion IV
78 ±11 yea s
Cl
CR
= 45
±
16 mL/min
100.8 (37.8) 16.6 (6.8) 5.8 (2.4) Hi a a e al., 1989 [63]
200 mg In usion IV
73 ±11 yea s
CLCR = 45 ±16
mL/min
(61.0–118.0) 18.4 (4.5) ND Cios e al., 2014 [61]
Acu ely ill pa ien s
200–400 mg In usion IV
24–91 yea s
Cl
CR
= 63
±
30 mL/min
111.0 (33.0) 17.0 (6.6) ND Fo es e al., 1993 [25]
400–1200 mg In usion IV
56–71 yea s
GFR = 32–101 mL/min
255.0 (51.0) 25.4 (67.8) ND Abdulla e al., 2020 [68]
400 mg In usion IV
23–79 yea s
ClCR =13–204 mL/min
107.5 (21) 18.6 (18.7) ND Li e al., 2019 [80]
An ibio ics 2022,11, 641 16 o 19
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