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71（ 13 ）Evaluation of antibacterial activities of flomoxef
against ESBL producing Enterobacteriaceae
analyzed by Monte Carlo Simulation
AKINOBU ITO, YUMIKO TATSUMI (MATSUO), TOSHIHIRO WAJIMA,RIO NAKAMURA and MASAKATSU TSUJI
Medicinal Research Laboratories, Shionogi & Co., Ltd.
(Received for publication November 12, 2012)

The growing number of infection caused by extended-spectrum ȕ-lactamase(ESBL) producing pathogens has prompted a more rational use of available
antibiotics because of the paucity of new, effective agents. Flomoxef (FMOX) is oneof the ȕ-lactam antibiotic which is stable against ȕ-lactamase. In this study, theantibacterial activity of FMOX was investigated, and Monte Carlo Simulation was
conducted to determine the appropriate dosing regimens of FMOX based on theprobability of target attainment (TA%) at the critical drug exposure metric of timethat drug concentrations remain above 40% (showing bacteriostatic effect) or 70%(showing bactericidal effect) of time during which plasma concentration above
minimum inhibitory concentration (MIC) of the drug (T＞MIC) against the ESBL
producing Enterobacteriaceae. The effective regimens to achieve 80% of TA% at
70% of T＞MIC were 1 g every 8 hours with 2–4 hours infusion, and 1 g every 6hours with 1–4 hours infusion. Moreover, all the tested regimens were effective toachieve 80% of TA% at 40% of T＞MIC. These results of pharmacokinetics/
SKDUPDFRG\QDPLFV 3.3'  PRGHOLQJ VKRZHG WKH SRWHQWLDO HI¿FDF\ RI )02;
against bacterial infections caused by ESBL producing Enterobacteriaceae.

Introduction
Extended-spectrum ȕ-lactamase (ESBL) is spreading among Enterobacteriaceae. Associatedinfectious syndromes include the infections following a surgical procedure, urinary tract infections, bloodstream and intra-abdominal infections. The rates of ESBL-expression among nosocomial Enterobacteriaceae isolates, particularly Klebsiella pneumoniae, have risen substantially inseveral countries1–3). In a recent study based on the Tigecycline Evaluation and Surveillance Trial

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Apr. 2013(TEST) global surveillance database, the rate of ESBL production among the K. pneumoniae andthe Escherichia coli isolates collected in Latin America were 44.0% and 13.5%, respectively4).
The increasing rate of ESBL producing Enterobacteriaceae in Japan has been also reported5–8).
Available therapeutic options for the treatment of ESBL-associated infections are limited bydrug resistance conferred by the ESBL9). Therefore, it is important to verify whether the dosage
and administration schedule of the currently available antibiotics are appropriate to cure infection, minimize safety risks, and curb the emergence of antibiotic resistance10).
Pharmacokinetics/pharmacodynamics (PK/PD) has been investigated to maximize clinicalresponse and to minimize the emergence of antibiotic resistance and exposure-related toxicities11,12). For cephalosporin antibiotics, the fraction of time during the dosing interval that drugconcentration remains above its MIC for the infecting pathogen (T＞MIC) is the target that best relates to patient outcomes11,12). Although T＞MIC is decided by PK of the antibiotics and MIC of thebacteria, both of them are variable among cases, and it is not always possible to obtain the information at the time of administration. Therefore, Monte Carlo Simulation has been applied to predict the outcome of the antibiotic treatment13–19). With the Monte Carlo Simulation, distributionof PK and MIC are processed to obtain a set of virtual population, and the various regimens areapplied to the set of virtual population to calculate the probability of target attainment (TA%) at
T＞MIC for the dosage interval. This simulation can predict the outcome of various dosage and administration schedule, which helps us to choose the appropriate regimens for the treatment.
Flomoxef (FMOX) is one of the cephamycins, characterized by its 7-methoxy, and also
called 1-oxacephem antibiotic different structurally from the cephalosporins and other cephamycins, in which sulfur molecule in the cephem nucleus is substituted with oxygen molecule. It has
potent in vitro activity against Gram-negative organisms with broad spectrum, and was stable in
the presence of ȕ-lactamase and active against cephalosporin-resistant strains. Although FMOX
has a potential to be effective against ȕ-lactamase producing strains, there is little information for
SUHGLFWLRQ RI HI¿FDF\ DJDLQVW (6%/ SURGXFLQJ (QWHUREDFWHULDFHDH LQ WKH FXUUHQW FOLQLFDO XVH
Therefore, it is important to understand the characteristics of FMOX with PK/PD analysis as wellas in vitro antibacterial activities against emerging ESBL such as SHV, TEM, and CTX-M. The
objective of this study was to investigate the potency of FMOX for the treatment of the infection
caused by ESBL producing Enterobacteriaceae in the clinical use by in vitro activities andMonte-Carlo Simulation.

I. Materials and Methods
1. Antimicrobial agents
Susceptibilities of the bacterial strains were tested with the following antimicrobial agents:
ÀRPR[HI )02; FHIPHWD]ROH &0= FHIWULD[RQH &75; FHIRWLDP &70 FHID]ROLQ &(= Apr. 2013

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73（ 15 ）cefepime (CFPM), piperacillin-tazobactam (piperacillin with 4 ȝJP/RIWD]REDFWDP3,3&7$= imipenem (IPM), and doripenem (DRPM).
2. Bacterial strains
Thirty-one isolates were used in this study. Ten isolates obtained from ATCC include 4 isolates of TEM producing E. coli, 4 isolates of SHV producing E. coli, an isolate of SHV producing
K. pneumoniae, and an isolate of SHV producing K. oxytoca. Twenty-one clinical isolates werecollected from 1992 to 2002 in 12 medical facilities in Japan. They include 3 isolates of CTX-M
producing E. coli, 6 isolates of CTX-M producing K. pneumoniae, an isolate of SHV producing
K. pneumoniae, 6 isolates of CTX-M producing K. oxytoca, 4 isolates of CTX-M producing Proteus mirabilis, and an isolate of TEM producing P. mirabilis.
3. MIC determination
The antimicrobial susceptibility testing was performed according to Clinical and Laboratory
Standards Institute (CLSI) standards M07-A8 for the micro-broth dilution method20,21) %ULHÀ\5×104 CFU/well was inoculated in cation-adjusted Mueller Hinton Broth containing drugs, andincubated at 35°&IRUWRKRXUV7KH0,&ZDVGH¿QHGDVWKHORZHVWFRQFHQWUDWLRQRIDQWLPLcrobial agent that completely inhibited bacterial growth as detected by the unaided eye.
4. Monte Carlo Simulation
Monte Carlo Simulation was employed to investigate the probability of target attainment(TA%) against the clinical isolates of ESBL producing strains. Virtual populations of 5,000 patients were created for each dosage regimen against each bacterial strain. Pharmacokinetic parameters of FMOX were taken from the Phase 1 studies in Japan22). Pharmacokinetic parameters of
FMOX for typical values of two-compartment model were as follows: Vc＝7.14 L, k10＝2.12 hr−1,
k12＝2.45 hr−1, and k21＝2.57 hr−1. A log-normal distribution was assumed for the interLQGLYLGXDOYDULDELOLW\IRUSKDUPDFRNLQHWLFSDUDPHWHUVZLWKRIFRHI¿FLHQWRIYDULDWLRQ,WZDV
assumed that free plasma concentration of FMOX would correlate with the bactericidal effect,
and free drug concentrations were used for the simulation based on a plasma protein binding ratioof 35%22). MIC values were generated from the discrete MIC distribution obtained from 31 isolates. The regimens used for the simulation were 1 g every 6, 8, or 12 hours (q6h, q8h, or q12h,
respectively) with 1 to 4 hours infusion, and 2 g q12h with 1 to 4 hours infusion (Table 1). TA%
was calculated based on the simulated plasma concentrations at 1-minute interval by using twocompartment model. The TA% at various T＞MIC for the dosage interval was calculated by using
5,000 virtual patients for each dosing regimen against each bacteria strain.

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II. Results
1. In vitro activity of FMOX against ESBL producing strains
Table 2 shows in vitro activity of antimicrobial agents including FMOX. FMOX showed potent in vitro activity against ESBL producing strains whose MIC90 was 0.5 ȝg/mL. FMOX waspotent against all the tested type of ESBL such as TEM，SHV，and CTX-M. DRPM also showed
potent in vitro activity whose MIC90 was 0.25 ȝg/mL. MIC90 RI&)30&75;&70&(=DQG
3,3&7$= DJDLQVW (6%/ SURGXFLQJ VWUDLQV ZHUH  RU ＞128 ȝg/mL. MIC of FMOX against
most of the tested strains were 0.5 or ＜0.5 ȝg/mL. There was only a strain whose MIC was 2 ȝg/mL which was SHV-2 producing E. coli (Table 3).
 3UHGLFWLRQ RI FOLQLFDO HI¿FDF\ E\ 0RQWH &DUOR 6LPXODWLRQ ZLWK WKH UHJLPHQ RI JTKZLWKWRKRXUVLQIXVLRQTable 4 and Figure 1 show TA% at each T＞MIC calculated by Monte Carlo Simulation withthe regimen of 1 g q12h with 1 to 4 hours infusion against ESBL producing strains. The TA%
achieved more than 80% with 1 to 4 hours infusion, and achieved more than 90% with 2 to 4
hours infusion at T＞MIC＝40%. At T＞MIC＝70%, even though TA% increased with the increase of

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Table 4. Probability of target attainment at each dosing regimen.

infusion time, the highest TA% was 49.4% with 4 hours infusion.
 3UHGLFWLRQ RI FOLQLFDO HI¿FDF\ E\ 0RQWH &DUOR 6LPXODWLRQ ZLWK WKH UHJLPHQ RI JTKZLWKWRKRXUVLQIXVLRQTable 4 and Figure 2 show TA% at each T＞MIC calculated by Monte Carlo Simulation withthe regimen of 2 g q12h with 1 to 4 hours infusion against ESBL producing strains. The TA%

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79（ 21 ）)LJ  3UREDELOLW\ RI WDUJHW DWWDLQPHQW RI ÀRPR[HI ZLWK J TK DW GLIIHUHQW IUHH GUXJ
T＞MIC targets against ESBL producing strains.

)LJ  3UREDELOLW\ RI WDUJHW DWWDLQPHQW RI ÀRPR[HI ZLWK J TK DW GLIIHUHQW IUHH GUXJ
T＞MIC targets against ESBL producing strains.

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achieved more than 90% with 1 to 4 hours infusion at T＞MIC＝40%. At T＞MIC＝70%, eventhough TA% increased with the increase of infusion time, the highest TA% was 67.6% with 4hours infusion.
3UHGLFWLRQRIFOLQLFDOHI¿FDF\E\0RQWH&DUOR6LPXODWLRQZLWKWKHUHJLPHQRIJTK
ZLWKWRKRXUVLQIXVLRQTable 4 and Figure 3 show the TA% at each T＞MIC calculated by Monte Carlo Simulation
with the regimen of 1 g q8h with 1 to 4 hours infusion against ESBL producing strains. The TA%
achieved more than 95% with 1 to 4 hours infusion at T＞MIC＝40%. At T＞MIC＝70%, the TA%
achieved more than 80% with 2 to 4 hours infusion, and achieved more than 90% with 3 to 4
hours infusion.
3UHGLFWLRQRIFOLQLFDOHI¿FDF\E\0RQWH&DUOR6LPXODWLRQZLWKWKHUHJLPHQRIJTK
ZLWKWRKRXUVLQIXVLRQTable 4 and Figure 4 show the TA% at each T＞MIC calculated by Monte Carlo Simulation
with the regimen of 1 g q6h with 1 to 4 hours infusion against ESBL producing strains. The TA%
achieved almost 100% with 1 to 4 hours infusion at T＞MIC＝40%. At T＞MIC＝70%, TA%achieved more than 90% with 1 to 4 hours infusion.
)LJ  3UREDELOLW\ RI WDUJHW DWWDLQPHQW RI ÀRPR[HI ZLWK J TK DW GLIIHUHQW IUHH GUXJ7＞MIC
targets against ESBL producing strains.

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81（ 23 ）)LJ  3UREDELOLW\ RI WDUJHW DWWDLQPHQW RI ÀRPR[HI ZLWK J TK DW GLIIHUHQW IUHH GUXJ7＞MIC
targets against ESBL producing strains.

III. Discussion,W KDV EHHQ EHFRPLQJ GLI¿FXOW WR WUHDW WKH (6%/DVVRFLDWHG LQIHFWLRQV EHFDXVH RI WKH LQcrease of resistant pathogens. K. pneumoniae producing SHV or TEM has been reported to because of nosocomial infections from 1980s. Moreover, E. coli producing CTX-M has been increasing in the community from 1990s, and has been reported to be a cause of community acquired infections including urinary tract infections 2,23–25). The reports included patients who do
not have record to be hospitalized, which indicated the spread of ESBL producing strains in thecommunity.
SADER reported the increased rate of resistant strains of E. coli and K. pneumoniae to CFPM
DQG3,3&7$=DFFRUGLQJWRWKHEUHDNSRLQWE\&/6,26). The rates of susceptible isolates to CFPM
are 65.8% and 42.0% among ESBL producing E. coli isolated in North America and the rest of
the world, respectively, and 89.4% and 51.2% among ESBL producing K. pneumoniae isolated in
North America and the rest of the world, respectively. The rates of susceptible isolates to PIPC/
7$=DUHDQGDPRQJ(6%/SURGXFLQJE. coli isolated in North America and the restof the world, respectively, and 52.6% and 45.0% among ESBL producing K. pneumoniae isolated
in North America and the rest of the world, respectively. As mentioned above, the rate of ESBLSURGXFLQJVWUDLQVUHVLVWDQWWR&)30DQG3,3&7$=KDVEHHQLQFUHDVLQJLQWKHUHJLRQRWKHUWKDQ82（ 24 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Apr. 2013

North America, and causing serious problems in the healthcare settings. The further increase andspread of ESBL producing strains could cause decrease of effective antimicrobial agents.
,QWKLVVWXG\DQWLEDFWHULDODFWLYLW\DQGFOLQLFDOHI¿FDF\RI)02;DJDLQVW(6%/SURGXFLQJ
Enterobacteriaceae was investigated by MIC determination and Monte Carlo Simulation. In theMonte Carlo Simulation, MIC of FMOX against ESBL producing strains isolated in Japan and
PK/PD parameter obtained in Phase 1 studies in Japan were used. The TA% at T＞MIC＝40% and
T＞MIC＝70% were determined, which show bacteriostatic and bactericidal activity, respectively,
according to CRAIG11,12).
It was revealed in this study that FMOX and DRPM showed a potent in vitro antibacterial
DFWLYLW\ DJDLQVW (6%/ SURGXFLQJ VWUDLQV$OWKRXJK &0= DQG ,30 VKRZHG DQWLEDFWHULDO DFWLYLW\against them, other antimicrobial agents tested in this study showed higher MIC whose MIC90
was 128 ȝg/mL or ＞128 ȝg/mL, which indicated the inadequate activity of these antimicrobial
agents against ESBL producing strains. The increase of ESBL producing strains has been reported in Japan5–8). YOSHIDA et al. reported the increased rate of ESBL from 0.7% in 2002 to 3.8%
in 2008 among E. coli, and from 1.3% in 2002 to 2.6% in 2008 among K. pneumoniae, and from
1.7% in 2002 to 6.8% in 2008 among K. oxytoca. However, MIC90 of FMOX against E. coli were0.125 ȝg/mL in 2002 and 0.25 ȝg/mL in 2008, and MIC90 of FMOX against K. pneumoniae andK. oxytoca were 0.125 ȝg/mL in 2002 and 2008, and it was concluded that FMOX has maintained
potent antibacterial activity against ESBL producing strains even though the rate of ESBL producing strains have increased among E. coli and K. pneumoniae. In the case of P. mirabilis, therate of ESBL producing isolates decreased from 7.5% in 2002 to 5.5% in 2008, and MIC90 of
FMOX were 0.5 ȝg/mL in 2002 and 0.25 ȝg/mL in 2008. In the present study, in vitro activities
and probability of target attainment were investigated with the ESBL producing strains obtainedby ATCC and those isolated in medical facilities in Japan. MIC ranges of FMOX against E. coli,
Klebsiella spp., and P. mirabilis used in the present study were 0.063–2 ȝg/mL, 0.063–0.5 ȝg/mL,
and 0.25–0.5 ȝg/mL, respectively. MIC90 of FMOX against 11 isolates of E. coli, 15 isolates ofKlebsiella spp., and 5 isolates of P. mirabilis were 0.5 ȝg/mL. Even though MIC90 of FMOX werehigher than those reported by YOSHIDA et al.WKHGLIIHUHQFHVZHUHQRWVLJQL¿FDQWDQGZHUHVHHPHG
to be appropriate for the analysis. In 2008, 14 out of 16 ESBL producing strains possess CTX-M
W\SHDQGVWUDLQVRIWKHPZHUHLGHQWL¿HGWRKDYH&7;0ZKRVHLQFUHDVHKDVEHHQUHSRUWHG
recently in the world wide. FMOX was reported to show a potent antibacterial activity against
CTX-M-15 producing strains where MIC of FMOX was 0.25–0.5 ȝg/mL8). One of the reasons of
the potent antibacterial activity of FMOX against these ESBL producing strains could be its
structural characteristic. FMOX known as one of the 7-methoxy ȕ-lactam antibiotic is one of the
1-oxacephem antibiotic different structurally from the cephalosporins and other cephamycins.
The 7-methoxy was reported to contribute to the stability against ȕ-lactamases27,28).
This study revealed that FMOX showed more than 80% of TA% at T＞MIC＝40% with theApr. 2013

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83（ 25 ）regimen of 1 g q12h with 1 to 4 hours infusion and 2 g q12h with 1 to 4 hours infusion, which inGLFDWHGWKHEDFWHULRVWDWLFDFWLYLW\DQGHI¿FDF\RI)02;DJDLQVWLPPXQRFRPSHWHQWSDWLHQWV2Q
the other hand, both of the regimen did not achive 80% of TA% at T＞MIC＝70%. Even though increase of dosage from 1 to 2 g increased the TA%, both of them did not achive 80% of TA%,
which indicated that regimens of q12h were not appropriate to obtain bactericidal activity, andwas not effective against the ESBL-associated infections of compromized patients. It has been rerpoted that the increase of T＞MIC helps for ȕ-lactam antibiotics to achieve bactericidal activity11,12), and the increase of T＞MICDOVRLQFUHDVHGWKHHI¿FDF\RI)02;SUHGLFWHGE\0RQWH&DUOR
Simulation. The regimen of 1 g q8h and q6h with 1 to 4 hours infusion achieved more than 80%
of TA% at T＞MIC＝40%, and the regimens of 1 g q8h and q6h with 2 to 4 hours infusion achieved
more than 80% of TA% at T＞MIC＝70%. Therefore, the regimens of 1 g q8h with 2 to 4 hours infusion and 1 g q6h with 1 to 4 hours infusion are appropriate to obtain bactericidal activity against
the ESBL-associated infections. These regimens are expected to be appropriate for the compromized patients.
REESE et al. UHSRUWHG WKH 0RQWH &DUOR 6LPXODWLRQ RI &)30 DQG 3,3&7$= DJDLQVW WKHESBL-associated infections29)3,3&7$=ZLWKWKHUHJLPHQRIJTKDFKLHYHGRI7$
at T＞MIC＝40%, and CFPM with 4.0 g continuous infusion achieved 77% of TA% at T＞MIC＝60%. REESE et al.FRQFOXGHGZLWKWKHVHUHVXOWVWKDWERWKRI3,3&7$=DQG&)30ZHUHQRWDSSURpriate for the treatment of the ESBL-associated infections. There are only a few antibiotics to be
used for the treatment of the ESBL-associated infections, and it is required to assess the existing
antibiotics to investigate the appropriate regimens for the treatment. At the current situation, carbapenems and quinolones are the effective antibiotics against ESBL producing strains. However,there are many hospitals to limit the use of carbapenems, and the increase of resistance against
quinolones by ESBL producing strains has been reported30). Therefore, there are increasing demand for effective antimicrobial agents other than carbapenems or quionolones to treat the
ESBL-associated infections.
According to JAID/JSC Guide to Clinical Management of Infectious Diseases 2011, FMOX
LVRQHRIWKH¿UVWOLQHDJHQWIRUWKHWUHDWPHQWRIVHYHULQIHFWLRQVVXFKDVXULQDU\WUDFWLQIHFWLRQV31).
$OWKRXJKTXLQRORQHVVXFKDVFLSURÀR[DFLQ &3); LVWKH¿UVWOLQHDJHQWIRUWKHWUHDWPHQWRIPLOG
RUPRGHUDWHFDVHVRIEODGGHULQÀDPPDWLRQDQGS\HORQHSKULWLVWKHUHVLVWDQFHDJDLQVWTXLRQRORQHV
has been increased among ESBL producing strains in the case of urinary tract infections, FMOX
could be another option for the treatment of mild or moderate cases to treat promptly and prevent
VHYHU LQIHFWLRQV 7KH HI¿FDF\ RI )02; WR SUHYHQW WKH LQIHFWLRQV IROORZLQJ VXUJLFDO SURFHGXUH
has been reported32–35). Although these report did not verify whether ESBL producing strains
were included in these cases or not, Monte Carlo Simulation in the present study showed the clinLFDO HI¿FDF\ RI )02; DJDLQVW (6%/ SURGXFLQJ VWUDLQV ZKLFK LQGLFDWHG WKH HIIHFWLYHQHVV RI
FMOX to prevent the ESBL-associated infections.

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7KLVVWXG\LQYHVWLJDWHGWKHHI¿FDF\RI)02;DJDLQVWWKH(6%/DVVRFLDWHGLQIHFWLRQVFDXVHG
by Enterobacteriaceae including E. coli and K. pneumoniae by using Monte Carlo Simulation.
FMOX showed bacteriostatic activity against ESBL producing strains by the regimens of 1 g
TKZLWKWRKRXUVLQIXVLRQZKLFKLQGLFDWHGSRWHQWHI¿FDF\IRUWKHWUHDWPHQWRIWKHLQIHFtions of competent patients. Moreover, FMOX showed bactericidal activity against ESBL producing strains with the regimens of 1 g q8h with 2 to 4 hours infusion and 1 g q6h with 1 to 4 hours
LQIXVLRQZKLFKLQGLFDWHGSRWHQWHI¿FDF\IRUWKHWUHDWPHQWRIWKHLQIHFWLRQVRIWKHFRPSURPLVHG
patients. These regimens are approved regimens of FMOX in Japan, which indicated that FMOX
can be used for the treatment of the ESBL-associated infections as well as for the prevention ofsevere infections following surgical procedure.
$FNQRZOHGJHPHQWThe authors thank I. HIGASHIYAMA for conducting experiments, technical assistance, and discussion.

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