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109（ 37 ）Potent antibacterial activities of latamoxef(moxalactam) against ESBL producing
Enterobacteriaceae analyzed
by Monte Carlo simulation
AKINOBU ITO1, YUMIKO TATSUMI (MATSUO)2, TOSHIHIRO WAJIMA2,RIO NAKAMURA1 and MASAKATSU TSUJI1
1

Medicinal Research Laboratories, Shionogi & Co., Ltd.
2
Clinical Research Department, Shionogi & Co., Ltd.
(Received for publication January 21, 2014)

Latamoxef (LMOX, Moxalactam) is one of the ȕ-lactam antibiotics which is stableagainst ȕ-lactamase. In this study, the antibacterial activity of LMOX wasinvestigated, and Monte Carlo simulation was conducted to determine theappropriate dosing regimens of LMOX against extended-spectrum ȕ-lactamase(ESBL) producing Enterobacteriaceae. The probability of target attainment (PTA)
was analyzed at 40% and 70% of time above minimum inhibitory concentration(MIC) (time above MIC, T＞MIC) for bacteriostatic and bactericidal effectrespectively. All the tested regimens achieved 85% of PTA at 40% of T＞MIC against
ESBL producing Escherichia coli, and all the tested regimens except 1g q12h with 1hour infusion achieved 85% of PTA at 40% of T＞MIC against ESBL producing
Klebsiella pneumoniae. The effective regimens to achieve 85% of PTA at 70% of
T＞MIC against E. coli were 1g q12h with 4 hours infusion, 1g q8h with 1–4 hours
infusion, 2g q12h with 2–4 hours infusion, and 1g q6h with 1–4 hours infusion. The
effective regimens to achieve 85% of PTA at 70% of T＞MIC against K. pneumoniae
were 1g q8h with 3–4 hours infusion and 1g q6h with 1–4 hours infusion. These
results of pharmacokinetics/pharmacodynamics (PK/PD) modeling showed theSRWHQW HI¿FDF\ RI /02; DJDLQVW EDFWHULDO LQIHFWLRQV FDXVHG E\ (6%/ SURGXFLQJ
Enterobacteriaceae.

Introduction
Extended-spectrum ȕ-lactamase (ESBL) is spreading among Enterobacteriaceae. Associatedinfections include urinary tract infections, bloodstream infections, and intra-abdominal infections.
The rates of ESBL expression among nosocomial Enterobacteriaceae isolates, particularly110（ 38 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Klebsiella pneumoniae, have risen substantially in several countries1〜3). In a recent study basedon the Tigecycline Evaluation and Surveillance Trial (TEST) global surveillance database, therate of ESBL production among the K. pneumoniae and the Escherichia coli isolates collected in
Latin America were 44.0% and 13.5%, respectively4).
Available therapeutic options for the treatment of ESBL associated infections are limited bydrug resistance conferred by the ESBL5). 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 resistance6, 7).
Pharmacokinetics/pharmacodynamics (PK/PD) has been investigated to maximize clinicalresponse and to minimize the emergence of antibiotic resistance and exposure-related toxicities8〜10). For cephalosporin antibiotics, the time above minimum inhibitory concentration (MIC)(time above MIC, T＞MIC) is the target that best relates to patient outcomes8, 9). Although T＞MIC is
decided by PK of the antibiotics and MIC against the bacteria, both of them are variable amongcases, 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 treatment11〜15). With the Monte Carlo simulation, distribution of PK and MIC are processed to obtaina set of virtual population, and the various regimens are applied to the set of virtual population to
calculate the probability of target attainment (PTA) at T＞MIC. This simulation can predict the outcome of various dosage and administration schedule, which helps us to choose the appropriate
regimens for the treatment.
Latamoxef (LMOX, Moxalactam) is one of the cephamycins, characterized by its 7-alphamethoxy, and also called 1-oxa-ȕ-lactam antibiotic which is different structurally from the cephalosporins and other cephamycins, in which sulfur atom in the cephem nucleus is substituted withoxygen atom16, 17). 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 cephalosporinresistant strains. Although LMOX has a potential to be effective against ȕ-lactamase producing
VWUDLQVWKHUHLVOLWWOHLQIRUPDWLRQIRUSUHGLFWLRQRIHI¿FDF\DJDLQVW(6%/SURGXFLQJ(QWHUREDFWHriaceae in the current clinical use. Therefore, it is important to understand the characteristics of
LMOX with PK/PD analysis as well as in vitro antibacterial activities against emerging ESBL
such as variants of SHV, TEM, and CTX-M families. The objective of this study was to investigate the potency of LMOX for the treatment of the infection caused by ESBL producing Enterobacteriaceae in the clinical use by in vitro activities and Monte Carlo simulation.

I. Materials and Methods
1. Bacterial strains
The clinical isolates used in this study were isolates collected from all over the world from

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111（ 39 ）2001 to 2009, isolates collected from various medical facilities in Japan from 1992 to 2002, andATCC strains. They include various variants of SHV, TEM, and CTX-M families.
2. MIC determination
The antimicrobial susceptibility testing was performed according to Clinical and Laboratory
Standards Institute (CLSI) standards M07-A8 for the micro-broth dilution method18)%ULHÀ\×104 CFU/well was inoculated in cation-adjusted Mueller Hinton Broth containing drugs, and incubated at 35°&IRUWRKRXUV7KH0,&ZDVGH¿QHGDVWKHORZHVWFRQFHQWUDWLRQRIGUXJWKDW
completely inhibited bacterial growth as detected by the unaided eye.
3. Antibacterial agents
Susceptibilities of the bacterial strains were tested for the following antimicrobial agents:
ODWDPR[HI /02;0R[DODFWDP ÀRPR[HI )02; FHIHSLPH &)30 DQGWD]REDFWDPSLSHUacillin (piperacillin with 4 ȝg/mL of tazobactam, TAZ/PIPC). Clavulanic acid (CVA) was used as
ȕ-lactamase inhibitor with 4 ȝg/mL.
4. Monte Carlo simulation
Monte Carlo simulation was employed to investigate the probability of target attainment(PTA) against the clinical isolates of ESBL producing E. coli and K. pneumoniae by using thesimulation software Crystal Ball® 7 (KOZO KEIKAKU ENGINEERING Inc., Japan). Virtual
populations of 5,000 patients were generated for each dosage regimen against each bacterial
strain. Pharmacokinetic parameters of LMOX (2 g over 2 hours infusion) were taken from thePhase 1 study in Japan19). Pharmacokinetic parameters of LMOX for typical values of 2-compartment model were as follows: Vc＝6.50 L, k10＝0.72 hr−1, k12＝0.76 hr−1, and k21＝1.33 hr−1. A
log-normal distribution was arbitrarily assumed for the inter-individual variability for pharmacoNLQHWLFSDUDPHWHUVZLWKRIFRHI¿FLHQWRIYDULDWLRQDVDFRQVHUYDWLYHYDOXH,WZDVDVVXPHG
that free plasma concentrations of LMOX would correlate with the bactericidal effect, and freedrug concentrations were used for the simulation based on a plasma protein binding ratio of
60%20, 21). MIC values were generated from the discrete MIC distributions obtained from 50 isolates of ESBL producing E. coli and 28 isolates of ESBL producing K. pneumoniae. The regimens used for the simulation were 1 g every 6, 8, or 12 hours (q6h, q8h, or q12h respectively)
with 1–4 hours infusion, which corresponded to 4, 3, and 2 g/day respectively, and 2g q12h with
1–4 hours infusion which corresponded to 4 g/day. The PTA was calculated based on the simulated plasma concentrations at 1-minute interval by using two-compartment model. The PTA atvarious T＞MIC was calculated by using 5,000 virtual patients for each dosing regimen against
each bacteria strain.

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II. Results
1. Antimicrobial activities of latamoxef against clinical isolates of ESBL producing
Enterobacteriaceae
Table 1 shows MIC of LMOX against clinical isolates of ESBL producing Enterobacteriaceae such as E. coli, K. pneumoniae, Enterobacter cloacae, Citrobacter freundii, Serratia
marcescens, and Indole-positive Proteus spp. collected from all over the world. MIC90 of CFPM
and TAZ/PIPC against ESBL non-producing bacteria were 2–8 ȝg/mL and 0.06–1 ȝg/mL, respectively, and MIC90 of CFPM and TAZ/PIPC against ESBL producing bacteria were 8–＞64 and
16 – ＞ 256 ȝg/mL, respectively. MIC90 of LMOX against ESBL non-producing and ESBL
producing bacteria were 0.12–0.5 and 1–32 ȝg/mL, respectively, which indicated potent antimicrobial activities of LMOX against ESBL producing strains. When LMOX were supplemented
with 4 ȝg/mL of CVA, MIC90 of LMOX against ESBL non-producing and ESBL producing bacteria were 0.12–0.5 and 1–16 ȝg/mL, respectively, which were similar with those without CVA.
These results indicated that LMOX was stable against ESBL.
Among the tested isolates, there were three isolates showing higher MIC of LMOX such as
E. cloacae 920, E. cloacae 2144, and K. pneumoniae 13731, which possesses SHV-12, SHV-30,
and SHV-5, respectively. MICs of LMOX against these isolates were 32, 128, and 32 ȝg/mL, respectively. MIC ranges of LMOX against the isolates producing SHV-12, SHV-30, and SHV-5
except these isolates were 0.12–1, 0.12–8, and 0.25–4 ȝg/mL, respectively. These results demonstrated that even though there were some isolates whose MICs of LMOX were high, LMOX waspotent against most of the isolates producing SHV-12, SHV-30, and SHV-5. Moreover, MIC
distribution of LMOX against E. cloacae and K. pneumoniae other than these three resistantisolates were 0.25–8 and 0.12–8 ȝg/mL, respectively, which showed potent activity of LMOX
against most of the clinical isolates of these species.
2. Frequency distribution of MIC of LMOX against clinical isolates of ESBL producing Enterobacteriaceae
Table 2 shows frequency distribution of MIC of LMOX against ESBL producing E. coli andK. pneumoniae which are same isolates on Table 1. MICs of CFPM and TAZ/PIPC against themost of the isolates of E. coli were more than 32 and 8 ȝg/mL, respectively, and MICs of CFPM
and TAZ/PIPC against the most of the isolates of K. pneumoniae were more than 8 and 16 ȝg/mL,
respectively. On the other hand, MICs of LMOX and LMOX supplemented with CVA against themost of the isolates of E. coli were less than 0.5 and 0.25 ȝg/mL, respectively, and MICs of
LMOX and LMOX supplemented with CVA against the most of the isolates of K. pneumoniae
were less than 0.5 and 0.25 ȝg/mL. These results indicated that LMOX had a potent in vitro activity against ESBL producing E. coli and K. pneumoniae that were resistant to CFPM and TAZ/PIPC.

LMOX: latamoxef (moxalactam), CVA: clavulanic acid, CFPM: cefepime, TAZ/PIPC: tazobactam/piperacillin.
CVA and TAZ were added with 4 ȝg/mL.

Table 1. In vitro activities against ESBL producing Enterobacteriaceae

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Table 2. Frequency distribution of MIC against ȕ-lactamase producing E. coli and K.
pneumoniae
LMOX: latamoxef (moxalactam), CVA: clavulanic acid, CFPM: cefepime, TAZ/PIPC:
tazobactam/piperacillin. CVA and TAZ were added with 4 ȝg/mL. *: MICs of CFPM
against these isolates were ＞64 ȝg/mL.

3. Effect of CVA on susceptibility of ESBL producing Enterobacteriaceae
Table 3 shows MICs of LMOX, CFPM, TAZ/PIPC, and FMOX against ESBL producing
Enterobacteriaceae such as E. coli, K. pneumoniae, K. oxytoca, and P. mirabilis collected fromvarious medical facilities in Japan and ATCC. These isolates possess various types of ESBL suchas variants of SHV, TEM, and CTX-M families. MIC90 of LMOX against these isolates was 2 ȝg/mL, and MIC90 of LMOX supplemented with 4 ȝg/mL of CVA was 1 ȝg/mL. These results
demonstrated that the in vitro activities of LMOX with the ȕ-lactamase inhibitor against ESBL
producing Enterobacteriaceae were similar with those without the ȕ-lactamase inhibitor, whichindicated that LMOX were stable against ESBL. Among these three types of ESBL, MICs of
LMOX with the ȕ-lactamase inhibitor against variants of SHV and TEM families were 2–8 times
lower than those without the ȕ-lactamase inhibitor, and MICs of LMOX with the ȕ-lactamase inhibitor against variants of CTX-M families were almost same with those without the ȕ-lactamase
inhibitor. These results indicated that LMOX were stable especially against variants of CTX-M
families.
MIC90 of CFPM against these isolates was ＞64 ȝg/mL, and MIC90 of CFPM supplemented
with 4 ȝg/mL of CVA was 0.25 ȝg/mL. These results showed that the in vitro activities of CFPM
against ESBL were dramatically increased by addition of the ȕ-lactamase inhibitor. MICs of
CFPM against most of the isolates possessing variants of SHV family were less than 8 ȝg/mL except isolates whose MICs of CFPM were 16 ȝg/mL and 64 ȝg/mL, and MICs of CFPM against allof the isolates possessing variants of TEM family were less than 8 ȝg/mL. On the other hand,
MICs of CFPM against 11 out of 18 isolates harboring variants of CTX-M family was ＞64 ȝg/
mL. When CFPM was supplemented with CVA, MICs against all of the isolates were less than

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115（ 43 ）Table 3. MIC against Enterobacteriaceae producing various types of ȕ-lactamase
LMOX: latamoxef (moxalactam), CFPM: cefepime, TAZ/PIPC: tazobactam/
SLSHUDFLOOLQ)02;ÀRPR[HI&9$FODYXODQLFDFLG
CVA and TAZ were added with 4 ȝg/mL.

2 ȝJP/DQGWKHUHZDVQRVLJQL¿FDQWGLIIHUHQFHDPRQJ0,&RI&)30VXSSOHPHQWHGZLWK&9$
against these three types of ESBL such as SHV, TEM, and CTX-M families. These results demonstrated that CFPM was less stable against variants of CTX-M family than that against variantsof SHV and TEM families.
4. Probabilities of target attainment against clinical isolates of ESBL producing E. coli
and K. pneumoniae
Figures 1 and 2 show probability of target attainment (PTA) at different time above MIC

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Apr. 2014(T＞MIC) in various regimens of LMOX against ESBL producing E. coli and K. pneumoniae, respectively. In the case of E. coli, all the tested regimens achieved 85% of PTA at 40% of T＞MIC(Figure 1 (a) and (b)). The effective regimens of 2- to 3-g dose/day to achieve 85% of PTA at
70% of T＞MIC were 1g q12h with 4 hours infusion and 1g q8h with 1 to 4 hours infusion (Figure
1 (a)). When the regimen was increased to 4-g dose/day, the effective regimens to achieve 85% of
PTA at 70% of T＞MIC were 2g q12h with 2 to 4 hours infusion and 1g q6h with 1 to 4 hours infusion (Figure 1 (b)).
In the case of K. pneumoniae, all the tested regimens except 1g q12h with 1 hour infusion
achieved 85% of PTA at 40% of T＞MIC (Figure 2 (a) and (b)). The effective regimens of 2- to 3-gdose/day to achieve 85% of PTA at 70% of T＞MIC were 1g q8h with 3 to 4 hours infusion (Figure
2 (a)). When the regimen was increased to 4-g dose/day, the effective regimens to achieve 85% of
PTA at 70% of T＞MIC were 1g q6h with 1 to 4 hours infusion (Figure 2 (b)).

III. Discussion,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, PK parameter obtained in Phase 1 studies in Japan were used, and the
PTA at T＞MIC＝40% and T＞MIC＝70% were determined for bacteriostatic and bactericidal activity, respectively, according to CRAIG8, 9) 2XU VWXG\ KDG WKUHH PDMRU ¿QGLQJV )LUVW /02; KDGpotent in vitro activities against ESBL producing Enterobacteriaceae. Second, LMOX was stableagainst clinical isolates producing ESBL such as variants of SHV, TEM, and CTX-M families.
Third, pharmacokinetics/pharmacodynamics (PK/PD) modeling by Monte Carlo simulation
VKRZHG WKH SRWHQW HI¿FDF\ RI /02; DJDLQVW EDFWHULDO LQIHFWLRQV FDXVHG E\ E. coli and K.
pneumoniae producing ESBL such as variants of SHV, TEM, and CTX-M families.
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. Currently, carbapenems are regarded as the drug of choice for infections caused
by ESBL producing pathogens22〜24). However, there are many hospitals to limit the use of
carbapenems, and the increase of resistance against quinolones by ESBL producing strains has
been reported25). Therefore, there are increasing demands for effective antimicrobial agents otherthan carbapenems or quinolones to treat the ESBL associated infections.
SADER, et al. reported the susceptibility of ESBL producing E. coli and Klebsiella spp. to
CFPM and TAZ/PIPC according to CLSI susceptible breakpoints26). The report demonstrated that
CFPM and TAZ/PIPC were not active against many of the isolates of ESBL producing E. coli andKlebsiella spp. YOSHIDA, et al. reported the increase of ESBL producing strains in Japan27〜30).
LMOX has maintained potent antibacterial activity against ESBL producing strains even thoughApr. 2014

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117（ 45 ）Fig. 1(a). Probability of target attainment of 2 or 3 g (1g q12h or 1g q8h, respectively) of
latamoxef at different free drug T＞MIC targets against ESBL producing E. coli

Fig. 1(b). Probability of target attainment of 4 g (1g q6h or 2g q12h) of latamoxef at different
free drug T＞MIC targets against ESBL producing E. coli

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Fig. 2(a). Probability of target attainment of 2 or 3 g (1g q12h or 1g q8h, respectively) of
latamoxef at different free drug T＞MIC targets against ESBL producing K. pneumoniae

Fig. 2(b). Probability of target attainment of 4 g (1g q6h or 2g q12h) of latamoxef at different
free drug T＞MIC targets against ESBL producing K. pneumoniae

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119（ 47 ）the rate of ESBL producing strains have increased among E. coli, K. pneumoniae, and K. oxytoca.
In the present study, MIC90 of LMOX against E. coli, and K. pneumoniae used in Monte Carlosimulation were 2 ȝg/mL and 8 ȝg/mL, respectively. MIC90 of LMOX against 11 isolates of E.
coli and 15 isolates of Klebsiella spp. were 2 ȝg/mL. Even though MIC90 of LMOX were higher
than those reported by YOSHIDA, et al.WKHGLIIHUHQFHVZHUHQRWVLJQL¿FDQWDQGZHUHVHHPHGWREH
appropriate for the analysis. Moreover, LMOX was reported to show a potent antibacterial activity against CTX-M-15 producing strains where MICs of LMOX were 2–4 ȝg/mL30).
In the present study, MIC90 of LMOX against E. cloacae was relatively higher than thoseagainst other bacteria. One of the reasons could be that the number of ESBL producing E. cloacae used in this study was small, and existence of two resistant isolates increased MIC90VLJQL¿cantly. MIC distribution other than 2 resistant isolates was 0.25–8 ȝg/mL which was comparable
to that of K. pneumoniae whose MIC distribution was 0.12–32 ȝg/mL, indicating potent activityof LMOX against most of the clinical isolates in both species. According to the results of Monte
Carlo simulation with K. pneumoniae which most of the clinical isolates showed MIC侑8 ȝg/mL,
LMOX was effective with all the tested regimens except 1g q12h with 1 hour infusion based on
40% of T＞MIC target, and LMOX was effective with 1g q8h with 3 to 4 hours infusion and 1g q6hwith 1 to 4 hours infusion based on 70% of T＞MIC target. Because MIC distribution of E. cloacae
other than 2 resistant isolates was similar to that of K. pneumoniae, LMOX should be effective
against E. cloacae by same regimens with those against K. pneumoniae. Moreover, because mostof the ESBL producing isolates were E. coli and K. pneumoniae2, 31), the results revealed by
0RQWH &DUOR VLPXODWLRQ LV LPSRUWDQW ¿QGLQJV ZKLFK VKRZHG WKDW /02; LV HIIHFWLYH DJDLQVW
ESBL producing E. coli and K. pneumoniae with dosing regimens currently approved and available in Japan.
There were a few PK/PD studies of CFPM and TAZ/PIPC against ESBL producing E. coli
and K. pneumoniae. AMBROSE, et al. demonstrated that the probability for attaining PK/PD target
measures with 30 to 40% T＞MIC against ESBL producing E. coli exceeded 0.86 by the regimen of
3.375 g of TAZ/PIPC i.v. every 4 or 6 hours, and the probability of meeting PK/PD targets with50 to 60% T＞MIC for CFPM was equal to or higher than that with TAZ/PIPC, which was an
acceptable probability of the target attainment32). However, most of the isolates used for the pharmacodynamic models reported by AMBROSE, et al. were susceptible to CFPM and TAZ/PIPC,
which was not consistent with the report by SADER, et al.26). REESE, et al. also reported the PTA of
TAZ/PIPC and CFPM against ESBL producing isolates33). They demonstrated that the TAZ/PIPC
achieved 43% of the PTA with the regimen of 3.375 g every 4 h, and CFPM achieved 77% of the
PTA with 4 g of continuous infusion. REESE, et al. concluded that neither TAZ/PIPC nor CFPM
achieved a high PTA and should not be used routinely for the treatment of ESBL infections.
7KH SUHVHQW VWXG\ LV WKH ¿UVW UHSRUW WR HYDOXDWH WKH SKDUPDFRG\QDPLFV RI /02; DJDLQVW
ESBL producing E. coli and K. pneumoniae7KH3.3'¿QGLQJVDVSUHVHQWHGLQWKLVVWXG\PD\120（ 48 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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facilitate customized dosing to optimize the PD behavior of LMOX. The simulations in the present study demonstrated that LMOX achieved a high likelihood of bactericidal activity against
ESBL producing Enterobacteriaceae including E. coli and K. pneumoniae with currently available dosing regimen approved and available in Japan. Therefore, LMOX could be an alternative
to carbapenems for the treatment of patients with ESBL producing Enterobacteriaceae.
Acknowledgement
The authors thank I. HIGASHIYAMA for conducting experiments, technical assistance, anddiscussion.

References
1） FALAGAS, M. E. & D. E. KARAGEORGOPOULOS: Extended-spectrum ȕ-lactamase-producing organisms. J. Hosp. Infect. 73: 345〜354, 2009
2） PITOUT, J. D. D. & K. B. LAUPLAND: Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging public-health concern. Lancet Infect. Dis. 8: 159〜166, 2008
3） CANTÓN, R. & T. M. COQUE: The CTX-M beta-lactamase pandemic. Curr. Opin. Microbiol. 9:466〜475, 2006
4） REINERT, R. R.; D. E. LOW, F. ROSSI, et al.: Antimicrobial susceptibility among organisms from the$VLD3DFL¿F5LP(XURSHDQG/DWLQDQG1RUWK$PHULFDFROOHFWHGDVSDUWRI7(67DQGWKHin vitro
activity of tigecycline. J. Antimicrob. Chemother. 60: 1018〜1029, 2007
5） TALBOT, G. H.; J. BRADLEY, J. E. EDWARDS JR., et al.: Bad bugs need drugs: An update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Societyof America. Clin. Infect. Dis. 42: 657〜668, 2006
6） NICOLAU, D. P.: Pharmacodynamic optimization of beta-lactams in the patient care setting. Crit.
Care 12 (Sppl. 4): S2, 2008
7） SAMTANI, M. N.; R. FLAMM, K. KANIGA, et al.: Pharmacokinetic-pharmacodynamic-model-guided
doripenem dosing in critically ill patients. Antimicrob. Agents Chemother. 54: 2360〜2364, 20108） CRAIG, W. A.: Pharmacokinetic/pharmacodynamic parameters: Rationale for antibacterial dosingof mice and men. Clin. Infect. Dis. 26: 1〜12, 1998
9） CRAIG, W. A.: Dose the dose matter? Clin. Infect. Dis. 33: 233〜237, 2001
10） DRUSANO, G. L.: Antimicrobial pharmacodynamics: critical interactions of “bug and drug”. Nat.
Rev. Microbiol. 2: 289〜300, 2004
11） KUTI, J. L.; C. H. NIGHTINGALE & D. P. NICOLAU: Optimizing pharmacodynamic target attainment
using the MYSTIC antibiogram: data collected in North America in 2002. Antimicrob. Agents
Chemother. 48: 2464〜2470, 2004
12） KUTI, J. L.; P. D. DANDEKAR & C. H. NIGHTINGALE: Use of Monte Carlo Simulation to design an
optimized pharmacodynamic dosing strategy for meropenem. J. Clin. Pharmacol. 43: 1116〜1123,
200313） LOMAESTRO, B. M. & G. L. DRUSANO: Pharmacodynamic evaluation of extending the administration time of meropenem using Monte Carlo Simulation pharmacodynamic. Antimicrob. Agents
Chemother. 49: 461〜463, 200514） SUN, H. K.; J. L. KUTI & D. P. NICOLAU: Pharmacodynamics of antimicrobial for the empiricalApr. 2014

THE JAPANESE JOURNAL OF ANTIBIOTICS

67―2

121（ 49 ）treatment of nosocomial pneumonia: A report from the OPTAMA program. Crit. Care Med. 33:
2222〜2227, 2005
15） KRUEGER, W. A.; J. BULITA, M. KINZIG-SCHIPPERS, et al.: Evaluation by Monte Carlo Simulation of
the pharmacokinetics of two doses of meropenem administered intermittently or as a continuous
infusion in healthy volunteers. Antimicrob. Agents Chemother. 49: 2464〜2476, 200516） NARISADA, M.; T. YOSHIDA, H. ONOUE, et al.: Synthetic studies on beta-lactam antibiotics. Part 10.
Synthesis of 7beta-[2-carboxy-2-(4-hydroxyphenyl)acetamido]-7-alpha-methoxy-3-[[1methyl-1H-tetrazol-5-yl)thio]-methyl]-1-oxa-1-dethia-3-cephem-4-carboxylic acid disodium salt
(6059-S) and its related 1-oxacephems. J. Med. Chem. 22: 757〜759, 197917） GOTO, S.: In vitro & in vivo antibacterial activity of moxalactam, an oxa-beta-lactam antibiotic.
Rev. Infect. Dis. 4: S501〜S510, 1982
18） Clinical & Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests
for bacteria that grow aerobically: Approved standard-eighth edition (M07-A8). Wayne, CLSI,
200919） YAMADA, H.; T. YOSHIDA, T. OGUMA, et al.: Clinical pharmacology of 6059-S in healthy volunteers.
Jpn. J. Chemother. 28(S-7): 251〜262, 1980
20） YOSHIDA, T.; S. MATSUURA, M. MAYAMA, et al.: Moxalactam (6059-S), a novel 1-oxa-ȕ-lactam withan expanded antibacterial spectrum: Laboratory evaluation. Antimicrob. Agents Chemother. 17:
302〜312, 1980
21） YOSHIDA, T.; Y. KIMURA & Y. TOCHINO: Pharmacokinetics of 6059-S in experimental animals. Jpn.
J. Chemother. 28(S-7): 194〜206, 1980
22） PATERSON, D. L. & R. A. BONOMO: Extended-spectrum beta-lactamase: A clinical update. Clin. Microbiol. Rev. 18: 657〜686, 200523） PATERSON, D. L.; W. C. KO, A. VON GOTTBERG, et al.: Antibiotic therapy for Klebsiella pneumoniae
bacteremia: Implications of production of extended-spectrum ȕ-lactamases. Clin. Infect. Dis. 39:
31〜37, 2004
24） PATERSON, D. L; W. C. CO, A. BON GOTTBERG, et al.: International prospective study of Klebsiellapneumoniae bacteremia: implications of extended-spectrum beta-lactamase production in nosocomial infections. Ann. Intern. Med. 140: 26〜32, 2004
25） NAKAMURA, T.; C. SHIMIZU, M. KASAHARA, et al.0RQWH&DUORVLPXODWLRQIRUHYDOXDWLRQRIWKHHI¿cacy of carbapenems and new quinolones against ESBL-producing Escherichia coli. J. Infect.
Chemother. 15: 13〜17, 200926） SADER, H. S.; A. HSIUNG, T. R. FRITSCHE, et al.: Comparative activities of cefepime and piperacillin/tazobactam tested against a global collection of Escherichia coli and Klebsiella spp. with an
ESBL phenotype. Diagn. Microbiol. Infect. Dis. 57: 341〜344, 200727） YOSHIDA, I.; T. FUJIMURA, Y. JINUSHI, et al.: Antimicrobial susceptibility of clinical isolates of aerobic Gram-negative bacteria in 2002. Jpn. J. Chemother. 54: 355〜377, 2006
28） YOSHIDA, I.; T. FUJIMURA, T. ITOH, et al.: Antimicrobial susceptibility of clinical isolates of aerobic
Gram-negative bacteria in 2004. Jpn. J. Chemother. 56: 562〜579, 2008
29） YOSHIDA, I.; T. YAMAGUCHI, Y. ITOH, et al.: Antimicrobial susceptibility of clinical isolates of aerobic Gram-negative bacteria in 2006. Jpn. J. Antibiotics 63: 457〜479, 201030） YOSHIDA, I.; T. YAMAGUCHI, R. KUDO, et al.: Antimicrobial susceptibility of clinical isolates of aerobic Gram-negative bacteria in 2008. Jpn. J. Antibiotics 65: 73〜96, 201231） PITOUT, J. D. D.; P. NORDMANN, K. B. LAUPLAND, et al.: Emergence of enterobacteriaceae producing extended-spectrum beta-lactamases (ESBLs) in the community. J. Antimicrob. Chemother. 56:

122（ 50 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

67―2

Apr. 201452〜59, 2005
32） AMBROSE, P. G.; S. M. BHAVNANI & R. N. JONSE: Pharmacokinetics-pharmacodynamics of cefepime and piperacillin-tazobactam against Escherichia coli and Klebsiella pneumoniae strains
producing extended-spectrum beta-lactamases: Report from the ARREST program. Antimicrob.
Agents Chemother. 47: 1643〜1646, 2003
33） REESE, A. M.; C. R. FREI & D. S. BURGESS: Pharmacodynamics of intermittent and continous infusion piperacillin-tazobactam and cefepime against extended-spectrum beta-lactamase-producing
organisms. Int. J. Antimicrob. Agents 26: 114〜119, 2005