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69―5319（ 19 ）Clinical experience with colistin in 9 Japanese patientswith infection due to multi-drug resistance pathogens
YUKIHIRO HAMADA1,2, JUN HIRAI1,3, HIROYUKI SUEMATSU1,YUKA YAMAGISHI1,3, DAVID P. NICOLAU2 and HIROSHIGE MIKAMO1,3
1Department of Infection Control and Prevention,
Aichi Medical University Hospital
2
Center for Anti-infective Research and Development, Hartford Hospital
3Department of Clinical Infectious Diseases, Aichi Medical University Hospital(Received for publication August 22, 2016)

Colistin is a polypeptide antibiotic of the polymyxin family (polymyxin E) which
has been reported to be active against many multidrug-resistant (MDR) Gramnegative aerobic bacteria collected across the globe. While this agent was not
currently licensed in Japan, the emergence of MDR organisms has necessitated its
off-label used in the country. However, colistin was approved in March, 2015. This
retrospective observational report includes nine patients with MDR Gram-negative
infections due to Pseudomonas aeruginosa (n＝6) and Klebsiella spp. (n＝3) who
received intravenous colistin therapy as part of their antimicrobial regimen. The
median age and duration of administration were 40 years (range 7-90) and 8 days
(range 1-19). Clinical success was observed in all eight patients for whom efﬁcacy
could be evaluated. Two patients encountered colistin related adverse effects 22.2%(2/9). In both cases the nephrotoxicity and dysgeusia resolved after discontinuationof colistin therapy. In vitro studies conducted with these clinical isolates of P.
aeruginosa displayed synergy with the combination of colistin plus ceftazidime,rifampicin, meropenem or aztreonam. This report provides early evidence thatcolistin is generally safe, effective and demonstrates in vitro synergy when used in
combination for the management of MDR Gram-negative pathogens derived fromJapanese patients.

Introduction
Colistin is a polypeptide antibiotic of the polymyxin family (polymyxin E) which is active
against most Gram-negative aerobic bacteria, including those displaying resistance to other parenteral antibiotics used in the hospital setting. As a result of emerging resistance in Gram-nega-320（ 20 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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tive bacteria and the lack of new medicinal entities, previously discovered agents like colistin arebeing increasingly utilized for the management of infection due to multi-drug resistant (MDR)
pathogens. While colistin has demonstrated in vitro potency against organisms displaying theMDR phenotype (i.e., resistance to three classes of antibiotics), the adverse event proﬁle, notably
nephrotoxicity and neurotoxicity, has limited the widespread general use of this agent. Moreover,the lack of a full understanding of how best to optimize the pharmacodynamic and minimize thetoxicodynamic proﬁles of this agent has also tempered the use of colistin in all but the sickest patient populations who have previous failed conventional therapeutic approaches1).

Patients and Methods
Prior to the initiation of the study, the methodology was reviewed and approved by the ethical committee of Aichi Medical University (approval number 11-055). A retrospective review wasperformed on all patients at Aichi Medical University Hospital who received intravenous colistin
for the treatment of resistant Gram-negative bacteria from November 2011 to April 2013. All patients provided written informed consent before inclusion in the study.
During this study period, colistin was prescribed as colistimethate for injection (Coly-Mycin®,each vial of colistimethate for injection contains 150 mg), which is a pro-drug that is hydrolyzed
in vivo to the active form, colistin. The dosing of colistin in these patients was based on the practical guide for appropriate use of colistin in Japan2). This guidance corresponded with package
insert recommendations for both the mg/kg dosing and renal function adjustments.
Microbiological susceptibility assessments were performed using a microdilution methodon the RAISUS system (Rapid Analyzer for Identiﬁcation and Susceptibility test system, Nissui
Pharmaceutical, Tokyo, Japan). The antibacterial activities of colistin, piperacillin, rifampicin,
ceftazidime, aztreonam, meropenem, amikacin and ciproﬂoxacin were examined alone or in combination. Susceptibility testing and interpretation followed the recommendations of the CLSI3).
If the organism was determined to be MDR by RAISUS, additional checkerboard studies wereundertaken using a commercially available “Break-point Checkerboard Plate” (Eiken Chemical,Tokyo, Japan)4).

Results
The evaluation of effectiveness in this study was based on the clinical outcome of the patient.
Over the study period, a total of 9 patients (including two children) were administered colistin

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69―5321（ 21 ）owing to infection with MDR Gram-negative bacteria after informed consent had been obtained.
When adverse events appeared the time course of the event, severity and potential relationshipwith colistin therapy were investigated. Nephrotoxicity was deﬁned as a serum creatinine level of＞0.5 mg/dL or ＞50% more than the value at study entry.

The demographics of the patient population are displayed in Table 1. This population included seven adults and two children with the primary infection source identiﬁed as the lung (n＝3),
blood (n＝3), urinary tract (n＝2), bile and soft tissue (n＝1). The infecting MDR pathogens werePseudomonas aeruginosa (n＝6) including one metallo-beta-lactamase producer, Klebsiella pneumoniae (n＝2) and one isolate of Klebsiella oxytoca. Colistin was administered for an average of
8.8 days (range 1-19) in combination with beta-lactam therapy as noted in the Table 1. MIC rangeof colistin was 0.125-2 mg/L. As deﬁned by dosing guidelines the patients with normal renal function received 2.5 mg/kg in two divided doses daily, while dose adjustments were made for thosewith reductions in creatinine clearance.2)
Clinical success was observed in all eight patients for whom efﬁcacy could be evaluated.
Since the fourth patient only received one day of colistin therapy prior to his death which was attributed to pneumonia, an assessment of colistin efﬁcacy for MDR infection in this patient was
not possible. After the successful clinical response to infection, a eighth patient was also noted toexpire due to acute lymphocytic leukemia.
Two patient encountered colistin related adverse effects 22.2% (2/9). In the patient with burnrelated injuries withdrawal of colistin was deemed necessary on day 4 of therapy due to elevations of serum creatinine to 2.70 mg/dL and blood urea nitrogen (BUN) to 23.4 mg/dL as noted inFigure 1A. Once colistin was discontinued the patientʼs renal function returned to normal in threedays. The other patient experienced dysgeusia which presented 2 days after colistin therapy wasinitiated and resolved after colistin was stopped (Fig. 1B).
In addition to the clinical outcomes, the synergistic potential of combination therapy wasalso assessed in the present study for the pseudomonal isolates. Despite the MDR proﬁle of theP. aeruginosa isolated from these patients, sufﬁciently high degrees of synergy were observedwith colistin when combined with ceftazidime, rifampicin, meropenem or aztreonam (Fig. 2).

Discussion
Recently, a few case reports have provided data regarding the efﬁcacy of colistin against
MDR P. aeruginosa originating from Japanese patients5,6). Since intravenous colistin is not approved for use in Japan, combination therapy is mandated when this agent is utilized. It is forTHE JAPANESE JOURNAL OF ANTIBIOTICSMDR: multidrug-resistant; MBL: metallo-beta-lactamase-producing; CL: colistin; BIPM: biapenem; CAZ: ceftazidime; PIPC/TAZ: piperacillin/tazobactam; PIPC: piperacillin; *Outcome could not beevaluated because patient received only 1 day of colistin therapy

Table 1. Patient demography, antimicrobial utilization and outcomes with colistin therapy

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323（ 23 ）Fig. 1. Presentation time-course of colistin-related adverse events: (A) nephrotoxicity in Case 6,(B) dysgeusia in Case 2
Fig. 1A

Fig. 1B

Abbreviations: Cre: serum creatinine; BUN: blood urea nitrogen; CRP: C-reactive protein; CL: colistin; BIPM: biapenem; PIPC: piperacillin

this reason that each of our patients received concomitant beta-lactam therapy, the majority (6/9)
were given biapenem. While meropenem displayed in vitro synergy using the commercially available testing plate, biapenem was used in the clinical setting because of is susceptible proﬁle by
RAISUS and the fact that this agent is the least affected carbapenem analogue with metallo-betalactamase (MBL)s when compared to doripenem, imipenem and meropenem7). Moreover, biapenem displays the lowest MICs for Enterobacteriaceae with OXA-48 enzyme, Acinetobacter spp.
with OXA-type carbapenemases, and has a similar MIC distribution to other carbapenems for
isolates porin loss, AmpC or extended spectrum β-lactamase (ESBL) mediated resistance7).
Several reports including the current study have demonstrated the nephrotoxic potential ofcolistimethate sodium8〜10). While the authors have related this toxicity to the total cumulativeTHE JAPANESE JOURNAL OF ANTIBIOTICS
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Abbreviations: CPFX: ciprofloxacin; AMK: amikacin; CL: colistin; PIPC: piperacillin; RFP: rifampicin; CAZ: ceftazidime; AZT: aztreonam; MEPM: meropenem
Checkerboard plate with colistin in MDRP of 5 patients'. The values given in parentheses were each of drug's MIC and values of 0–100 were sensitive rates (%).

Antibiotic combinations and concentrations were designed in 96-well microplate, as shown in Fig. 2, in which synergistic effects weredemonstrated in several combinations of antibiotics

Fig. 2. Assessment of antibiotic synergy for multidrug-resistant P. aeruginosa
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69―5325（ 25 ）dose, utilization of a higher mg/kg dose, and duration of therapy, other investigators have notshown such associations11,12). As a result of this potential toxic event, HARTZELL, J. D. et al. havesuggested that providers need to be prudent in monitoring serum creatinine levels in patients given colistimethate sodium especially if prolonged courses are required13). Although kidney related
toxicity is generally observed with prolonged exposure, toxicity has also been observed within
the ﬁrst 5 days of treatment14) which is similar to the time course in our patient (Fig. 1).
While arbekacin inhalation therapy may be an important therapeutic option for patients suffering with for MDR Gram-negative pneumonia in situations where systemic therapy alone islikely to be inadequate or systemic exposure will result in elevated toxicity, this approach is notsuitable for the management of extrapulmonary infections15). Thus expanded therapeutic approaches will be required for the optimal management of these MDR infections. While new betalactam/beta-lactamase inhibitor combinations hold great promise, their lack of commercial availability makes our study of colistin in Japanese patients of great clinical value. Although our study
is limited by the small number of patients with MDR organisms, the experience gained from theseobservations is important when taken with the currently available efﬁcacy and toxicity data accumulated in country with colistin.
In conclusion, our study shows that colistin appears to be generally safe and effective in acohort of Japanese patients with limited therapeutic options. While colistin is increasingly being
utilized for the treatment of MDR Gram-negative infections within Japan, dosing varies greatly
and additional study is required to determine the optimal regimen.
Disclosures: HIROSHIGE MIKAMO has received advisory fee from Toyama Pharmaceutical Co.,
Ltd., a speakerʼs honorarium from Astellas Pharma Inc., MSD K.K., Daiichi Sankyo Co., Ltd.,Taisho Toyama Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Pﬁzer Japan
Inc., Meiji Seika Pharma Co., Ltd., and Miyarisan Pharmaceutical Co., Ltd., donation from MSD
K.K., Daiichi Sankyo Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Toyama Chemical Co.,
Ltd., Pﬁzer Japan Inc., Dainippon Sumitomo Pharma Co., Ltd., Meiji Seika Pharma Co., Ltd., andFujiﬁlm Pharma Co., Ltd. The other authors declare no conﬂict of interest.

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