Introduction

Pseudomonas aeruginosa is widely spread in humid environments such as plants, soil and a wide range of aquatic habitats, and could be colonizing in hospital environments [1]. This may include sinks, shower rooms, and bath rooms, thus, it is a common cause of nosocomial infections [1]. P. aeruginosa is a common pathogen of blood stream infections in patients with hematologic malignancy and other critical diseases [2, 3]. Blood stream infections could be associated with higher mortality rates depending on the patient’s conditions [4].

Pseudomonas aeruginosa has an intrinsic resistance to several antibiotics, because of a low permeability of the outer-membrane, various efflux pumps and production of enzymes, e.g., cephalosporinases [5]. Furthermore, P. aeruginosa could acquire several mechanisms of resistance, such as reduced membrane permeability, target modification (DNA gyrase, methylation of 16S rRNA), and production of metallo-beta-lactamases. This is why it is difficult to treat infected patients.

Appropriate use of antibiotics is one of the most important infection control measures [6]. Several reports indicated the correlation of antibiotic usage and resistance [7–9]. On the other hand, one report indicated no relation of antimicrobial usage and resistance of P. aeruginosa in the hospitals in United States [10]. In our hospital, susceptibilities of P. aeruginosa to several antibiotics declined in 2010, however, subsequently improved in 2011. In this study, we show the consumption of anti-pseudomonal antibiotics and their susceptibility to those agents in a university hospital in Japan.

Methods

The University of Tokyo Hospital is a 1217-bed tertiary care teaching hospital in Tokyo, Japan. Two hundred and eighty-two strains of P. aeruginosa were isolated from blood samples from April 2009 to March 2012. Strains isolated from the same patient within 2 weeks from previous isolations were regarded as duplicate isolates and excluded from the analysis. We included 163 isolates from 151 patients in the analysis. Finally, 149 strains that remained viable in our storage from 137 patients were included in the analysis.

Minimum inhibitory concentrations to anti-pseudomonal intravenous antibiotics used in the hospital, including cefepime (CFPM), ceftazidime (CAZ), piperacillin–tazobactam (PIPC–TAZ), piperacillin (PIPC), meropenem (MEPM), doripenem (DRPM), imipenem–cilastatin (IPM), biapenem (BIPM), panipenem–betamipron (PAPM), ciprofloxacin (CPFX), levofloxacin (LVFX) and amikacin (AMK) were determined by microdilution method. They were performed and interpreted according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI) M100-S23 [11]. The breakpoints for carbapenems were applied to BIPM and PAPM.

Antimicrobial utilization was assessed for anti-pseudomonal intravenous antibiotics from the hospital databases. The amount of antibiotics used was expressed by antimicrobial use density, defined daily dose (DDD) per 1000 patient days. DDDs were defined by the World Health Organization [12].

Usual dose regimens for adults with normal kidney function in our hospital were as follows; CFPM: 1 g three times daily (TID), CAZ 1 g TID, PIPC–TAZ: 4.5 g TID, PIPC: 1.0 g twice daily (BID), MEPM 0.5 g TID, DRPM 0.5 g TID, IPM 0.5 g TID, BIPM 0.3 g four times daily (QID), PAPM 0.5 g TID, CPFX 200 mg BID, LVFX 500 mg once daily (QD), AMK 400 mg QD. Usual infusion duration of CPFX and LVFX was 60 min and the other antibiotics was 30 min.

Regression line equations and corresponding correlation coefficients were calculated using JMP Pro 11.0.0 (SAS Institute Japan, Tokyo, Japan) to evaluate the relation between antimicrobial usages and susceptibilities.

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Results

Antibiotic Utilizations

Annual consumptions of antibiotics are listed as DDD in Table 1. The most used anti-pseudomonal agents were cephalosporins from 2009 to 2010 and 2012 and penicillins in 2011. Ninety percent of cephalosporins used were cefepime, and almost all penicillins used were piperacillin–tazobactam. Usages of carbapenems and anti-pseudomonal cephalosporins decreased 44% and 31% from 2009 to 2011, and then increased 30% and 24% in 2012, respectively. Usage of piperacillin–tazobactam increased 87% from 2009 to 2012, which was introduced in the hospital in 2008. Consumption of fluoroquinolones and aminoglycoside remained low in those years.

Table 1 Antimicrobial usage by year (DDD/1000 patient days) in the University of Tokyo Hospital from 2009 to 2011
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Susceptibilities of P. aeruginosa to Antibiotics

Susceptibilities of P. aeruginosa to antibiotics are listed in Table 2. Susceptibilities to cephalosporins, carbapenems except for PAPM, penicillins, and fluoroquinolones declined between 22% and 39% in 2010 and increased in the range of 16–31% in 2011, and furthermore increased by 1–14% in 2012. Susceptibility to PAPM ranged between 25% and 32%. Susceptibility to aminoglycoside was more than 90% during this period.

Table 2 Susceptibilities (%) of Pseudomonas aeruginosa to anti-pseudomonal antibiotics from 2009 to 2012
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Susceptibilities of P. aeruginosa and Usages of Antibiotics

Correlation of susceptibilities and antimicrobial usage was not observed in cephalosporins and carbapenems (Fig. 1). Susceptibilities to fluoroquinolones changed simultaneously with other beta lactams, although the consumptions of fluoroquinolones did not change. Susceptibility to piperacillin–tazobactam did not change, despite the significant increase of consumption (Table 1).

Fig. 1
figure 1

Relationship between antimicrobial usage and susceptibility. CFPM cefepime, DDD defined daily dose, MEPM meropenem, PIPC–TAZ piperacillin–tazobactam

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Discussion

We investigated susceptibilities of P. aeruginosa to anti-pseudomonal agents and utilization of these antibiotics for 4 years. Susceptibilities of P. aeruginosa declined in 2010 and increased in the following years. However, corresponding changes in antimicrobial usages were not observed, and correlation between susceptibilities and antimicrobial usages was not seen in our data.

Several reports indicated that increased antimicrobial usage was associated with a decline in susceptibilities or emergence of resistant P. aeruginosa. Xu et al. [8] indicated that the resistance rate of P. aeruginosa to meropenem increased 1.2% when anti-pseudomonal carbapenems usage increased 1 DDDs/1000 patient days. Nakamura et al. [13] reported the relation of meropenem consumption and emergence of multidrug resistant P. aeruginosa. Appropriate use of antibiotics is essential to avoid the emergence of resistant bacteria. However, antimicrobial usage is not the only factor that determines the susceptibilities of bacteria. Other infection control measures, including hand hygiene, contact precautions, education, environmental cleaning, and antimicrobial stewardship, are also important to avoid the emergence of resistant P. aeruginosa [14]. Correlation between antibiotic usage and susceptibility of P. aeruginosa was not observed in our data or in a report by Mutnick et al. [10]. Factors other than antimicrobial usage might contribute to these results. Moreover, the usages of anti-pseudomonal antibiotics, except carbapenems, in the report by Xu et al. [8] were three to five times higher than in our hospital. Initial resistance rates of P. aeruginosa to aminoglycoside and fluoroquinolones in the report were significantly higher than our data, nevertheless, we used more strict breakpoints according to CLSI M100-S23. We evaluated only blood samples, because we considered causative bacteria of infection more important than those of colonization, while other reports included colonized strains. These factors might affect the result. We compared the total usage of antibiotics in the hospital and susceptibilities of all isolates of P. aeruginosa in the hospital, while correlations might be observed in wards with a high consumption of antibiotics, such as the intensive care unit (ICU). Loeffler et al. [15] reported that correlation between antibiotic consumption and resistance in ICU was observed for piperacillin, cephalosporins and aminoglycosides in P. aeruginosa. However, Slain et al. [16] reported that statistically significant relationships of antibiotic consumption and resistance were not seen in their ICU despite an antimicrobial stewardship program. Furthermore, Jonas et al. [17] indicated that an increased resistance rate was associated with cross-transmission rather than antimicrobial usage. The declines of susceptibilities in our hospital might have been associated with cross-transmission.

We compared the usage of antibiotics and susceptibilities of bacteria on an annual basis. To clarify the exact relationship between antimicrobial usages and susceptibilities, shorter-period comparisons are desirable. Our isolates were only 30–40 a year. A larger number of isolates are required for short-term comparisons.

Conclusion

Susceptibilities of P. aeruginosa did not correlate with the usages of antibiotics in our hospital. Several infection control measures and other factors might contribute to the susceptibilities of bacteria. Further studies are needed to clarify the factors that determine susceptibility to antibiotics.