Published on Ear, Nose & Throat Journal (http://www.entjournal.

com)
Home > Changes in antibiotic resistance in recurrent Pseudomonas aeruginosa infections of
chronic suppurative otitis media

Changes in antibiotic resistance in recurrent Pseudomonas

aeruginosa infections of chronic suppurative otitis media
| Reprints
October 25, 2016
by Jae-Jun Song, MD; Byung Don Lee, MD; Koen Hyeong Lee, MD; Jong Dae Lee, MD;
Young Joo Park, MD; Moo Kyun Park, MD, PhD

Abstract
This study investigated the changes in antibiotic resistance in recurrent Pseudomonas
aeruginosa infections in chronic suppurative otitis media (CSOM). Its aim was to provide a
treatment strategy for P aeruginosa infections in CSOM for the prevention of multidrug
resistance. A case-control study was conducted in tertiary teaching hospitals in Korea. The
experimental group included patients with recurrent P aeruginosa infection who had relapsed
within 2 months after the successful control of a previous P aeruginosa infection. The control
group consisted of patients with a P aeruginosa infection who had no history of such an
infection. An antibiotic sensitivity test was performed for each culture. The proportion of
recurrent P aeruginosa infection was 22.69% (98 of 432 cases). Drug resistance to amikacin,
tobramycin, netilmicin, ciprofloxacin, and levofloxacin was significantly changed after
recurrent infection. The fluoroquinolone strains seen in recurrent P aeruginosa showed high
cross-resistance to other drugs. Antibiotic resistance of P aeruginosa in CSOM changed with
recurrent infection.

Introduction
Chronic suppurative otitis media (CSOM) is one of the most common bacterial infections
seen in the field of otolaryngology. The bacteriology of chronic otitis media has been
extensively investigated. The most common pathogen of this disease is Pseudomonas
aeruginosa.1P aeruginosa is an aerobic, gram-negative rod that does not ferment glucose. It
can grow under nutrient-poor conditions and extreme temperatures. Moisture is known to
play a critical role in the epidemiology of this pathogen.
Funding/Support: This work was supported by the Research Resettlement Fund for the new
faculty of Seoul National University.

P aeruginosa is a common pathogenic bacteria of nosocomial infections ranging from skin

and wound infections to septicemia.2P aeruginosa infections in CSOM are commonly treated
with aminoglycosides, fluoroquinolones, and cephalosporins. However, the antibiotic
susceptibility of P aeruginosa to these drug classes is variable and unpredictable.
The emergence and spread of multidrug-resistant strains is of great concern for CSOM
patients and other patients chronically infected with P aeruginosa. This emergence has a
significant effect on the duration of hospital stay and daily hospital charges.3 In addition, the
increase in multidrug resistance (MDR) makes it difficult to choose effective antibiotics.4
However, there are few reports on antibiotic susceptibility changes in recurrent P aeruginosa
infections in CSOM patients.
This study investigated the changes in antibiotic susceptibility in recurrent P aeruginosa
infection in CSOM and to provide a treatment strategy for recurrent infection with this
pathogen.

Patients and methods

Patient selection. A case-control study was conducted retrospectively from March 2001
through February 2011. The medical records of patients with a diagnosis of CSOM (a
nonintact tympanic membrane and otorrhea for at least the preceding 2 weeks) who visited
the Department of Otorhinolaryngology-Head and Neck Surgery at Soonchunhyang
University Bucheon Hospital during this period were included in this study. Our hospital is
the only tertiary referral hospital in the city. The data collected included demographic
information, clinical history, and antibiotic susceptibility.
Patients who had a previous P aeruginosa infection or polymicrobial infections, were
younger than 19 years, or were pregnant were excluded from this study. The experimental
group included patients with recurrent P aeruginosa infection who had relapsed within 2
months after the successful control of previous P aeruginosa otorrhea. The control group
included patients with a P aeruginosa infection who had no known history of this infection.
The results of antibiotic susceptibility tests that were repeated more than once were not
included so that the change in antibiotic susceptibility after one course of antibiotic treatment
could be determined. Control of otorrhea was defined as a resolution of otorrhea more than 2
weeks after optimal treatment. The initial treatment of otorrhea in CSOM was with topical
fluoroquinolone antibiotics. If the otorrhea was not controlled, we added systemic antibiotics
according to the antibiotic sensitivity test. MDR was defined as resistance to all -lactams,
aminoglycosides, and fluoroquinolones tested in this study. The sensitivity results of the
antibiotic treatment were collected from the original laboratory records.
Microbial identification and antimicrobial sensitivity. A sterile ear speculum was inserted
into the infected ear, and the otorrhea was swabbed with a disposable commercial transport
swab. The swabs were used to inoculate a blood agar medium or MacConkey agar medium.
Microbial identification and antimicrobial sensitivity were assayed by VITEK 2 (bioMrieux;
Marcy l'Etoile, France) according to the guidelines of the National Committee for Clinical
Laboratory Standards.

The following antibiotic susceptibilities were reported: -lactams (ticarcillin,

ticarcillin/clavulanate, ceftazidime, cefepime, and cefpirome); aminoglycosides (amikacin,
gentamicin, isepamicin, netilmicin, and tobramycin); fluoroquinolones (ciprofloxacin,
levofloxacin, and pefloxacin); carbapenems (imipenem and meropenem); extended-spectrum
-lactams (aztreonam, piperacillin, and piperacillin/tazobactam); sulfonamides
(trimethoprim/sulfamethoxazole); tetracyclines (minocycline), and polymyxins (colistin).
Antibiotic susceptibility tests for levofloxacin, pefloxacin, minocycline, and cefpirome were
performed only after 2008.
Statistical methods. Our results are given as the mean standard deviation or as a
percentage. Two-sample t tests and chi-square tests were used to compare differences
between the P aeruginosa infection group and the recurrent P aeruginosa infection group.
Paired t tests were performed to compare the antimicrobial susceptibility change of recurrent
P aeruginosa infection in CSOM. A p value of <0.05 was considered statistically significant.
All analyses were performed using the Statistical Package for the Social Sciences (SPSS)
version 11.0 for Windows.
Ethical considerations. This study was approved by the Soonchunhyang University Bucheon
Hospital Institutional Review Board (IRB number: SCHBC-IRB 2010-57).

Results
We collected the medical records of 3,016 cases of infection from 2,121 consecutive patients
(1,407 males and 1,609 females; age range: 1 to 98 years) with a diagnosis of CSOM. The
prevalence rate of P aeruginosa in CSOM patients was 18.07% (545 of 3,016 cultures; 526 of
2,121 patients). Of the P aeruginosa cases, 432 cases (425 patients) were classified as the
control group (P aeruginosa) and 98 cases (82 patients) as the experimental group (recurrent
P aeruginosa). P aeruginosa recurred in 22.69% (98 of 432 cases; 82 patients) of the cases.
The characteristics of the patients in the P aeruginosa and recurrent P aeruginosa infection
groups were similar in terms of age and sex (36 males, 46 females; age range: 2 to 78 years;
mean age: 48.1 years; p = 0.096) (table 1). The mean number of ineffective antibiotics and
MDR strains of P aeruginosa did not differ significantly between the P aeruginosa and
recurrent P aeruginosa groups in CSOM (p = 0.061). The difference was not significant after
removing sulfonamides (trimethoprim/sulfamethoxazole) and tetracyclines (minocycline)
because those drugs showed resistance in most of the cases (p = 0.081). However, cases of
cholesteatoma were significantly more common in recurrent P aeruginosa infection than in
the control group (p < 0.001).

Table 1. Characteristics of the P aeruginosa and recurrent

P aeruginosa in CSOM groups
Characteristics

* p < 0.05 was considered statistically significant.

P
Recurrent P
aeruginosa aeruginosa

p
Value*

P
Recurrent P
aeruginosa aeruginosa

p
Value*

Age (yr)

46.1 19.6 48.1 17.6

0.096

Ineffective antibiotics

5.3 4.2

0.061

(without sulfonamide and minocycline)

(3.3 3.9) (4.6 4.2)

(0.081)

MDR, n (%)

11 (2.6)

4 (4.1)

0.423

Cholesteatoma, n (%)

40 (9.3)

26 (26.5)

<0.000

Total cases

432

98

Characteristics

Key: MDR = Multidrug resistance: resistance to all lactams, aminoglycosides, and fluoroquinolones tested
in this study.

6.6 4.4

Drug resistance to P aeruginosa changed with recurrent infection (table 2). Resistance to
ticarcillin, amikacin, gentamicin, netilmicin, tobramycin, ciprofloxacin, and levofloxacin
significantly changed after recurrent infection (p < 0.05). In the recurrent P aeruginosa
group, the antimicrobial sensitivity test showed low resistance (ratio of resistance <20%) to
carbapenems (imipenem and meropenem), extended-spectrum -lactams (aztreonam,
piperacillin, and piperacillin/tazobactam), and polymyxin, but higher resistance (ratio of
resistance >80%) to sulfonamides (trimethoprim/sulfamethoxazole) and tetracyclines
(minocycline).

Table 2. The antibiotic change of recurrent P aeruginosa

infection in CSOM (antibiotic susceptibility tests for
levofloxacin, pefloxacin, minocycline, and cefpirome were
performed only after 2008)

Resistant (%)

No.
cases

P
Recurrent P
aeruginosa aeruginosa

p Value*

Ticarcillin

97

43.1

59.8

0.00

Ticarcillin/clavulanate

98

39.1

56.1

0.00

Ceftazidime

89

24.5

33.7

0.07

Cefepime

96

25.9

21.9

0.40

Cefpirome

60

55.9

63.3

0.28

Amikacin

98

16.6

26.5

0.02

Gentamicin

95

45.9

62.1

0.00

Isepamicin

95

24.6

33.7

0.06

Netilmicin

97

45.0

59.8

0.01

Tobramycin

95

37.0

50.5

0.01

Ciprofloxacin

96

42.9

56.3

0.02

Drug

* p < 0.05 was considered statistically

significant.

Trimethoprim/sulfametholxazole.

Resistant (%)

Drug

No.
cases

P
Recurrent P
aeruginosa aeruginosa

p Value*

Levofloxacin

32

44.8

65.6

0.03

Pefloxacin

63

47.5

54.0

0.34

Imipenem

95

3.6

3.2

0.83

Meropenem

96

2.1

2.1

1.00

Aztreonam

97

47.9

56.7

0.11

Piperacillin

97

7.6

9.3

0.58

Piperacillin/ tazobactam

97

1.7

0.0

0.20

TMP/SMX

94

98.2

98.9

0.61

Minocycline

32

98.2

100

0.45

Colistin

95

5.5

2.1

0.17

The fluoroquinolone-resistant strains in recurrent infection showed high cross-resistance to

aminoglycosides (amikacin, gentamicin, netilmicin, isepamicin, and tobramycin), -lactams
(ticarcillin, ticarcillin/clavulanate, cefpirome, ceftazidime, and cefepime), and extendedspectrum -lactams (aztreonam) (p < 0.05) (figure).

Figure. Graph compares the antibiotic resistance of

fluoroquinolone-resistant strains in recurrent
Pseudomonas infection, which show high cross-resistance

to aminoglycosides, -lactams, and extended-spectrum lactams. Ticarcillin/CA = ticarcillin/clavulanate.

Discussion
P aeruginosa is a common pathogen of infectious diseases in otolaryngology and is notorious
for its multi-drug resistance to antibiotics. A recent concern has emerged regarding the
increasing incidence of MDR in chronically recurrent infection.5 Earlier studies reported that
the antibiotic susceptibility pattern of P aeruginosa in CSOM showed low resistance to
ceftazidime (11.6%), amikacin (20.4%), and piperacillin (20.7%) but showed higher
resistance to fluoroquinolones (60.5 to 62.9%).1 Additionally, the antibiotic resistance of
pathogens involved in CSOM was significantly lower than those in general clinical samples.1
Our study demonstrates a significant change in the antibiotic resistance in recurrent
Pseudomonas infection in CSOM patients. The strains of recurrent P aeruginosa showed high
cross-resistance to other drugs. Our findings also showed low resistance of strains involved in
CSOM to ceftazidime (24.5%), amikacin (16.6%), and piperacillin (7.6%) and higher
resistance to fluoroquinolones (42.9 to 47.5%).
A variety of resistance mechanisms have been identified in P aeruginosa, including enzyme
production, overexpression of efflux pumps, porin deficiencies, and target-site alterations.6 lactamase resistance in P aeruginosa is often associated with the increased expression of
AmpC -lactamase.
Recent reports describe the occurrence of extended-spectrum -lactamase enzymes, which
confer resistance to all penicillins and cephalosporins but are difficult to detect
phenotypically.7 Resistance to aminoglycosides is related to the overexpression of efflux
pumps or production of modified enzymes of phosphorylate, acetylate, or adenylate.8

The most important mechanism of fluoroquinolone resistance is the overexpression of efflux

pumps with DNA gyrase and topoisomerase IV mutations.9 Resistance to fluoroquinolones is
often related to other antibiotics, as well, which may be associated with the overexpression of
efflux pumps.10 Resistance to carbapenems is caused by the loss or reduced expression of the
outer membrane porin OprD or by acquired carbapenemase.2 The resistance mechanism may
develop during treatment11 or may be acquired by existing strains.12 In addition, the ability
of P aeruginosa to form biofilms and grow within biofilms increases its genetic diversity and
enhances its antibiotic resistance.13,14
In P aeruginosa, strains resistant to one antibiotic class are often resistant to other antibiotic
classes, as well. For example, piperacillin-resistant strains show a high prevalence of
resistance to ticarcillin, imipenem, ciprofloxacin, and amikacin.15 The multidrug resistance
of P aeruginosa may be caused in part by cross-resistance.6
In this study, the fluoroquinolone-resistant strains also exhibited a high prevalence of crossresistance to other antibiotics, and this may be explained in part by the multidrug resistance
of recurrent P aeruginosa in CSOM. However, the results of this study do not imply that
topical quinolones, or the use of quinolones in CSOM, increased resistance to quinolones. A
high prevalence of cross-resistance to other antibiotics in the fluoroquinolone-resistant strains
suggests that systemic fluoroquinolones cannot be first-line treatment agents for recurrent P
aeruginosa infection. However, topical fluoroquinolones can be used in recurrent P
aeruginosa infection because a topical otic solution of fluoroquinolone showed a higher drug
concentration in otorrhea.16
Risk factors for MDR are an immunocompromised status, longer hospital stay, invasive
devices, and exposure to antibiotics, especially -lactams and fluoroquinolones.15 We found
no risk factors for MDR in CSOM. However, our results show that cholesteatoma was a risk
factor for recurrent P aeruginosa infection in CSOM. P aeruginosa has been shown to easily
acquire MDR after recurrent and chronic pneumonia treatment.17 Although the antibiotic
resistance of P aeruginosa in CSOM increased in recurrent infection, this study showed that
P aeruginosa in CSOM did not acquire MDR after recurrent and chronic otitis media
treatment.
In conclusion, the antibiotic susceptibility of P aeruginosa in CSOM changed with recurrent
infection. Therefore, ticarcillin, amikacin, gentamicin, netilmicin, tobramycin, ciprofloxacin,
and levofloxacin cannot be first-line systemic treatment agents for recurrent P aeruginosa
infection. The fluoroquinolone-resistant strains in recurrent P aeruginosa infection showed
high cross-resistance to other drugs. When treating recurrent P aeruginosa infection in
CSOM, the physician should consider these changes in antibiotic susceptibility and select
antibiotics more carefully.

References
1. Yeo SG, Park DC, Hong SM ,et al. Bacteriology of chronic suppurative otitis media-a
multicenter study. Acta Otolaryngol 2007; 127 (10): 1062-7.
2. Navon-Venezia S, Ben-Ami R, Carmeli Y. Update on Pseudomonas aeruginosa and
Acinetobacter baumannii infections in the healthcare setting. Curr Opin Infect Dis
2005; 18 (4): 306-13.
3. Carmeli Y, Troillet N, Karchmer AW, Samore MH. Health and economic outcomes of
antibiotic resistance in Pseudomonas aeruginosa. Arch Intern Med 1999; 159 (10):
1127-32.
4. Rice LB. Emerging issues in the management of infections caused by multidrugresistant gram-negative bacteria. Cleve Clin J Med 2007; 74 (Suppl 4): S12-20.
5. Fridkin SK, Gaynes RP. Antimicrobial resistance in intensive care units. Clin Chest
Med 1999; 20 (2): 303-16, viii.
6. McGowan JE Jr.. Resistance in nonfermenting gram-negative bacteria: Multidrug
resistance to the maximum. Am J Med 2006; 119 (Suppl 1): S29-36; discussion S6270.
7. Weldhagen GF, Poirel L, Nordmann P. Ambler class A extended-spectrum betalactamases in Pseudomonas aeruginosa: Novel developments and clinical impact.
Antimicrob Agents Chemother 2003; 47 (8): 2385-92.
8. Poole K. Aminoglycoside resistance in Pseudomonas aeruginosa. Antimicrob Agents
Chemother 2005; 49 (2): 479-87.
9. Nakajima A, Sugimoto Y, Yoneyama H, Nakae T. High-level fluoroquinolone
resistance in Pseudomonas aeruginosa due to interplay of the MexAB-OprM efflux
pump and the DNA gyrase mutation. Microbiol Immunol 2002; 46 (6): 391-5.
10. Kriengkauykiat J, Porter E, Lomovskaya O ,et al. Use of an efflux pump inhibitor to
determine the prevalence of efflux pump-mediated fluoroquinolone resistance and
multidrug resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother
2005; 49 (2): 565-70.
11. Tsukayama DT, van Loon HJ, Cartwright C ,et al. The evolution of Pseudomonas
aeruginosa during antibiotic rotation in a medical intensive care unit: The RADARtrial. Int J Antimicrob Agents 2004; 24 (4): 339-45.
12. Crespo MP, Woodford N, Sinclair A ,et al. Outbreak of carbapenem-resistant
Pseudomonas aeruginosa producing VIM-8, a novel metallo-beta-lactamase, in a
tertiary care center in Cali, Colombia. J Clin Microbiol 2004; 42 (11): 5094-101.
13. Boles BR, Thoendel M, Singh PK. Self-generated diversity produces insurance
effects in biofilm communities. Proc Natl Acad Sci U S A 2004; 101 (47): 16630-5.

14. Hassett DJ, Korfhagen TR, Irvin RT ,et al. Pseudomonas aeruginosa biofilm
infections in cystic fibrosis: Insights into pathogenic processes and treatment
strategies. Expert Opin Ther Targets 2010; 14 (2): 117-30.
15. Trouillet JL, Vuagnat A, Combes A ,et al. Pseudomonas aeruginosa ventilatorassociated pneumonia: Comparison of episodes due to piperacillin-resistant versus
piperacillin-susceptible organisms. Clin Infect Dis 2002; 34 (8): 1047-54.
16. Ohyama M, Furuta S, Ueno K ,et al. Ofloxacin otic solution in patients with otitis
media: An analysis of drug concentrations. Arch Otolaryngol Head Neck Surg 1999;
125 (3): 337-40.
17. Oliver A. Mutators in cystic fibrosis chronic lung infection: Prevalence, mechanisms,
and consequences for antimicrobial therapy. Int J Med Microbiol 2010; 300 (8): 56372.
From the Department of Otorhinolaryngology-Head and Neck Surgery, Korea University
Guro Hospital (Dr. Song); the Department of Otolaryngology-Head and Neck Surgery,
Soonchunhyang University College of Medicine (Dr. BD Lee, Dr. H Lee, Dr. JD Lee, Dr. YJ
Park); and the Department of Otolaryngology-Head and Neck Surgery, Seoul National
University College of Medicine (Dr. MK Park), Seoul, Korea. The study described in this
article was conducted at Soonchunhyang University Bucheon Hospital.
Corresponding author: Moo Kyun Park, MD, PhD, Department of Otolaryngology-Head and
Neck Surgery, Seoul National University College of Medicine, 101 Daehak-ro Jongno-gu,
Seoul 110-744 Korea. Email: aseptic@snu.ac.kr [1]
Ear Nose Throat J. 2016 October-November;95(10-11):446-451
Topics
Otology [2]
Otitis [3]
Source URL: http://www.entjournal.com/article/changes-antibiotic-resistance-recurrentpseudomonas-aeruginosa-infections-chronic
Links
[1] mailto:aseptic@snu.ac.kr
[2] http://www.entjournal.com/category/section/otology
[3] http://www.entjournal.com/category/keyword-topics/otitis