Changes in antibiotic resistance in recurrent Pseudomonas aeruginosa infections of chronic suppurative otitis media.
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? 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.
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. (1) P 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.
P aeruginosa is a common pathogenic bacteria of nosocomial infections ranging from skin and wound infections to septicemia. (2) P 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 [beta]-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 (bioMerieux; Marcy l'Etoile, France) according to the guidelines of the National Committee for Clinical Laboratory Standards.
The following antibiotic susceptibilities were reported: [beta]-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 [beta]-lactams (aztreonam, piperacillin, andpiperacillin/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 [+ or -] 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).
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).
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 Paeruginosa group, the antimicrobial sensitivity test showed low resistance (ratio of resistance <20%) to carbapenems (imipenem and meropenem), extended-spectrum [beta]-lactams (aztreonam, piperacillin, and piperacillin/tazobactam), and polymyxin, but higher resistance (ratio of resistance >80%) to sulfonamides (trimethoprim/ sulfamethoxazole) and tetracyclines (minocycline).
The fluoroquinolone-resistant strains in recurrent infection showed high cross-resistance to aminoglycosides (amikacin, gentamicin, netilmicin, isepamicin, and tobramycin), [beta]-lactams (ticarcillin, ticarcillin/clavulanate, cefpirome, ceftazidime, and cefepime), and extended-spectrum [beta]-lactams (aztreonam) (p < 0.05figure).
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) [beta]-lactamase resistance in P aeruginosa is often associated with the increased expression of AmpC [beta]-lactamase.
Recent reports describe the occurrence of extendedspectrum [beta]-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 treatment (11) 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 cross-resistance 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 immune-compromised status, longer hospital stay, invasive devices, and exposure to antibiotics, especially [beta]-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.
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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
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: email@example.com
Funding/Support: This work was supported by the Research Resettlement Fund for the new faculty of Seoul National University.
Table 1. Characteristics of the P aeruginosa and recurrent P aeruginosa in CSOM groups Recurrent Characteristics P aeruginosa P aeruginosa Age (yr) 46.1 [+ or -] 19.6 48.1 [+ or -] 17.6 Ineffective antibiotics 5.3 [+ or -] 4.2 6.6 [+ or -] 4.4 (without sulfonamide (3.3 [+ or -] 3.9) (4.6 [+ or -] 4.2) and minocycline) MDR, n (%) 11 (2.6) 4 (4.1) Cholesteatoma, n (%) 40 (9.3) 26 (26.5) Total cases 432 98 Characteristics p Value * Age (yr) 0.096 Ineffective antibiotics 0.061 (without sulfonamide (0.081) and minocycline) MDR, n (%) 0.423 Cholesteatoma, n (%) <0.000 Total cases * p <0.05 was considered statistically significant. Key: MDR = Multidrug resistance: resistance to all p-lactams, aminoglycosides, and fluoroquinolones tested in this study. 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. Recurrent p Drug cases P aeruginosa P aeruginosa 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 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 ([dagger]) 94 98.2 98.9 0.61 Minocycline 32 98.2 100 0.45 Colistin 95 5.5 2.1 0.17 * p < 0.05 was considered statistically significant. ([dagger]) Trimethoprim/sulfametholxazole.
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|Author:||Song, Jae-Jun; Lee, Byung Don; Lee, Koen Hyeong; Lee, Jong Dae; Park, Young Joo; Park, Moo Kyun|
|Publication:||Ear, Nose and Throat Journal|
|Date:||Oct 1, 2016|
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