Declining susceptibility to neomycin and polymyxin B of pathogens recovered in otitis externa clinical trials.

Background: Otitis externa is usually treated empirically with topical neomycin/polymyxin B/hydrocortisone. The predominant pathogens associated with this infection are Pseudomonas aeruginosa and Staphylococcus aureus.

Methods: Two multicenter clinical trials (one in adults and adolescents, and one in children), conducted between 1995 and 1996, compared neomycin/polymyxin B/hydrocortisone with ofloxacin for the treatment of otitis externa; two similar trials were conducted between 1999 and 2000. Assessments included the minimum inhibitory concentrations (MICs) of each antimicrobial drug for the major pathogens, bacterial eradication, and clinical efficacy.

Results: The MICs of all bacterial isolates (including P aeruginosa) for neomycin and polymyxin B increased markedly in the 1999 to 2000 studies compared with the 1995 to 1996 studies. In the later studies, mean MICs for all major pathogens tested had increased above the breakpoint for polymyxin B ([greater than or equal to]4 [micro]g/ml). In contrast, MICs of all isolates for ofloxacin remained similar between the two study periods and were within the susceptible range for this drug.

Conclusions: Although the bacterial eradication rates for both treatments in each study were equivalent, the clinical cure rate for neomycin/polymyxin B/hydrocortisone was lower (87%) than for ofloxacin (93%). Therefore, the organisms most often causing otitis externa appear to be developing resistance to neomycin and polymyxin B but not to ofloxacin.

Key Words: antimicrobial drug resistance, neomycin, ofloxacin, otitis externa, polymyxin B

**********

Otitis externa, also known as "swimmer's ear," is a common inflammatory condition of the external ear canal and the auricle. The condition is usually acute at onset, with intensity ranging from mild to severe. The acute stage may present as a pustule, furuncle, or cellulitis of the external canal. As the infection advances, symptoms may include itching, swelling, drainage, or granulomatous lesions. The "itch-and-scratch" process often accelerates and exacerbates the inflammation. Gram-positive organisms are often the etiologic agents in acute, community-acquired cases, whereas Pseudomonas aeruginosa and other Gram-negative rods have been implicated in more serious infections. (1) Although diagnosis may be enhanced by Gram stain and culture, most cases are treated empirically.

The increasing incidence of antimicrobial resistance to many antibiotics adds to the challenge of optimizing empiric treatment for complicated otitis externa. Acute or mild cases of otitis externa are often treated with a combination of neomycin and polymyxin B in a hydrocortisone base. Alternatively, otitis externa can be effectively treated with topical ofloxacin, an antibiotic of the fluoroquinolone class with a broad spectrum of in vitro activity against Gram-positive and Gram-negative bacteria, including those that are known pathogens of external ear infections. Contemporary susceptibility test data for ofloxacin for the primary pathogens associated with otitis externa are available and confirm the effective antimicrobial activity of ofloxacin. (2) Current routine susceptibility testing procedures or antibacterial susceptibility test panels rarely include neomycin and polymyxin B, so susceptibility profiles for these agents are not available at most clinical sites.

The National Committee for Clinical Laboratory Standards (NCCLS) does not provide current interpretative criteria for antimicrobial susceptibility testing of polymyxin B. However, the NCCLS did assign a disk-diffusion antimicrobial susceptibility testing interpretive breakpoint criteria guideline of 4 [micro]g/mL or higher for this agent in 1981. (3) A minimum inhibitory concentration (MIC) breakpoint criterion of 50 U/mL (5 [micro]g/mL) or higher was also proposed in 1974. (4) Recently, the antimicrobial activity of polymyxin B was evaluated using 200 Gram-negative clinical isolates. The investigators concluded that an MIC breakpoint criterion of 4 [micro]g/mL or higher should be used, thereby supporting the previous MIC breakpoint assignment. (5) Therefore, an MIC breakpoint of 4 [micro]g/mL or higher remains a valid interpretative value for resistance to polymyxin B.

This study presents data from four clinical trials comparing ofloxacin with neomycin/polymyxin B/hydrocortisone solution/suspension in the treatment of otitis externa. A trial conducted in adult and adolescent subjects ([greater than or equal to]12 years old) and a trial in pediatric subjects ([greater than or equal to]1 year and <12 years old) were each performed between 1995 and 1996; two similar trials, one in adults and the other in children, were performed between 1999 and 2000. The bacterial eradication rates and clinical cure rates for each drug were compared between the two study periods to determine whether bacterial resistance had developed over time.

Materials and Methods

Study Subjects

The results from four clinical trials are presented in this study. The first two trials (one in adults and adolescents, and one in children [<12 years old]) were conducted between 1995 and 1996. The second two trials (one in adults and one in children) were conducted between 1999 and 2000. Both pairs of studies were conducted in 34 distinct cities. In the 1999 to 2000 trials, 31 of the cities were either the same or within 250 miles of the cities in the earlier trials. Collectively, a total of 1,079 study subjects were randomized at study sites; 539 were randomized to receive ofloxacin and 540 were randomized to receive neomycin/polymyxin B/hydrocortisone. The 1995 to 1996 trials included 256 adults and 202 children, and the 1999 to 2000 trials included 344 adults and 277 children. The intent-to-treat (ITT) population from whom cultures were obtained included 256 adult patients and 202 children in the 1995 to 1996 studies and 331 adult patients and 268 children in the 1999 to 2000 studies. The majority of the ITT subjects (66.2%) were between 18 and 65 years of age in the adult trials. Similar age distributions occurred in the ITT and all other subpopulations.

Inclusion criteria included 1) clinical evidence of stable or exacerbating acute otitis externa of less than 2 weeks' duration; 2) men, nonpregnant nonlactating women, or women using investigator-approved contraceptive measures that had to be maintained throughout the study period, which ended 30 days after last study drug administration; 3) diagnosis of otitis externa based on moderate to severe edema and tenderness, mild to severe erythema, serous to purulent secretion/exudates (sufficient for culture); and 4) informed consent by either the subject or by the subject's parent or guardian if the subject was younger than 18 years old.

Interventions

Patients in the ofloxacin groups received ofloxacin solution containing 0.3% ofloxacin, 0.0025% benzalkonium chloride, 0.9% sodium chloride, hydrochloric acid, and sodium hydroxide to adjust the pH to 6.0 [+ or -] 0.5. Patients in the neomycin/polymyxin B/hydrocortisone groups received a solution (1995-1996 studies) or a suspension (1999-2000 studies) containing neomycin sulfate (3.5 mg/mL neomycin base), polymyxin B sulfate equivalent to 10,000 U/mL of polymyxin B, and 10 mg/mL hydrocortisone 1%. In the 1995 to 1996 studies, ofloxacin was administered as 10 drops in the affected ear(s) twice daily for 10 days in adults and adolescents and five drops twice daily for 10 days in children; neomycin/polymyxin B/hydrocortisone was administered as four drops in the affected ear(s) four times per day, approximately 6 hours apart, for 7 to 10 days. Study participants were randomized and were instructed to administer the drug as described above. In the 1999 to 2000 studies, the same number of drops of ofloxacin was administered once per day for 7 to 10 days and a suspension of neomycin/polymyxin B/hydrocortisone was administered as previously described for the 1995 to 1996 studies, for 7 to 10 days.

Analyses

The following time points were used to evaluate the study subjects: first visit as pretreatment (day 1); second visit at end of therapy (days 7-9); and third visit as test of cure follow-up visit (7-10 days post-treatment). Subjects were evaluated for clinical and microbiologic response. The sponsor and the investigator assessed clinical responses in the assessed subpopulations. Bacterial eradication was assessed by subject and by pathogens. In addition, the MICs of ofloxacin, neomycin, and polymyxin B for the major pathogens were determined by microdilution panels using the NCCLS antibiotic susceptibility testing criteria (M100-S6, 1995) and Becton-Dickinson Microbiologic Systems (Cockeysville, MD). (4) All isolates were tested at a central laboratory for identification and susceptibility.

Results

Patients

The combined patient characteristics for all studies at both time periods were similar between the treatment groups. However, there were significantly more male patients in the ofloxacin treatment group than in the neomycin/polymyxin B/hydrocortisone group (Table 1). The numbers of patients in each subject population for each study are shown in Table 2.

Distribution of Pathogens

Pretreatment bacteriologic cultures were obtained from each subject in the ITT population of the study. A total of 208 pathogens were identified in the 1995 to 1996 studies, and 249 were isolated in the 1999 to 2000 studies (Fig. 1). P. aeruginosa was the most common pathogenic organism recovered at study entry; 64.4% (134 of 208) and 70.7% (176 of 249) of the isolates were identified as P. aeruginosa in the 1995 to 1996 and the 1999 to 2000 studies, respectively (Fig. 1). The remaining organisms were present in small numbers (2-8%). For those pathogens identified, Staphylococcus aureus declined in incidence from 8% in the 1995 to 1996 studies to 4% in the 1999 to 2000 studies. Changes in the incidence of other organisms were minimal.

Eradication of Pathogens

Eradication was determined in subjects who had a repeat otic fluid culture obtained at the follow-up visit. Eradication was considered confirmed if the baseline pathogen was shown to be absent in a follow-up culture or presumed if signs and symptoms resolved and no material could be cultured. Both treatments eradicated 99% of the organisms in the 1995 to 1996 studies (Table 3). In the 1999 to 2000 studies, the bacterial eradication rate for ofloxacin treatment was also 99% (93 of 94), and the eradication rate for neomycin/polymyxin B/hydrocortisone was 98% (77 of 79). Thus, for both time periods, the bacteriologic eradication rates for the two treatments were equivalent.

Clinical Cure Rate

In the ITT population, the overall clinical cure rates in the earlier studies (1995-1996) were similar in both treatment groups: 72.8% in the ofloxacin group and 75.6% in the neomycin/polymyxin B/hydrocortisone group (Table 4). However, in the later studies (1999-2000), the clinical cure rate was significantly higher in the ofloxacin treatment group than in the neomycin/polymyxin B/hydrocortisone group (73.9% versus 63.7%, respectively; P = 0.021).

A similar trend was observed in the patients evaluable for clinical and bacteriologic responses. For example, in the clinically evaluable population, the overall clinical cure rate in the early studies (1995-1996) for the ofloxacin treatment group and the neomycin/polymyxin B/hydrocortisone group was 85.6% (154 of 180) and 85.8% (151 of 176), respectively. However, in the later studies (1999-2000), the overall clinical cure rate for the ofloxacin group was 4.2% higher than the clinical cure rate for the neomycin/polymyxin B/hydrocortisone group--90.6% (213 of 235) and 86.4% (185 of 214), respectively. Similarly, in the microbiologically evaluable population, the overall clinical cure rates in the earlier studies were equivalent in both treatment groups (91% [71 of 78] for ofloxacin and 93% [85 of 91] for neomycin/polymyxin B/hydrocortisone). However, in the later studies (1999-2000), the clinical cure rate was 5% higher in the ofloxacin treatment group (92% [105 of 114]) than in the neomycin/polymyxin B/hydrocortisone treatment group (87% [83 of 95]).

As shown in Table 5, each of the organisms tested against ofloxacin in both study periods had mean MICs of 1.0 [micro]g/mL or less; the mean MICs for ofloxacin did not increase during the later study period. In contrast, the mean MIC for neomycin and polymyxin B increased in the 1999 to 2000 studies for each of the organisms. Four of five organisms had MICs greater than 128 [micro]g/mL for polymyxin B.

Discussion

The selection of treatment options for otitis externa has been debated for centuries. As early as 1500 BC, various chemical agents were used to treat infections of the outer ear. By the early 1900s, nonspecific antiseptics were used to treat these infections, and some were potentially ototoxic. With the advent of the antibiotic era, the treatment of otitis externa included more antibiotics and fewer antiseptics. However, in 1990, Clayton et al (6) in England compared a topical antiseptic (aluminum acetate) and a topical antibiotic (gentamicin sulfate) for initial treatment of otorrhea. These authors favored the topical antiseptic because of costs, avoidance of resistance, and lower toxicity. The clinical outcomes were comparable for the two treatment options. However, a review of the study indicated that at least two conclusions had a bias involving sample size and grading of infections. An experimental study in animals that compared a topical steroid and an antibiotic also showed comparable clinical outcomes. (7) Thus, a debate over the merit of treatment with antiseptics versus treatment with antibiotics and treatment versus no treatment for otitis externa has created questions for clinicians. Dohar, (8) in a study to evaluate management of otitis externa, suggested that the use of antiseptics has been replaced with the use of fluoroquinolone antimicrobials to improve efficacy and to avoid some toxicity issues of older antimicrobial agents.

Otitis externa is most commonly inflammatory, and due to a bacterial infection of the external ear canal. (9) In an era where antibiotic resistance is increasing, it is important to correctly diagnose and treat patients with bacterial otitis externa. Resistance is best prevented by confirming the diagnosis of a bacterial infection and using the most rapidly bactericidal agent available to definitively eradicate the pathogen. This is first done by establishing the diagnosis. The presence of purulent exudates from the external ear is initially a suggestive finding but merits further evaluation. It seems prudent for physicians to carefully evaluate the exudates, ideally by Gram stain and culture to determine the presence of white cells and bacteria. Although not reliable for specific pathogen identification, Gram stain at least offers the possibility of being able to observe the presence of bacteria at the time of the patient's visit. The culture will later confirm the identification and susceptibility data useful in directing therapy. By treatment based on information rather than empiric guidelines, one has an indication that the agents are appropriate and the development of resistance will be minimized. Otologic therapy typically provides many times the MIC of the specific pathogen at the site of the infection. Unless the pathogen is extremely resistant to the antibiotic, eradication of the organism can be expected. Not eradicating the organism will likely lead to development of resistance and recurrent infections. Fluoroquinolone antibiotics are rapidly bactericidal and are highly effective in eradicating the pathogens observed in otitis externa, as evidenced by the high eradication rates in this study.

Neomycin/polymyxin B/hydrocortisone and ofloxacin were compared for the treatment of otitis externa in four studies conducted during two different time periods (1995-1996 and 1999-2000). The distribution of pathogens in each study at both time periods was similar and compared well with other investigations of otitis externa. (9) P aeruginosa was the most common pathogen isolated in all studies. This organism and other Gram-negative rods are often associated with more severe cases of otitis externa. S aureus constituted 8% of total isolates in the 1995 to 1996 studies and 4% in the 1999 to 2000 studies. Other organisms included Enterobacter cloacae, Enterococcus faecalis, and Proteus mirabilis. The incidence of these organisms varied up to 3% between studies. These findings are consistent with previously published reports. (10-12)

Bacterial eradication of pathogens was determined both presumptively (on the basis of the disappearance of pretreatment signs and symptoms of otitis externa) and by repeat of standard bacteriologic culture methods in both studies. The eradication rates were identical for both treatments in the 1995 to 1996 studies and varied by only 1% in the 1999 to 2000 studies. Both drugs were administered in relatively high concentrations; ofloxacin contained 0.3% ofloxacin (standard five drop pediatric unit dose: 0.25 mL/0.75 mg; standard adult unit dose: 0.5 mL/1.5 mg) and neomycin/polymyxin B/hydrocortisone contained 3.5 mg neomycin base and polymyxin B sulfate, equivalent to 10,000 polymyxin B units. These relatively high concentrations are likely to be responsible for the high eradication rates, even among resistant strains. The concentration of active drug in these preparations is severalfold higher than blood levels achievable with routine oral dosing. The traditional principles governing antimicrobial pharmacokinetic/pharmacodynamic interrelationships that have been held to be predictive for clinical efficacy (ie, area under the curve/MIC, [C.sub.max]/MIC, and proportion of time that drug serum level curve is above MIC over the dosing interval) for systemically dosed drugs are calculated on the basis of cure rates at achievable systemic concentrations and therefore are not useful in predicting the clinical utility of ototopically administered antimicrobials.

Because of the high concentrations used, organisms coming into direct contact with the drugs are probably killed, but organisms embedded in inflamed, swollen tissues in the canal might avoid interaction with the drugs. In addition, the high local concentration of an otic formulation declines rather rapidly (usually within 1 hour after administration) in a nonbiologic manner via external drainage due to shifts in the position of the patient's head. Once high levels of a drug are reduced, the organisms have an increased chance of surviving and multiplying. In a study by Ohyama et al, (13) the highest concentration of ofloxacin in otorrhea fluid was observed at the initial sampling, followed by a rapid decline. Interestingly, concentrations in otorrhea above the MIC were still observed at 6-8 hours after ototopical application in sampled patients.

The clinical cure rates with ofloxacin were slightly higher in the later studies than in the earlier studies, whereas the clinical cure rates with neomycin/polymyxin B/hydrocortisone decreased in the later studies. Given the current high rate of antimicrobial resistance development, this difference in clinical outcome between the two treatment groups, although numerically small, may be clinically important. A possible explanation for the decrease in clinical cure rates for the subjects treated with neomycin/polymyxin B/hydrocortisone in the 1999 to 2000 period is the change in antibiotic susceptibility for the relevant pathogenic organisms. The MIC determinations for P aeruginosa and other organisms indicated that all organisms tested against polymyxin B became resistant to it by the time of the more recent studies. In the later studies, the mean MICs for polymyxin B were well above the NCCLS breakpoint of this agent ([greater than or equal to]4 [micro]g/mL for polymyxin B), whereas the mean MICs for all pathogens tested in both time periods were below the NCCLS breakpoint for ofloxacin ([greater than or equal to]2 [micro]g/mL). In addition, E faecalis was resistant to neomycin, and susceptibility of other organisms to this drug was decreasing. The marked increase in mean MICs for both neomycin and polymyxin B in the 1999 to 2000 trials suggests development of resistance and loss of antimicrobial activity for these agents. Resistance to these agents was reported by Jones et al (12) in an earlier comparison of these treatments in otitis externa. The increased mean MICs for these agents may be responsible for the decreased clinical cure rate in patients treated with neomycin/polymyxin B/hydrocortisone. Furthermore, all of the organisms tested in each of the studies, including P aeruginosa, were susceptible to ofloxacin. This suggests that the pathogens in otitis externa appear to be developing resistance to standard ototopical doses of neomycin and polymyxin B but are not developing resistance to standard doses of ofloxacin.

Although neomycin/polymyxin B/hydrocortisone has been a standard treatment for otitis externa for many years, ofloxacin now offers an alternative that has demonstrated equivalent eradication rates in four studies, a slightly better clinical cure rate in the most recent study period, and a susceptibility profile with fewer resistant strains. If the trend of increasing MIC values in pathogens such as P aeruginosa and S aureus for patients treated with polymyxin and neomycin continues, a time might arrive soon when these agents will cease to be effective for empiric treatment of otitis externa no matter how high their concentrations. The only significant complication of an incomplete eradication of P aeruginosa in active otitis externa is malignant external otitis. This is not commonly seen in the pediatric age group, except in children with chronic illness, malnourishment, or immunosuppression. It occurs most frequently in elderly patients with diabetes and is caused primarily by P aeruginosa. (14) The infection begins in the canal, often after minor trauma, and rapidly spreads to soft tissue, cartilage, bone, nerves, and the parotid gland. This potential complication of improperly treating otitis externa warrants selection of therapy that ensures eradication of the pathogens associated with this infection.

Education is what survives when what has been learned has been
forgotten.
--B.F. Skinner

Table 1. Combined patient demographics for all studies in 1995-1996 and
1999-2000

                                 Ofloxacin
Characteristic                   (n = 539) (%)

Age, mean [+ or -] SD (yr)        22.4 [+ or -] 18.09
Age groups
  [greater than or equal to]6
  mo-<1 yr                         0 (0.0)
  [greater than or equal to]1-
  <2 yr                            2 (0.4)
  [greater than or equal to]2-
  <11 yr                         198 (36.7)
  [greater than or equal to]11-
  <12 yr                          39 (7.2)
  [greater than or equal to]12-
  <18 yr                          71 (13.2)
  [greater than or equal to]18-
  <65 yr                         214 (39.7)
  [greater than or equal to]65
  yr                              15 (2.8)
Gender
  Male                           278 (51.6)
  Female                         261 (48.4)
Race
  White                          469 (87.0)
  Nonwhite                        70 (13.0)
  Hispanic                        37 (6.9)
  Black                           26 (4.8)
  Asian/Pacific Islander           4 (0.7)
  Native American/ Alaskan         0 (0.0)
  Other                            3 (0.6)

                                 Neomycin/polymyxin B
Characteristic                   (n = 540) (%)         P value (a)

Age, mean [+ or -] SD (yr)        23.2 [+ or -] 19.08  0.488
Age groups                                             0.639
  [greater than or equal to]6
  mo-<1 yr                         1 (0.2)
  [greater than or equal to]1-
  <2 yr                            1 (0.2)
  [greater than or equal to]2-
  <11 yr                         202 (37.4)
  [greater than or equal to]11-
  <12 yr                          35 (6.5)
  [greater than or equal to]12-
  <18 yr                          71 (13.1)
  [greater than or equal to]18-
  <65 yr                         205 (38.0)
  [greater than or equal to]65
  yr                              25 (4.6)
Gender
  Male                           239 (44.3)            0.016 (b)
  Female                         301 (55.7)
Race
  White                          482 (89.3)            0.254
  Nonwhite                        58 (10.7)
  Hispanic                        32 (5.9)
  Black                           17 (3.1)
  Asian/Pacific Islander           2 (0.4)
  Native American/ Alaskan         1 (0.2)
  Other                            6 (1.1)

(a) P values for the age comparison were computed using a two-sample t
test. P values for the gender and race comparison were computed using
the Pearson [chi square] test. For race, white versus nonwhite were the
only categories tested.
(b) Significant difference.

Table 2. Summary of subject populations (a)

               Ofloxacin         Neomycin/polymyxin B
                    Clin  Micro       Clin  Micro
Study          ITT  eval  eval   ITT  eval  eval

1995-1996
  Adult        129   99    45    127   98   47
  Pediatric    100   81    33    102   78   44
  Total        229  180    78    229  176   91
1999-2000
  Adult        164  122    58    167  119   61
  Pediatric    135  113    56    133   95   34
  Total        299  235   114    300  214   95

(a) ITT, intent-to-treat population; Clin eval, clinically evaluable
population; Micro eval, microbiologically evaluable population.

1995-1996

Pseudomonas aeruginosa  65%
Staphylococcus aureus    8%
Enterobacter cloacae     4%
Enterococcus faecalis    6%
Kiebsielia pneamoniae    3%
Proteus mirabilis        5%
Other                    9%

N = 208 Pathogens

1999-2000

Pseudomonas aeruginosa  71%
Staphylococcus aureus    4%
Enterobacter cloacae     3%
Enterococcus faecalis    4%
Kiebsielia pneamoniae    2%
Proteus mirabilis        2%
Other                   14%

N = 249 Pathogens

Fig. 1 Pathogens identified from both treatment groups in the 1995 to
1996 and 1999 to 2000 studies.

Note: Table made from pie chart.

Table 3. Pathogen eradication rate per patient in the microbiologically
evaluable population in 1995-1996 studies versus 1999-2000 studies (a)

             Ofloxacin pathogen   Neomycin/polymyxin B
             eradication rate,    pathogen eradication
Study years  n/N (%)              rate, n/N (%)

1995-1996       77/78 (99)            90/91 (99)
1999-2000       93/94 (99)            77/79 (98)

(a) n, number of subjects with pathogen eradication; N, total number of
subjects in the treatment group.

Table 4. Overall clinical cure rate per patient in the intent-to-treat
population in 1995-1996 studies versus 1999-2000 studies (a)

                               Neomycin/

             Ofloxacin         polymyxin B
             overall clinical  overall clinical
             cure rate,        cure rate,
Study years  n/N (%)           n/N (%)           P value

1995-1996    198/272 (72.8)    205/271 (75.6)    NS
1999-2000    221/299 (73.9)    191/300 (63.7)    0.021 (b)

(a) n, number of subjects with clinical cure; N, total number of
subjects in treatment group; NS, not statistically significant.
(b) Statistically significant.

Table 5. Mean MICs for ofloxacin, neomycin, and polymyxin B for major
pathogens in two time periods of study for otitis externa (a,b)

                            Ofloxacin (breakpoint
                            [greater than or equal to]2 [micro]g/mL)
                            1995-1996      1999-2000

Pseudomonas aeruginosa (n)   1.0 (134) (b)  1.0 (176)
Staphylococcus aureus (n)    0.25 (17)      0.5 (11)
Enterobacter cloacae (n)     0.12 (8)       0.12 (7)
Enterococcus faecalis (n)    1.0 (13)       1.0 (10)
Proteus mirabilis (n)       <0.12 (10)      0.12 (4)

                            Neomycin (breakpoint
                            [greater than or equal to]10 [micro]g/mL)
                            1995-1996   1999-2000

Pseudomonas aeruginosa (n)   2.5 (134)     8.0 (176)
Staphylococcus aureus (n)    0.25 (17)     1.0 (11)
Enterobacter cloacae (n)     0.925 (8)     2.0 (7)
Enterococcus faecalis (n)   40 (13)     >128 (10)
Proteus mirabilis (n)        2.5 (10)      4.0 (4)

                            Polymyxin B (breakpoint
                            [greater than or equal to]4 [micro]g/mL)
                            1995-1996   1999-2000

Pseudomonas aeruginosa (n)  0.06 (134)    16.0 (176)
Staphylococcus aureus (n)   4.0 (17)    >128 (11)
Enterobacter cloacae (n)    0.03 (8)    >128 (7)
Enterococcus faecalis (n)   2.0 (13)    >128 (10)
Proteus mirabilis (n)       4.0 (10)    >128 (4)

(a) n, number of pathogen isolates; MIC, minimum inhibitory
concentration.
(b) MIC values are micrograms per milliliter.

Acknowledgment

We thank Nilda V. Jacobus, MPH, for technical assistance with the early stages of this study; Mindell Seidlin, MD, for assistance with the design of these trials; John Riefler, MD, for assistance with preparation of the manuscript; and Victor Fernandez for assistance with preparation of tables and figures.

Accepted July 9, 2003.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9705-0465

References

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2. Data on file at Daiichi Pharmaceutical Corp., Montvale, NJ, 2002.

3. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobic disc susceptibility tests (Approved Standard M2-A2 S2). Wayne, PA, National Committee for Clinical Laboratory Standards, 1981.

4. Matsen JM, Barry AL. Susceptibility testing: Diffusion test procedures, in Lennette EH, Spaulding EH, Truant JP (eds): Manual of Clinical Microbiology. Washington, DC, American Society for Microbiology, 1974, ed 2, pp 418-427.

5. Gales AC, Reis AO, Jones RN. Contemporary assessment of antimicrobial susceptibility testing methods for polymyxin B and colistin: review of available interpretative criteria and quality control guidelines. J Clin Microbiol 2001;39:183-190.

6. Clayton MI, Osborne JE, Rutherford D, et al. A double-blind, randomized, prospective trial of a topical antiseptic versus a topical antibiotic in the treatment of otorrhoea. Clin Otolaryngol 1990;15:7-10.

7. Emgard P, Hellstrom S. A topical steroid without an antibiotic cures external otitis efficiently: a study in an animal model. Eur Arch Otorhinolaryngol 2001;258:287-291.

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9. Dohar JE, Kenna MA, Wadowsky RM. Therapeutic implications in the treatment of aural Pseudomonas infections based on in vitro susceptibility patterns. Arch Otolaryngol Head Neck Surg 1995;121:1022-1025.

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RELATED ARTICLE: Key Points

* The predominant pathogens associated with otitis externa are Pseudomonas aeruginosa and Staphylococcus aureus.

* Two clinical studies conducted from 1995 to 1996 and two studies conducted from 1999 to 2000 compared the efficacy of topical neomycin/polymyxin B to topical ofloxacin in otitis externa.

* Observations from these studies indicate that the pathogens associated with otitis externa are developing resistance to neomycin and polymyxin B but not to ofloxacin.

H. Furman Cantrell, PHD, Elyane E. Lombardy, MD, Frederick P. Duncanson, MD, Ephraim Katz, PHD, and Joseph S. Barone, MD

From Daiichi Pharmaceutical Co., Ltd., Montvale, NJ.

Reprint requests to H. Furman Cantrell, PhD, Microbiology, Anti-Infectives, Daiichi Pharmaceutical Co., Ltd., 11 Philips Parkway, Montvale, NJ 07645. Email: [e-mail]