- Email: [email protected]
The development of antibiotic resistant organisms with the use of ototopical medications
The development of antibiotic resistant organisms with the use of ototopical medications PETER C. WEBER, MD, PETER S. ROLAND, MD, MAUREEN HANNLEY, PHD, RICK FRIEDMAN, MD, PHD, SPIROS MANOLIDIS, MD, GREG MATZ, MD, FRED OWENS, MD, LEONARD RYBAK, MD, PHD, and MICHAEL G. STEWART, MD, MPH, Cleveland, Ohio, Dallas
and Houston, Texas, Alexandria, Virginia, Los Angeles, California, and Chicago and Springfield, Illinois OBJECTIVE: There is growing concern over the use of systemic antibiotics and the development of bacterial resistance. The question remains as to whether ototopical medications may also promote antibiotic-resistant organisms, either on a local level (in the ear) or in other areas of the aerodigestive tract. We performed an evidence-based review to answer the following clinical question, “Do antibiotic ototopical medications induce antibiotic resistant organisms?” STUDY DESIGN: We performed a MEDLINE search of the published literature from 1966 to the present. We used appropriate search terms such as “ototopical antibiotics,” “ototopical drops,” “antibiotic resistance,” “topical antibiotics and otitis externa,” “otitis externa and treatment,” “otitis externa and antibiotic drops,” “otitis externa and ototopical drops,” “otitis media,” “otitis media and treatment,” “otitis media and antibiotic drops,” “chronic suppurative otitis media,” “chronic suppurative otitis media and treatment,” “chronic suppurative otitis media and antibiotic drops,” “ otitis externa and resistant organisms,” “otitis media and resistant organisms,” “chronic suppurative otitis media and resistant organisms,” “ophthalmic antibiotic drops,” “draining
From the Department of Otolaryngology and Communicative Disorders, Cleveland Clinic Foundation, Ohio (Dr Weber), Department of Otolaryngology–Head and Neck Surgery, The University of Texas Southwestern Medical Center at Dallas (Dr Roland), American Academy of Otolaryngology–Head and Neck Surgery, Alexandria (Dr Hannley), House Ear Clinic, Los Angeles (Dr Friedman), Bobby R. Alford Department of Otorhinolaryngology, Baylor College of Medicine, Houston (Drs Manolidis and Stewart) Loyola University Medical Center (Dr Matz), Chicago, Division of Otolaryngology, Southern Illinois School of Medicine (Dr Rybak), Springfield. Dr Owens is in private practice in Dallas, Tex. Reprint requests: Peter C. Weber, MD, The Cleveland Clinic Foundation, 9500 Euclid Ave, A-71, Cleveland, OH 44195. 0194-5998/$30.00 Copyright © 2004 by the American Academy of Otolaryngology–Head and Neck Surgery Foundation, Inc. doi:10.1016/j.otohns.2003.12.009
ear,” “P.E. tube otorrhea,” “pressure equalizing tube otorrhea,” “pressure equalizing tube otorrhea and treatment,” and “pressure equalizing tube otorrhea and ototopical therapy” to identify pertinent articles. These articles were reviewed and graded according to the evidence quality. RESULTS: After an initial screening of over 2,500 articles, 38 articles were analyzed further; of these, 11 were determined to warrant extensive review. Eight articles evaluated chronic suppurative otitis media; 2, otitis externa; and 1, post–tympanostomy tube otorrhea, whereas 3 others studied systemic absorption. Of the 8 chronic suppurative otitis media studies, there were thought to be 5 grade 2B studies, 1 grade 1B study, and 1 grade 2C study. These studies did not demonstrate a propensity for the development of resistant organisms. No study answered the question as to whether resistance to systemic antibiotics might occur in otitis externa. CONCLUSIONS: Overall grade B evidence seems to indicate that no significant antibiotic resistance develops from the use of ototopical antibiotic treatment. (Otolaryngol Head Neck Surg 2004;130: S89-S94.)
T he development of resistant bacterial organisms to antibiotic therapy is an increasing problem for physicians treating a variety of infections. Bacterial resistance to amoxicillin has doubled in the past 5 years, and the scientific literature documents ever-increasing resistance to other -lactamase– containing antibiotics, cephalosporins, fluoroquinolones, and macrolides. Thus, there has been a call for the more judicious use of antibiotic therapy in the treatment of infections, because many infections may be viral and not bacterial. Indeed, Klein1 recently proposed the use of topical agents in place of oral or parenteral antibiotics for patients with chronic suppurative otitis media (CSOM), acute otitis media (AOM), and tympanostomy tube otorrhea to decrease the risk of the development of resistant strains of bacteria for the patient and the community. Klein1 suggests that topical fluoroquinolones are a good choice beS89
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cause they have a high cure rate without systemic absorption. Thus, they do not affect the resident flora of the upper respiratory tract and do not increase selection pressure for the development of resistant bacteria. The possibility of the emergence of significant bacterial resistance after the use of ototopical medications raises concern that such resistant organisms might be a source for reinfection by organisms not sensitive to the usual systemic or topical therapies. The basis for such concern comes from the ophthalmology literature on the use of topical antibiotics for corneal ulcers, which has produced resistant organisms. These studies have included fluoroquinolones drops and have demonstrated an increase in bacterial resistance from 5% to 12% in a 1-year time span.2 Most of the organisms recovered were gram-positive organisms such as Staphylococcus aureus, and S. aureus is not an uncommon causative agent in external or middle ear disease. The lack of significant systemic absorption after topical administration of ear drops and the ability of topical antibiotics to achieve very high concentrations in the middle ear are often given as reasons why topical drops are less likely to produce resistant organisms. However, given the experience documented in the ophthalmologic literature where these same conditions apply, there is reason for concern. Because of such uncertainties, we performed this evidence-based review. METHODS The methodology for evidence-based review has been described in detail elsewhere3,4; briefly, it consists of 4 steps: 1) development of a focused clinical question, 2) systemic search of the published literature, 3) critical evaluation of the literature for methodology and quality, and 4) recommendations made on the basis of the quality of the evidence and the study results. Finally, for the practice of evidence-based medicine, a fifth step is included: The clinician must integrate the results of the evidence-based review with their own clinical experience in combination with the wishes of the patient to identify the best treatment for each individual patient.3 This evidence-based review is intended to synthesize and summarize what is thought to be the best clinical evidence to assist
Otolaryngology– Head and Neck Surgery MARCH 2004
clinicians, but it does not necessarily represent a standard of care. Our focused clinical questions were “Does the use of ototopical antibiotic therapy promote the development of resistant bacterial organisms in the ear?” and “Does the use of ototopical medications promote the development of resistant bacterial organisms in other portions of the aerodigestive tract?” We performed a MEDLINE literature search using the MeSH search terms of “ototopical antibiotics,” “topical antibiotics,” “antibiotic resistance,” “chronic otitis media treatment,” “ototopical antibiotics and resistance,” “topical antibiotics and resistance,” “otitis externa treatment,” “otorrhea treatment,” and others with the following search limits: publication date of 1996 to the present and English language only. In addition, we reviewed the bibliographies of articles retrieved from the search to identify other potential articles. For each article retrieved from the search, the title and abstract were reviewed to identify articles that were potentially pertinent to the specific focus question. The entire text of each identified article was then reviewed in more detail, including entry and exclusion criteria, sample size, study methodology, appropriate randomization, matching and/or blinding, vindicated duration of follow-up, completion of follow-up, and statistical analysis. Articles that were deemed pertinent to answer the 2 questions were assigned an evidence level used in the grading system of Sackett et al.3 An evidence table was created containing the reference, its evidence level, and a brief report of study findings. An overall grade of A, B, C, or D was assigned to the cumulative evidence used in the method of Sackett et al.3,4 RESULTS The initial searches yielded over 2500 potential articles. After a brief initial review (title and abstract), most of these articles were eliminated. Thirty-eight articles were then identified for a more detailed review. After a detailed review, only 10 articles were determined to warrant extensive review (Table 1): 8 articles evaluated CSOM; 2 articles, OE; and 1 article, post–tympanostomy tube. Three other articles provided significant information on systemic absorption. A more detailed review of the evidence follows.
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Table 1. The Emergence of Ototopical Resistance Organisms Reference
Overall Grade
van Hasselt et al, 2000
2C
Agro et al, 1998
2B
Dohar et al, 1996
2B
Tutkun et al, 1995
1B
Supiyaphun et al, 1995
2B
Clayton et al, 1990
2B
Miro, 2000
2B
Alper et al, 2000
Jones et al, 1997
2B
Dohar et al, 1999
2C
Roland and Stroman, 2001
1B
DISCUSSION Chronic Suppurative Otitis Media From the start, we note that no study was set up to specifically address the question of antibiotic resistance. However, the studies selected did include antibiotic resistance as one study parameter in the overall design. A study by van Hasselt et al5 (evidence level of 2C) was able to demonstrate that the development of resistance after treatment with ofloxacin was not a major cause for treatment failure. Their study was performed in Africa, where a much higher percentage of fecal bacteria was identified than is usually cultured in the United States. However, of the 124 ears, there were 108 bacterial water pathogens, such as Pseudomonas aeruginosa, and other common otitis media pathogens (S. pneumonia, H. influenza, and M. catarhallis). Of the 124 ears, 33 still had a draining ear after treatment, but these were due to fecal bacteria (like Enterobacter, E. coli, and others). Thirty-five bacterial strains were
Summary
Development of resistant organisms after ofloxacin treatment. Not a major cause for treatment failure No development of resistant organisms after use of ototopical ofloxacin No development of resistant organisms after use of ototopicals as demonstrated by high in vitro activity to Pseudomonas with either polymyxin B, colistin, or norfloxacin No development of resistant organisms with Cipro HC drops, but a slight chance of resistant organisms with the use of gentamicin drops All patients cured. One patient developed resistant Pseudomonas during treatment No resistant organisms with use of aluminum acetate. One patient developed resistance to gentamicin drops during treatment, and 12 were resistant to gentamicin before treatment. No resistant organisms after use of ciprofloxin. There were 5 reinfections with different susceptible organisms. PNH had 7 ears with persistent drainage and 2 reinfections Animal study comparing tobramycin/dexamethasone, tobramycin alone, and control of saline. No resistant organisms developed with Pseudomonas infections. Only one persistence in ofloxacin, which was not resistant. No resistant organisms after use of PNH. Four persistent organisms after use of ofloxacin, but no MICs done in study. No increases in MICs during therapy.
noted to be resistant to ofloxacin pretreatment, and 30 were eradicated. Only 5 of 16 bacterial strains initially susceptible to ofloxacin developed resistance during the course of treatment. The majority of organisms cultured from treatment failure were sensitive to ofloxacin. The authors concluded that rather than the development of resistant bacteria as a cause of failure, the main cause of failure was recolonization with different bacteria. Agro et al6 (evidence level 2B) reported on the topical treatment of CSOM with ototopical ofloxacin. They enrolled 207 patients; but 45 did not complete the study. Of the remaining 162, only 99 ears had full microbiology available for full evaluation. There was a 100% clinical cure of the 162 patients in their study. One patient was infected with Pseudomonas that was resistant in vitro to ofloxacin pretreatment, but clinically, the ear was cured. The resistance is questionable because in the laboratory the minimum inhibitory concentration (MIC) value was 8, only twice normal. It
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should be noted, however, MIC levels may have limited value when using topical agents because much higher concentrations can be achieved with ototopical preparations than that with systemic preparations. Dohar et al7 (evidence level 2B) evaluated 231 ears treated for either otitis externa (OE), subacute otitis media, or CSOM without cholesteatoma. In their study, they did not separate these 3 groups. Thirty-six percent were treated with topical therapeutic agents within 30 days of the culture. There was no significant increase in resistance to the agents being studied; polymyxin B, colistin, or norfloxacin. The in vitro activity against Pseudomonas was 99.6% against polymyxin B, 97.4% against colistin, and 98.3% against norfloxacin. The authors concluded that no significant resistance had developed from the previous use of ototopical antibiotics. Tutkun et al,8 in a level 1B study, compared topical treatment with gentamicin to ciprofloxacin in patients with CSOM. The most common organism recovered was P. aeruginosa. Other organisms included S. aureus and Enterobacter. In this study, 24 patients were treated with ciprofloxacin and 20 with gentamicin. In the ciprofloxacin group, there were no pretreatment resistant organisms identified. There was a clinical cure rate of 88%, or 21 patients. Of the 3 for whom treatment was a failure, none showed resistant strains of an organism, but rather these patients yielded positive cultures for Candida albicans. In the 20 patients who received gentamicin, 12 (60%) had microorganisms resistant to gentamicin before treatment. Eight (40%) of the 20 were not resistant to the gentamicin before treatment. Only 6 (30%) of the gentamicin group were cured, and the remaining 14 (70%) patients were found to be resistant to gentamicin after treatment, based on MIC values. Thus, this particular study did demonstrate a slight increase in resistance to gentamicin during therapy. Supiyaphun et al9 (evidence level 2B) looked at the treatment of CSOM and OE with ofloxacin. In their study, there were 96 patients or 103 ears: 71 with CSOM and 32 with OE. Eighty-eight ears were available for follow-up: 61 with CSOM and 27 with OE. The drug studied was ofloxacin. There were 2 cases of Pseudomonas that were
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resistant to ofloxacin before treatment, but these 2 patients did have a good clinical outcome. There was 1 case of Pseudomonas that developed resistance during treatment (based on high MIC values) but still resolved clinically over time. Resistances was defined as an MIC of greater than 8 mg/mL. The overall clinical success rate was 92% for CSOM and 85% for OE. Clayton et al10 (evidence level 2B) performed a double-blinded, randomized prospective trial looking at the treatment of otorrhea due to either OE, mastoid bowl drainage, or CSOM. Aluminum acetate or gentamicin (0.3%) was the treatment agent. One hundred thirty-nine ears were entered into the trial, and 102 (74%) completed the study. Improvement in otorrhea occurred in 68% of the gentamicin-treated ears and in 67% of the aluminum acetate–treated ears. No organisms resistant to aluminum acetate were encountered. Twelve organisms recovered from 12 gentamicin-treated ears were resistant before treatment, and 1 organism in another ear developed further gentamicin resistance during treatment. Of the 12 patients who demonstrated resistance to gentamicin before treatment, the bacteria were either -hemolytic Streptococcus, Pseudomonas, bacteriodes, or yeast. Miro11 (evidence level 2B), with cooperation from the Spanish ENT study group, developed a multicenter study comparing the treatment of CSOM with ciprofloxacin 0.2% versus polymyxin B/neomycin/hydrocortisone suspension (PNH). In their study, 322 ears were enrolled. However, for final analysis only 232 ears were available. One hundred nineteen of these patients were treated with ciprofloxacin, and 113 with PNH suspension. In the ciprofloxacin group, 93% showed eradication of all original organisms. In 5 patients, a reinfection occurred, meaning a new organism was isolated that had not been isolated previously. These new organisms were Staphylococcus epidermidis, Proteus mirabilis, or Candida. The PNH group demonstrated persistence in 7 ears with 2 additional reinfections. These reinfections were due to Candida and Streptococcus. Persistent organisms included Pseudomonas, Proteus, S. aureus, and Streptococcus. Alper et al12 (evidence level 1B) designed a blinded, randomized, placebo-controlled trial in an
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animal model of monkeys comparing CSOM treatment with tobramycin/dexamethasone, tobramycin alone, and a control of phosphate-buffered saline. The organism used to establish the CSOM was P. aeruginosa. There was rapid resolution of otorrhea and eradication of the Pseudomonas in all groups receiving tobramycin. The inclusion of dexamethasone did seem to accelerate resolution and the percentage of negative cultures compared with tobramycin alone. No resistant organisms were found in any of the posttreatment cultures. Thus, no resistance was observed in this animal study. Acute Otitis Externa There were only 2 studies that were dedicated to evaluating OE alone. Of these, Jones et al13 (evidence level 2B) looked at ofloxacin topical therapy versus PNH for the treatment of OE. There were 247 adults and 227 children in their clinical study. Microbiologic studies were performed on only 98 adults and 98 children. Before treatment, 2% of the ears had an organism resistant to ofloxacin, and 8%, to the PNH. There was 98% eradication of organisms after treatment in both treatment groups. There was only one persistent Pseudomonas infection in the ofloxacin-treated group, which was not resistant by MIC levels to ofloxacin pretreatment. There was one Pseudomonas organism in the PNH-treated group that was resistant to ofloxacin but not to the PNH. Clinical success was demonstrated in 85% of adults treated with ofloxacin, and in 88%, with PNH. Children demonstrated higher clinical cure rates at 98% with ofloxacin and 100% with PNH. A study by Roland and Stroman14 (evidence level 1B) evaluated the microbiology of 2039 ears with OE. No acquired resistance was identified during treatment. The highest overall acquired resistance rates in pretherapy isolates were seen in staphylococcal species, especially S. aureus and S. epidermidis. However, overall susceptibility of organisms recovered from ears with OE remains good using the National Committee for Clinical Laboratory Standards breakpoints. The highest level of acquired aminoglycoside resistance in pretherapy isolates was seen in E. coli; next was Actinobacter. It should be noted that gentamicin resistance did not correlate well with tobramycin
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resistance. S. aureus had the highest level of pretherapy quinolone resistance, with Acinetobacter close behind. Tube Otorrhea Dohar et al15 (evidence level 2B) evaluated tube otorrhea, and they used topical ofloxacin as treatment. In this study, 226 patients were enrolled, but only 107 ears were available to evaluate by the end of the study. Ninety-six percent (96%) of bacteria were eradicated during treatment. There were 4 failures; 2 of these were due to persistent P. aeruginosa, 1 was due to a persistent S. pneumococcus, and there was 1 reinfection due to a new Pseudomonas organism. MIC tests were not performed, and thus there is no evidence of an in vitro nature of whether there was acquired resistance. One can only say that there was persistence of the same organism. Systemic Absorption Very few studies looked at systemic absorption of topical therapy. There is one case report by Green et al16 that demonstrates systemic absorption of topical gentamicin producing a serum gentamicin level of 6.2 g/mL. A study by Force et al17 looked at plasma levels of ciprofloxacin in patients treated with ciprofloxacin for tympanostomy tube otorrhea. Ohyama et al18 performed a similar study with ofloxacin. Neither study demonstrated any systemic uptake of the fluoroquinolone. CONCLUSION Although these studies did not specifically investigate the emergence of resistance during ototopical treatment, they do indicate that the development of resistant organisms is relatively rare. Most clinical failures are due to persistence of the original organism without the development of resistance or from a brand-new organism. The chance of developing bacteriologic resistance in the upper airway/digestive tract is exceedingly rare, as commented on by Klein,1 because 1) there is little systemic absorption and therefore 2) there is no selective pressure for the development of resistant organisms in the upper airway. Even when organisms are “resistant” before treatment with ototopical therapy, the organisms often do
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respond to the topical therapy to which they are “resistant” because of the higher drug concentrations that can be achieved with ototopical therapy. We conclude that grade B evidence supports the assertion that only rarely (if ever) does topical therapy produce resistant organisms, either locally within the external auditory canal and middle ear or more remotely in other parts of the aerodigestive tract. REFERENCES
1. Klein JO. Strategies for decreasing multidrug antibiotic resistance: role of ototopical agents for treatment of middle ear infections. Am J Manage Care 20028(14 suppl): S345-52. 2. Stonecipher KG, Jensen H. Diagnosis, laboratory analysis and treatment of bacterial corneal ulcers. In: Stonecipher KG, Jensen H, editors: Bacterial Corneal Ulcers. Princeton, NJ: Lister Hill, pp 53-63. 3. Sackett DL, Straus SE, Richardson WS, et al. Evidencebased Medicine: How to Practice and Teach EBM, 2nd edition. Edinburg: Churchhill Livingstone; 2000. 4. Phillips B, Ball C, Sackett DL, et al. Levels of evidence and grades recommendation. http://cebm.jr2.ox.ac.uk/ docslevels.html. 5. van Hasselt P, van Kregten E. Treatment of chronic suppurative otitis media with ofloxacin in hydroxypropyl methylcellulose ear drops: a clinical/bacteriological study in a rural area of Malawi. Int J Pediatr Otorhinolaryngol 2000;63:49-56. 6. Agro AS, Garner ET, Wright M III, et al. Clinical trial of ototopical ofloxacin for treatment of chronic suppurative otitis media. Clin Therap 1998;20:744-59. 7. Dohar JE, Kenna MA, Wadowsky RM. In vitro susceptibility of aural isolates of Pseudomonas aeruginosa to commonly used ototopical antibiotics. Am J Otol 1996; 17:207-9.
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¨ zagar A, Kol A, et al. Treatment of chronic 8. Tutkun A, O ear disease. Arch Otolaryngol Head Neck Surg 1995;121: 1414-6. 9. Supiyaphun P, Tonsakulrungruang K, Chochaipanichnon L, et al. The treatment of chronic suppurative otitis media and otitis externa with 0.3% ofloxacin otic solution: a clinicomicrobiological study. J Med Assoc Thai 1995;78: 18-21. 10. Clayton MI, Osborne JE, Rutherford D, et al. A doubleblind, randomized prospective trial of a topical antiseptic vs a topical antibiotic in the treatment of otorrhea. Clin Otolaryngol 1990;15:7-10. 11. Miro N. Controlled multicenter study on chronic suppurative otitis media treated with topical applications of ciprofloxacin 0.2% solution in single-dose containers or combination of polymyxin B, neomycin, and hydrocortisone suspension. Otolaryngol Head Neck Surg 2000; 123:617-23. 12. Alper CM, Dohar JE, Gulhan M, et al. Treatment of chronic suppurative otitis media with topical tobramycin and dexamethasone. Arch Otolaryngol Head Neck Surg 2000;126:165-73. 13. Jones RN, Milazzo J, Seidlin M. Ofloxacin otic solution for treatment of otitis externa in children and adults. Arch Otolaryngol Head Neck Surg 1997;123:1193-2000. 14. Roland PS, Stroman DW. Microbiology of acute otitis externa. Laryngoscope 2002;112:1166-77. 15. Dohar JE, Garner ET, Nielsen RW, et al. Topical ofloxacin treatment of otorrhea in children with tympanostomy tubes. Arch Otolaryngol Head Neck Surg 1999;125:53745. 16. Green KMJ, Lappin DWP, Curley JWA, et al. Clinical records. Systemic absorption of gentamicin ear drops. J Laryngol Otol 1997;111:960-2. 17. Force RW, Hart MC, Plummer SA, et al. Topical ciprofloxacin for otorrhea after tympanostomy tube placement. Arch Otolaryngol Head Neck Surg 1995;121:880-4. 18. Ohyama M, Furuta S, Ueno K, et al. Ofloxacin otic solution in patients with otitis media. Arch Otolaryngol Head Neck Surg 1999;125:337-40.
and Houston, Texas, Alexandria, Virginia, Los Angeles, California, and Chicago and Springfield, Illinois OBJECTIVE: There is growing concern over the use of systemic antibiotics and the development of bacterial resistance. The question remains as to whether ototopical medications may also promote antibiotic-resistant organisms, either on a local level (in the ear) or in other areas of the aerodigestive tract. We performed an evidence-based review to answer the following clinical question, “Do antibiotic ototopical medications induce antibiotic resistant organisms?” STUDY DESIGN: We performed a MEDLINE search of the published literature from 1966 to the present. We used appropriate search terms such as “ototopical antibiotics,” “ototopical drops,” “antibiotic resistance,” “topical antibiotics and otitis externa,” “otitis externa and treatment,” “otitis externa and antibiotic drops,” “otitis externa and ototopical drops,” “otitis media,” “otitis media and treatment,” “otitis media and antibiotic drops,” “chronic suppurative otitis media,” “chronic suppurative otitis media and treatment,” “chronic suppurative otitis media and antibiotic drops,” “ otitis externa and resistant organisms,” “otitis media and resistant organisms,” “chronic suppurative otitis media and resistant organisms,” “ophthalmic antibiotic drops,” “draining
From the Department of Otolaryngology and Communicative Disorders, Cleveland Clinic Foundation, Ohio (Dr Weber), Department of Otolaryngology–Head and Neck Surgery, The University of Texas Southwestern Medical Center at Dallas (Dr Roland), American Academy of Otolaryngology–Head and Neck Surgery, Alexandria (Dr Hannley), House Ear Clinic, Los Angeles (Dr Friedman), Bobby R. Alford Department of Otorhinolaryngology, Baylor College of Medicine, Houston (Drs Manolidis and Stewart) Loyola University Medical Center (Dr Matz), Chicago, Division of Otolaryngology, Southern Illinois School of Medicine (Dr Rybak), Springfield. Dr Owens is in private practice in Dallas, Tex. Reprint requests: Peter C. Weber, MD, The Cleveland Clinic Foundation, 9500 Euclid Ave, A-71, Cleveland, OH 44195. 0194-5998/$30.00 Copyright © 2004 by the American Academy of Otolaryngology–Head and Neck Surgery Foundation, Inc. doi:10.1016/j.otohns.2003.12.009
ear,” “P.E. tube otorrhea,” “pressure equalizing tube otorrhea,” “pressure equalizing tube otorrhea and treatment,” and “pressure equalizing tube otorrhea and ototopical therapy” to identify pertinent articles. These articles were reviewed and graded according to the evidence quality. RESULTS: After an initial screening of over 2,500 articles, 38 articles were analyzed further; of these, 11 were determined to warrant extensive review. Eight articles evaluated chronic suppurative otitis media; 2, otitis externa; and 1, post–tympanostomy tube otorrhea, whereas 3 others studied systemic absorption. Of the 8 chronic suppurative otitis media studies, there were thought to be 5 grade 2B studies, 1 grade 1B study, and 1 grade 2C study. These studies did not demonstrate a propensity for the development of resistant organisms. No study answered the question as to whether resistance to systemic antibiotics might occur in otitis externa. CONCLUSIONS: Overall grade B evidence seems to indicate that no significant antibiotic resistance develops from the use of ototopical antibiotic treatment. (Otolaryngol Head Neck Surg 2004;130: S89-S94.)
T he development of resistant bacterial organisms to antibiotic therapy is an increasing problem for physicians treating a variety of infections. Bacterial resistance to amoxicillin has doubled in the past 5 years, and the scientific literature documents ever-increasing resistance to other -lactamase– containing antibiotics, cephalosporins, fluoroquinolones, and macrolides. Thus, there has been a call for the more judicious use of antibiotic therapy in the treatment of infections, because many infections may be viral and not bacterial. Indeed, Klein1 recently proposed the use of topical agents in place of oral or parenteral antibiotics for patients with chronic suppurative otitis media (CSOM), acute otitis media (AOM), and tympanostomy tube otorrhea to decrease the risk of the development of resistant strains of bacteria for the patient and the community. Klein1 suggests that topical fluoroquinolones are a good choice beS89
S90 WEBER et al
cause they have a high cure rate without systemic absorption. Thus, they do not affect the resident flora of the upper respiratory tract and do not increase selection pressure for the development of resistant bacteria. The possibility of the emergence of significant bacterial resistance after the use of ototopical medications raises concern that such resistant organisms might be a source for reinfection by organisms not sensitive to the usual systemic or topical therapies. The basis for such concern comes from the ophthalmology literature on the use of topical antibiotics for corneal ulcers, which has produced resistant organisms. These studies have included fluoroquinolones drops and have demonstrated an increase in bacterial resistance from 5% to 12% in a 1-year time span.2 Most of the organisms recovered were gram-positive organisms such as Staphylococcus aureus, and S. aureus is not an uncommon causative agent in external or middle ear disease. The lack of significant systemic absorption after topical administration of ear drops and the ability of topical antibiotics to achieve very high concentrations in the middle ear are often given as reasons why topical drops are less likely to produce resistant organisms. However, given the experience documented in the ophthalmologic literature where these same conditions apply, there is reason for concern. Because of such uncertainties, we performed this evidence-based review. METHODS The methodology for evidence-based review has been described in detail elsewhere3,4; briefly, it consists of 4 steps: 1) development of a focused clinical question, 2) systemic search of the published literature, 3) critical evaluation of the literature for methodology and quality, and 4) recommendations made on the basis of the quality of the evidence and the study results. Finally, for the practice of evidence-based medicine, a fifth step is included: The clinician must integrate the results of the evidence-based review with their own clinical experience in combination with the wishes of the patient to identify the best treatment for each individual patient.3 This evidence-based review is intended to synthesize and summarize what is thought to be the best clinical evidence to assist
Otolaryngology– Head and Neck Surgery MARCH 2004
clinicians, but it does not necessarily represent a standard of care. Our focused clinical questions were “Does the use of ototopical antibiotic therapy promote the development of resistant bacterial organisms in the ear?” and “Does the use of ototopical medications promote the development of resistant bacterial organisms in other portions of the aerodigestive tract?” We performed a MEDLINE literature search using the MeSH search terms of “ototopical antibiotics,” “topical antibiotics,” “antibiotic resistance,” “chronic otitis media treatment,” “ototopical antibiotics and resistance,” “topical antibiotics and resistance,” “otitis externa treatment,” “otorrhea treatment,” and others with the following search limits: publication date of 1996 to the present and English language only. In addition, we reviewed the bibliographies of articles retrieved from the search to identify other potential articles. For each article retrieved from the search, the title and abstract were reviewed to identify articles that were potentially pertinent to the specific focus question. The entire text of each identified article was then reviewed in more detail, including entry and exclusion criteria, sample size, study methodology, appropriate randomization, matching and/or blinding, vindicated duration of follow-up, completion of follow-up, and statistical analysis. Articles that were deemed pertinent to answer the 2 questions were assigned an evidence level used in the grading system of Sackett et al.3 An evidence table was created containing the reference, its evidence level, and a brief report of study findings. An overall grade of A, B, C, or D was assigned to the cumulative evidence used in the method of Sackett et al.3,4 RESULTS The initial searches yielded over 2500 potential articles. After a brief initial review (title and abstract), most of these articles were eliminated. Thirty-eight articles were then identified for a more detailed review. After a detailed review, only 10 articles were determined to warrant extensive review (Table 1): 8 articles evaluated CSOM; 2 articles, OE; and 1 article, post–tympanostomy tube. Three other articles provided significant information on systemic absorption. A more detailed review of the evidence follows.
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Table 1. The Emergence of Ototopical Resistance Organisms Reference
Overall Grade
van Hasselt et al, 2000
2C
Agro et al, 1998
2B
Dohar et al, 1996
2B
Tutkun et al, 1995
1B
Supiyaphun et al, 1995
2B
Clayton et al, 1990
2B
Miro, 2000
2B
Alper et al, 2000
Jones et al, 1997
2B
Dohar et al, 1999
2C
Roland and Stroman, 2001
1B
DISCUSSION Chronic Suppurative Otitis Media From the start, we note that no study was set up to specifically address the question of antibiotic resistance. However, the studies selected did include antibiotic resistance as one study parameter in the overall design. A study by van Hasselt et al5 (evidence level of 2C) was able to demonstrate that the development of resistance after treatment with ofloxacin was not a major cause for treatment failure. Their study was performed in Africa, where a much higher percentage of fecal bacteria was identified than is usually cultured in the United States. However, of the 124 ears, there were 108 bacterial water pathogens, such as Pseudomonas aeruginosa, and other common otitis media pathogens (S. pneumonia, H. influenza, and M. catarhallis). Of the 124 ears, 33 still had a draining ear after treatment, but these were due to fecal bacteria (like Enterobacter, E. coli, and others). Thirty-five bacterial strains were
Summary
Development of resistant organisms after ofloxacin treatment. Not a major cause for treatment failure No development of resistant organisms after use of ototopical ofloxacin No development of resistant organisms after use of ototopicals as demonstrated by high in vitro activity to Pseudomonas with either polymyxin B, colistin, or norfloxacin No development of resistant organisms with Cipro HC drops, but a slight chance of resistant organisms with the use of gentamicin drops All patients cured. One patient developed resistant Pseudomonas during treatment No resistant organisms with use of aluminum acetate. One patient developed resistance to gentamicin drops during treatment, and 12 were resistant to gentamicin before treatment. No resistant organisms after use of ciprofloxin. There were 5 reinfections with different susceptible organisms. PNH had 7 ears with persistent drainage and 2 reinfections Animal study comparing tobramycin/dexamethasone, tobramycin alone, and control of saline. No resistant organisms developed with Pseudomonas infections. Only one persistence in ofloxacin, which was not resistant. No resistant organisms after use of PNH. Four persistent organisms after use of ofloxacin, but no MICs done in study. No increases in MICs during therapy.
noted to be resistant to ofloxacin pretreatment, and 30 were eradicated. Only 5 of 16 bacterial strains initially susceptible to ofloxacin developed resistance during the course of treatment. The majority of organisms cultured from treatment failure were sensitive to ofloxacin. The authors concluded that rather than the development of resistant bacteria as a cause of failure, the main cause of failure was recolonization with different bacteria. Agro et al6 (evidence level 2B) reported on the topical treatment of CSOM with ototopical ofloxacin. They enrolled 207 patients; but 45 did not complete the study. Of the remaining 162, only 99 ears had full microbiology available for full evaluation. There was a 100% clinical cure of the 162 patients in their study. One patient was infected with Pseudomonas that was resistant in vitro to ofloxacin pretreatment, but clinically, the ear was cured. The resistance is questionable because in the laboratory the minimum inhibitory concentration (MIC) value was 8, only twice normal. It
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should be noted, however, MIC levels may have limited value when using topical agents because much higher concentrations can be achieved with ototopical preparations than that with systemic preparations. Dohar et al7 (evidence level 2B) evaluated 231 ears treated for either otitis externa (OE), subacute otitis media, or CSOM without cholesteatoma. In their study, they did not separate these 3 groups. Thirty-six percent were treated with topical therapeutic agents within 30 days of the culture. There was no significant increase in resistance to the agents being studied; polymyxin B, colistin, or norfloxacin. The in vitro activity against Pseudomonas was 99.6% against polymyxin B, 97.4% against colistin, and 98.3% against norfloxacin. The authors concluded that no significant resistance had developed from the previous use of ototopical antibiotics. Tutkun et al,8 in a level 1B study, compared topical treatment with gentamicin to ciprofloxacin in patients with CSOM. The most common organism recovered was P. aeruginosa. Other organisms included S. aureus and Enterobacter. In this study, 24 patients were treated with ciprofloxacin and 20 with gentamicin. In the ciprofloxacin group, there were no pretreatment resistant organisms identified. There was a clinical cure rate of 88%, or 21 patients. Of the 3 for whom treatment was a failure, none showed resistant strains of an organism, but rather these patients yielded positive cultures for Candida albicans. In the 20 patients who received gentamicin, 12 (60%) had microorganisms resistant to gentamicin before treatment. Eight (40%) of the 20 were not resistant to the gentamicin before treatment. Only 6 (30%) of the gentamicin group were cured, and the remaining 14 (70%) patients were found to be resistant to gentamicin after treatment, based on MIC values. Thus, this particular study did demonstrate a slight increase in resistance to gentamicin during therapy. Supiyaphun et al9 (evidence level 2B) looked at the treatment of CSOM and OE with ofloxacin. In their study, there were 96 patients or 103 ears: 71 with CSOM and 32 with OE. Eighty-eight ears were available for follow-up: 61 with CSOM and 27 with OE. The drug studied was ofloxacin. There were 2 cases of Pseudomonas that were
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resistant to ofloxacin before treatment, but these 2 patients did have a good clinical outcome. There was 1 case of Pseudomonas that developed resistance during treatment (based on high MIC values) but still resolved clinically over time. Resistances was defined as an MIC of greater than 8 mg/mL. The overall clinical success rate was 92% for CSOM and 85% for OE. Clayton et al10 (evidence level 2B) performed a double-blinded, randomized prospective trial looking at the treatment of otorrhea due to either OE, mastoid bowl drainage, or CSOM. Aluminum acetate or gentamicin (0.3%) was the treatment agent. One hundred thirty-nine ears were entered into the trial, and 102 (74%) completed the study. Improvement in otorrhea occurred in 68% of the gentamicin-treated ears and in 67% of the aluminum acetate–treated ears. No organisms resistant to aluminum acetate were encountered. Twelve organisms recovered from 12 gentamicin-treated ears were resistant before treatment, and 1 organism in another ear developed further gentamicin resistance during treatment. Of the 12 patients who demonstrated resistance to gentamicin before treatment, the bacteria were either -hemolytic Streptococcus, Pseudomonas, bacteriodes, or yeast. Miro11 (evidence level 2B), with cooperation from the Spanish ENT study group, developed a multicenter study comparing the treatment of CSOM with ciprofloxacin 0.2% versus polymyxin B/neomycin/hydrocortisone suspension (PNH). In their study, 322 ears were enrolled. However, for final analysis only 232 ears were available. One hundred nineteen of these patients were treated with ciprofloxacin, and 113 with PNH suspension. In the ciprofloxacin group, 93% showed eradication of all original organisms. In 5 patients, a reinfection occurred, meaning a new organism was isolated that had not been isolated previously. These new organisms were Staphylococcus epidermidis, Proteus mirabilis, or Candida. The PNH group demonstrated persistence in 7 ears with 2 additional reinfections. These reinfections were due to Candida and Streptococcus. Persistent organisms included Pseudomonas, Proteus, S. aureus, and Streptococcus. Alper et al12 (evidence level 1B) designed a blinded, randomized, placebo-controlled trial in an
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animal model of monkeys comparing CSOM treatment with tobramycin/dexamethasone, tobramycin alone, and a control of phosphate-buffered saline. The organism used to establish the CSOM was P. aeruginosa. There was rapid resolution of otorrhea and eradication of the Pseudomonas in all groups receiving tobramycin. The inclusion of dexamethasone did seem to accelerate resolution and the percentage of negative cultures compared with tobramycin alone. No resistant organisms were found in any of the posttreatment cultures. Thus, no resistance was observed in this animal study. Acute Otitis Externa There were only 2 studies that were dedicated to evaluating OE alone. Of these, Jones et al13 (evidence level 2B) looked at ofloxacin topical therapy versus PNH for the treatment of OE. There were 247 adults and 227 children in their clinical study. Microbiologic studies were performed on only 98 adults and 98 children. Before treatment, 2% of the ears had an organism resistant to ofloxacin, and 8%, to the PNH. There was 98% eradication of organisms after treatment in both treatment groups. There was only one persistent Pseudomonas infection in the ofloxacin-treated group, which was not resistant by MIC levels to ofloxacin pretreatment. There was one Pseudomonas organism in the PNH-treated group that was resistant to ofloxacin but not to the PNH. Clinical success was demonstrated in 85% of adults treated with ofloxacin, and in 88%, with PNH. Children demonstrated higher clinical cure rates at 98% with ofloxacin and 100% with PNH. A study by Roland and Stroman14 (evidence level 1B) evaluated the microbiology of 2039 ears with OE. No acquired resistance was identified during treatment. The highest overall acquired resistance rates in pretherapy isolates were seen in staphylococcal species, especially S. aureus and S. epidermidis. However, overall susceptibility of organisms recovered from ears with OE remains good using the National Committee for Clinical Laboratory Standards breakpoints. The highest level of acquired aminoglycoside resistance in pretherapy isolates was seen in E. coli; next was Actinobacter. It should be noted that gentamicin resistance did not correlate well with tobramycin
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resistance. S. aureus had the highest level of pretherapy quinolone resistance, with Acinetobacter close behind. Tube Otorrhea Dohar et al15 (evidence level 2B) evaluated tube otorrhea, and they used topical ofloxacin as treatment. In this study, 226 patients were enrolled, but only 107 ears were available to evaluate by the end of the study. Ninety-six percent (96%) of bacteria were eradicated during treatment. There were 4 failures; 2 of these were due to persistent P. aeruginosa, 1 was due to a persistent S. pneumococcus, and there was 1 reinfection due to a new Pseudomonas organism. MIC tests were not performed, and thus there is no evidence of an in vitro nature of whether there was acquired resistance. One can only say that there was persistence of the same organism. Systemic Absorption Very few studies looked at systemic absorption of topical therapy. There is one case report by Green et al16 that demonstrates systemic absorption of topical gentamicin producing a serum gentamicin level of 6.2 g/mL. A study by Force et al17 looked at plasma levels of ciprofloxacin in patients treated with ciprofloxacin for tympanostomy tube otorrhea. Ohyama et al18 performed a similar study with ofloxacin. Neither study demonstrated any systemic uptake of the fluoroquinolone. CONCLUSION Although these studies did not specifically investigate the emergence of resistance during ototopical treatment, they do indicate that the development of resistant organisms is relatively rare. Most clinical failures are due to persistence of the original organism without the development of resistance or from a brand-new organism. The chance of developing bacteriologic resistance in the upper airway/digestive tract is exceedingly rare, as commented on by Klein,1 because 1) there is little systemic absorption and therefore 2) there is no selective pressure for the development of resistant organisms in the upper airway. Even when organisms are “resistant” before treatment with ototopical therapy, the organisms often do
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respond to the topical therapy to which they are “resistant” because of the higher drug concentrations that can be achieved with ototopical therapy. We conclude that grade B evidence supports the assertion that only rarely (if ever) does topical therapy produce resistant organisms, either locally within the external auditory canal and middle ear or more remotely in other parts of the aerodigestive tract. REFERENCES
1. Klein JO. Strategies for decreasing multidrug antibiotic resistance: role of ototopical agents for treatment of middle ear infections. Am J Manage Care 20028(14 suppl): S345-52. 2. Stonecipher KG, Jensen H. Diagnosis, laboratory analysis and treatment of bacterial corneal ulcers. In: Stonecipher KG, Jensen H, editors: Bacterial Corneal Ulcers. Princeton, NJ: Lister Hill, pp 53-63. 3. Sackett DL, Straus SE, Richardson WS, et al. Evidencebased Medicine: How to Practice and Teach EBM, 2nd edition. Edinburg: Churchhill Livingstone; 2000. 4. Phillips B, Ball C, Sackett DL, et al. Levels of evidence and grades recommendation. http://cebm.jr2.ox.ac.uk/ docslevels.html. 5. van Hasselt P, van Kregten E. Treatment of chronic suppurative otitis media with ofloxacin in hydroxypropyl methylcellulose ear drops: a clinical/bacteriological study in a rural area of Malawi. Int J Pediatr Otorhinolaryngol 2000;63:49-56. 6. Agro AS, Garner ET, Wright M III, et al. Clinical trial of ototopical ofloxacin for treatment of chronic suppurative otitis media. Clin Therap 1998;20:744-59. 7. Dohar JE, Kenna MA, Wadowsky RM. In vitro susceptibility of aural isolates of Pseudomonas aeruginosa to commonly used ototopical antibiotics. Am J Otol 1996; 17:207-9.
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¨ zagar A, Kol A, et al. Treatment of chronic 8. Tutkun A, O ear disease. Arch Otolaryngol Head Neck Surg 1995;121: 1414-6. 9. Supiyaphun P, Tonsakulrungruang K, Chochaipanichnon L, et al. The treatment of chronic suppurative otitis media and otitis externa with 0.3% ofloxacin otic solution: a clinicomicrobiological study. J Med Assoc Thai 1995;78: 18-21. 10. Clayton MI, Osborne JE, Rutherford D, et al. A doubleblind, randomized prospective trial of a topical antiseptic vs a topical antibiotic in the treatment of otorrhea. Clin Otolaryngol 1990;15:7-10. 11. Miro N. Controlled multicenter study on chronic suppurative otitis media treated with topical applications of ciprofloxacin 0.2% solution in single-dose containers or combination of polymyxin B, neomycin, and hydrocortisone suspension. Otolaryngol Head Neck Surg 2000; 123:617-23. 12. Alper CM, Dohar JE, Gulhan M, et al. Treatment of chronic suppurative otitis media with topical tobramycin and dexamethasone. Arch Otolaryngol Head Neck Surg 2000;126:165-73. 13. Jones RN, Milazzo J, Seidlin M. Ofloxacin otic solution for treatment of otitis externa in children and adults. Arch Otolaryngol Head Neck Surg 1997;123:1193-2000. 14. Roland PS, Stroman DW. Microbiology of acute otitis externa. Laryngoscope 2002;112:1166-77. 15. Dohar JE, Garner ET, Nielsen RW, et al. Topical ofloxacin treatment of otorrhea in children with tympanostomy tubes. Arch Otolaryngol Head Neck Surg 1999;125:53745. 16. Green KMJ, Lappin DWP, Curley JWA, et al. Clinical records. Systemic absorption of gentamicin ear drops. J Laryngol Otol 1997;111:960-2. 17. Force RW, Hart MC, Plummer SA, et al. Topical ciprofloxacin for otorrhea after tympanostomy tube placement. Arch Otolaryngol Head Neck Surg 1995;121:880-4. 18. Ohyama M, Furuta S, Ueno K, et al. Ofloxacin otic solution in patients with otitis media. Arch Otolaryngol Head Neck Surg 1999;125:337-40.