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Impact of biofilms on the treatment of otitis.

The emergence of the biofilm model of otitis media holds tremendous potential implications for treatment. Biofilms are thought by many investigators to be the underlying cause of most recalcitrant infections. (1) Biofilms impart resistance both to host immune defense mechanisms (2,3) and antibiotic treatment. (4) Simply changing antibiotics or raising their levels will prove futile in the case of most pathogens and antimicrobial agents because a biofilm elevates minimum inhibitory concentrations well beyond what can be delivered with systemic therapy. (5) Ototopical therapy can deliver much higher antibiotic concentrations, which may or may not be sufficient to achieve microbial inhibition or killing. (6,7)

Biofilm-mediated survival of pathogens in the presence of antibiotics promotes the development of resistant planktonic forms. (8,9) This effectively extends the impact of biofilm-mediated resistance to infections that are not mediated by biofilms. If systemic antimicrobial therapy is unlikely to eradicate a biofilm-mediated infection and such therapy may well propagate resistance, restriction of systemic antibiotic therapy in biofilm-mediated infections must be considered.

Mechanisms of biofilm-mediated resistance

The mechanisms responsible for biofilm-mediated antibiotic resistance are poorly understood. The exopolymeric matrix may impede the diffusion of some antibiotics, but it will not prevent microbial cell death. (10) Lysis of the matrix does not necessarily return antimicrobial sensitivities to planktonic patterns immediately. (10) The presence of beta-lactamase-producing strains of Pseudomonas aeruginosa increases in the biofilm state. (11)


Drug efflux pumps, which play key roles in the resistance of planktonic microorganisms, may also play a role in biofilm-phenotype resistance to some antimicrobial agents (e.g., ofloxacin but not ciprofloxacin). (10) Subpopulations of super-resistant bacteria have been reported in biofilms of pathogens that are deficient in energy-dependent resistance mechanisms. (10) These organisms are thought to be metabolically dormant. Unfortunately, treatment strategies based on these microbial mechanisms of biofilm resistance are lacking.

Disruption of biofilms

Disruption of microbial biofilms is routinely accomplished in laboratory models by the application of ultrasound and/or detergents. Unfortunately, neither treatment is practical in vivo because both are potentially damaging to the inner ear. (12,13) Furthermore, efforts to disrupt biofilms must avoid causing damage to the beneficial biofilms that are found throughout the body because a loss of commensal organisms in biofilm may also lead to disease states (e.g., thrush).

Modulating the host response to biofilm-forming pathogens may prove to be an effective alternative for treating biofilm-mediated infections. Bacterial toxins secreted from the biofilm lead to a host inflammatory response. Post suggested that "collateral damage" from the host inflammatory response may be responsible for the persistence of middle ear inflammation in chronic otitis media with effusion. (14) Paradoxically, P aeruginosa biofilm formation is promoted by the presence of lysed neutrophils. (15) Neutrophils are vulnerable to the cell lysis that occurs as a result of the production of Pseudomonas toxins in biofilm phenotypes. This vicious cycle promotes biofilm development. (16) Attenuating the host inflammatory response with corticosteroids, either alone or in combination with antibiotics, has proven to be beneficial in the treatment of otitis media and otitis externa. (17-22)

Prevention of biofilms

With the options available for treating established biofilm diseases so limited, we must consider intervention aimed at preventing biofilm formation. However, there is very little literature that addresses such possibilities. In vitro data suggest that early antimicrobial intervention, even with immature biofilm formation, may be more advantageous relative to the eradication of mature biofilms. (23) Early antimicrobial intervention does, however, conflict with the Centers for Disease Control and Prevention's recommendation to withhold antibiotics for early disease, such as uncomplicated otitis media.

The potential for preventing or treating biofilm development is greatest in patients with post-tympanostomy tube otorrhea. Bacterial adherence and biofilm formation may be prevented by avoiding tympanostomy tube exposure to blood (i.e., by meticulous surgical technique). (24) Biofilm formation (figure) might also be avoided by coating the tube's surface with albumin (25,26) or by using tubes composed of biofilm-resistant materials. (27) Most research to date has suggested that using the smoothest biomaterial with the fewest recesses will yield the lowest risk of biofilm formation. (28-31) Finally, certain engineered surface microtopographies (e.g., those that resemble shark skin) have been shown to dramatically decrease the development of biofilms. (32) By reducing biofilm formation on tympanostomy tubes, reduction in post-tympanostomy tube otorrhea and tube occlusion may be possible. (32-35)


(1.) Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: A common cause of persistent infections. Science 1999;284(5418): 1318-22.

(2.) Buret A, Ward KH, Olson ME, Costerton JW. An in vivo model to study the pathobiology of infectious biofilms on biomaterial surfaces. J Biomed Mater Res 1991;25(7):865-74.

(3.) Gilbert P, Collier PJ, Brown MR. Influence of growth rate on susceptibility to antimicrobial agents: Biofilms, cell cycle, dormancy, and stringent response. Antimicrob Agents Chemother 1990;34(10): 1865-8.

(4.) Hoyle BD, Jass J, Costerton JW. The biofilm glycocalyx as a resistance factor. J Antimicrob Chemother 1990;26(1):1-5.

(5.) Olson ME, Ceri H, Morck DW, et al. Biofilm bacteria: Formation and comparative susceptibility to antibiotics. Can J Vet Res 2002; 66(2):86-92.

(6.) Desrosiers M, Bendouah Z, Barbeau J. Effectiveness of topical antibiotics on Staphylococcus aureus biofilm in vitro. Am J Rhinol 2007;21(2):149-53.

(7.) Chiu AG, Antunes MB, Palmer JN, Cohen NA. Evaluation of the in vivo efficacy of topical tobramycin against Pseudomonas sinonasal biofilms. J Antimicrob Chemother 2007;59(6):1130-4.

(8.) Vaudaux P, Francois P, Berger-Bachi B, Lew DP. In vivo emergence of subpopulations expressing teicoplanin or vancomycin resistance phenotypes in a glycopeptide-susceptible, methicillin-resistant strain of Staphylococcus aureus. J Antimicrob Chemother 2001;47(2): 163-70.

(9.) Chen HY, Yuan M, Livermore DM. Mechanisms of resistance to beta-lactam antibiotics amongst Pseudomonas aeruginosa isolates collected in the UK in 1993. J Med Microbiol 1995;43(4):300-9.

(10.) Brooun A, Liu S, Lewis, K. A dose-response study of antibiotic resistance in Pseudomonas aeruginosa biofilms. Antimicrob Agents Chemother 2000;44(3):640-6.

(11.) Giwercman B, Jensen ET, Hoiby N, et al. Induction of beta-lactamase production in Pseudomonas aeruginosa biofilm. Antimicrob Agents Chemother 1991;35(5):1008-10.

(12.) Peron DL, Kitamura K, Carniol PJ, Schuknecht HF. Clinical and experimental results with focused ultrasound. Laryngoscope 1983; 93(9):1217-21.

(13.) Morizono T, Sikora MA. The ototoxicity of topically applied povidone-iodine preparations. Arch Otolaryngol 1982;108(4):210-13.

(14.) Post JC. Direct evidence of bacterial biofilms in otitis media. Laryngoscope 2001;111(12):2083-94.

(15.) Walker TS, Tomlin KL, Worthen GS, et al. Enhanced Pseudomonas aeruginosa biofilm development mediated by human neutrophils. Infect Immun 2005;73(6):3693-3701.

(16.) Jensen PO, Bjarnsholt T, Phipps R, et al. Rapid necrotic killing of polymorphonuclear leukocytes is caused by quorum-sensing-controlled production of rhamnolipid by Pseudomonas aeruginosa. Microbiology 2007;153(Pt 5):1329-38.

(17.) 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(2):165-73.

(18.) Roland PS, Kreisler LS, Reese B, et al. Topical ciprofloxacin/dexamethasone otic suspension is superior to ofloxacin otic solution in the treatment of children with acute otitis media with otorrhea through tympanostomy tubes. Pediatrics 2004;113(1 Pt 1):e40-6.

(19.) Roland PS, Dohar JE, Lanier BJ, et al; CIPRODEX AOMT Study Group. Topical ciprofloxacin/dexamethasone otic suspension is superior to ofloxacin otic solution in the treatment of granulation tissue in children with acute otitis media with otorrhea through tympanostomy tubes. Otolaryngol Head Neck Surg 2004;130(6): 736-41.

(20.) Roland PS, Anon JB, Moe RD, et al. Topical ciprofloxacin/dexamethasone is superior to ciprofloxacin alone in pediatric patients with acute otitis media and otorrhea through tympanostomy tubes. Laryngoscope 2003;113(12):2116-22.

(21.) van Balen FA, Smit WM, ZuithoffNP, Verheij TJ. Clinical efficacy of three common treatments in acute otitis externa in primary care: Randomised controlled trial. BMJ 2003;327(7425): 1201-5.

(22.) Tsikoudas A, Jasser P, England RJ. Are topical antibiotics necessary in the management of otitis externa? Clin Otolaryngol Allied Sci 2002;27(4):260-2.

(23.) Anwar H, Strap JL, Chen K, Costerton JW. Dynamic interactions of biofilms of mucoid Pseudomonas aeruginosa with tobramycin and piperacillin. Antimicrob Agents Chemother 1992;36(6):1208-14.

(24.) Malaty J, Antonelli PJ. Effect of body fluids on tympanostomy tube biofilm formation with Pseudomonas aeruginosa. Submitted for presentation at the Southern Section meeting of the Triological Society; January 2008; Naples, Fla.

(25.) Kinnari TJ, Salonen EM, Jero J. Durability of the binding inhibition of albumin coating on tympanostomy tubes. Int J Pediatr Otorhinolaryngol 2003;67(2):157-64.

(26.) Kinnari TJ, Rihkanen H, Laine T, et al. Albumin-coated tympanostomy tubes: Prospective, double-blind clinical study. Laryngoscope 2004;114(11):2038-43.

(27.) Berry JA, Biedlingmaier JF, Whelan PJ. In vitro resistance to bacterial biofilm formation on coated fluoroplastic tympanostomy tubes. Otolaryngol Head Neck Surg 2000;123(3):246-51.

(28.) Loeffler KA, Johnson TA, Burne RA, Antonelli PJ. Biofilm formation in an in vitro model of cochlear implants with removable magnets. Otolaryngol Head Neck Surg 2007;136(4):583-8.

(29.) Johnson TA, Loeffler TA, Burne RA, et al. Biofilm formation in cochlear implants with cochlear drug delivery channels in an in vitro model. Otolaryngol Head Neck Surg 2007;136(4):577-82.

(30.) Pasmore M,ToddR Smith S, et al. Effects of ultrafiltration membrane surface properties on Pseudomonas aeruginosa biofilm initiation for the purpose of reducing biofouling. Journal of Membrane Science 2001;194(1):15-32.

(31.) Scheuerman TR, Camper AK, Hamilton MA. Effects of substratum topography on bacterial adhesion. J Colloid Interface Sci 1998; 208(1):23-33.

(32.) Chung K, Schumacher J, Sampson E, et al. Engineered substratum topography to disrupt bacterial biofilm formation. Presented at the 32nd annual meeting of the Society for Biomaterials; April 18-21, 2007; Chicago.

(33.) Bothwell MR, Smith AL, Phillips T. Recalcitrant otorrhea due to Pseudomonas biofilm. Otolaryngol Head Neck Surg 2003;129(5): 599-601.

(34.) Tatar EC, Unal FO, Tatar I, et al. Investigation of surface changes in different types of ventilation tubes using scanning electron microscopy and correlation of findings with clinical follow-up. Int J Pediatr Otorhinolaryngol 2006;70(3):411-17.

(35.) Mehta AJ, Lee JC, Stevens GR, Antonelli PJ. Opening plugged tympanostomy tubes: Effect of biofilm formation. Otolaryngol Head Neck Surg 2006;134(1):121-5.

Patrick J. Antonelli, MD, MS, FACS
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Author:Antonelli, Patrick J.
Publication:Ear, Nose and Throat Journal
Date:Nov 1, 2007
Previous Article:Controversial etiopathologic agents in otitis media.
Next Article:Evidence that otitis media is not a biofilm disease.

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