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Bacterial resistance to quinolone otic drops is nearly zero.

Antibiotic resistance in upper respiratory tract bacterial infections continues to increase. Since oral fluoroquinolones have a unique role as a second-line therapy for respiratory infections and as a therapy against enteric organisms such as Pseudomonas aeruginosa or Escherichia coli, resistance to these antibiotics has contributed to the global concern that we are rapidly running out of effective anti-infectives.

In many locations in the United States and elsewhere, methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis are more common than the sensitive strains of those species. Many of these multidrug-resistant staphylococci are resistant, by laboratory definitions, to fluoroquinolones such as ciprofloxacin, ofloxacin, levofloxacin, and moxifloxacin. P aeruginosa, a relatively common cause of acute otitis media with tympanostomy tubes (AOMT) and otitis externa, is increasingly resistant to our mainstays of oral therapy for infections caused by this organism: ciprofloxacin and levofloxacin.

As noted above, the frequency of isolation of "resistant" gram-positive organisms (staphylococci and streptococci) and certain gram-negative organisms (especially pseudomonads) from infected middle and external ears has increased significantly in the past 5 years, just as their isolation rate from all other sites has increased. This has led a number of authors to suggest that when selecting an ototopical antibiotic, one should carefully consider the results of laboratory antibiotic sensitivity testing. While such prudence might, on the surface, appear appropriate, the suggestion is mostly wrong.

Antibiotic efficacy

For antibiotics to be effective, they must generally exceed the concentrations required to inhibit the target organism(s) at the site of infection. Microbiologists often refer to this as "meeting the pharmacokinetic/pharmacodynamic (PK/PD) parameters that are necessary for antibacterial therapy." In this setting, and as explained in recent antimicrobial guidelines, the term pharmacokinetics refers to factors that contribute to tissue or serum levels, while pharmacodynamics relates to the intrinsic activities of the antibiotic against the bacteria.

To assess the effectiveness of given antibiotics against an organism, laboratories usually establish an in vitro minimum inhibitory concentration (MIC) and then interpret those values so they can report the organism as being sensitive, intermediate, or resistant to the antibiotic(s) tested. The important point is that the laboratory definitions of sensitive and resistant apply to the levels of antibiotics that can be achieved by systemic administration. They do not apply to the dramatically higher concentrations that are present in topical preparations. This holds true for the classes of antibiotics (quinolones and aminoglycosides) for which the prevalent mechanisms of resistance confer relative degrees of resistance, as opposed to those mechanisms (e.g., beta-lactamase destruction of lactams) that cause an all-or-none type of resistance. For example, systemic administration of fluoroquinolones such as ciprofloxacin or levofloxacin commonly results in tissue levels that range from 1 to 4 [micro]g/ml, while "resistant" strains of staphylococci or pseudomonads are often inhibited only at antibiotic concentrations (MICs) ranging from 8 to 64 [micro]g/ml. Obviously, the tissue levels are inadequate for effective therapy. Commonly used quinolone ototopicals, on the other hand, typically contain 3,000 [micro]g/ml of the antibiotic.

Given the above considerations, at what MIC does an organism become resistant to ototopical preparations of ciprofloxacin or ofloxacin? In otitis externa (if we assume reasonable removal of ear canal debris and the use of wicks when appropriate), the MIC would be close to the concentration in the ear drop, since that is the concentration that reaches the organisms.

The concentration of the antibiotic in the middle ear or mastoid with otic preparations in AOMT is a more complex issue. A number of factors might affect the concentration achieved behind the tympanic membrane (table). Not surprisingly, the measured middle ear antibiotic concentrations in patients with ototopically treated AOMT have been found to range widely. For instance, Ohyama et al reported middle ear levels of ofloxacin that ranged from 389 to 2,850 [micro]g/ml. (1) As MICs are usually tested in a series of two-fold dilutions, I propose that we consider the dilution closest to the lowest measured concentration as the breakpoint for defining resistance. So for preparations that contain 3,000 [micro]g/ml of ciprofloxacin, strains with measured MICs of 256 [micro]g/ml or greater might reasonably be considered resistant, and therapy might fail as a consequence of inadequate PK/PD performance. Ofloxacin otic contains a lesser amount of active antibiotic because the racemic mixture of ofloxacin contains only 1,500 [micro]g/ml of the active levo isomer; therefore organisms might be considered to be potentially resistant if the MIC is 128 [micro]g/ml.
Table. Variables that affect middle ear and mastoid
concentrations following ototopical antibiotic use
for AOMT

1. Factors that affect antibiotic concentration at the site of
 infection
 A. Drug concentration in the medication
 B. Factors that affect middle ear penetration and
 distribution
 i. Volume administered
 ii. Tympanostomy tube characteristics and
 lumen size
 iii. Application pressure
 iv. Dilutional effects and purulence
 characteristics
 a. Volume
 b. Production rate
 c. Viscosity

2. Duration of exposure
 A. Dosing interval
 B. Drug elimination/inactivation
 i. Drug metabolism or systemic absorption
 ii. Drug egress via tympanostomy or
 eustachian tubes


The largest collection of (potential) pathogens isolated from external otitis (2) or AOMT (3) has been accumulated and analyzed by Alcon Laboratories during clinical trials of their otic preparations. Of the thousands of isolates, less than 0.1% had MICs of at least 256 [micro]g/ml.

Antibiotic resistance and treatment failure

Two final points should be considered by clinicians who manage AOMT and who are interested in these highly resistant strains:

* Most clinical laboratories do not perform MIC endpoint testing. Therefore, they often report an MIC as, for example, >8 [micro]g/ml or >64 [micro]g/ml. As a result, the clinician is left wondering whether the MIC might actually be 128 or 256 [micro]g/ml.

* Clinical failures with ototopicals occur more often than the rare occurrence of truly high resistance would predict. I believe these failures are almost always attributable to inadequate delivery of the otic drops to the middle ear. I have admitted to the hospital a small number of such "clinical failures." When our staff administered the drops as (we thought) we had instructed the family to do, the otorrhea promptly ceased. Clinical failure of ototopicals is not related to antibiotic resistance per se but is most often attributable to poor drug delivery, related to failure to adequately remove copious amounts of ear canal purulence, or to other delivery failures. Otolaryngologists typically employ or recommend one of four methods to remove ear canal purulence (usually on a daily basis): (1) acetic irrigations, (2) placement of ear canal wicks, (3) suction, and (4) dry mopping. Inadequate drop volume and a lack of tragal pumping may also impede middle ear delivery. Recognition of the importance of these mechanical issues by primary care clinicians and compliance by the families is, however, less than optimal.

In summary, clinical resistance among the bacteria associated with AOMT, chronic suppurative otitis media, or otitis externa is almost nonexistent when ototopical quinolones are used appropriately. The laboratory definitions of resistance to these antibiotics, in general, are not pertinent to topical preparations. Further, unlike systemically administered antibiotics, these topical agents are highly unlikely to increase resistance rates of target and nontarget bacteria of interest, since they do not target the populations of the pathogens at the primary site(s) where they typically colonize.

References

(1.) Ohyama M, Furuta S, Ueno K, et al. Ofloxacin otic solution in patients with otitis media: An analysis of drug concentrations. Arch Otolaryngol Head Neck Surg 1999;125(3):337-40.

(2.) Roland PS, Stroman DW. Microbiology of acute otitis externa. Laryngoscope 2002;112(7 Pt 1):1166-77.

(3.) Roland PS, Parry DA, Stroman DW. Microbiology of acute otitis media with tympanostomy tubes. Otolaryngol Head Neck Surg 2005;133(4):585-95.

Michael D. Poole, MD, PhD
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Author:Poole, Michael D.
Publication:Ear, Nose and Throat Journal
Date:Nov 1, 2007
Words:1299
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