Ecologic impact of broad-spectrum quinolones.

That theory is worthless. It isn't even wrong!

--Wolfgang Pauli (1900-1958)

Introduction

Dr. Joseph E. Dohar: In this article, we address arguably one of the most important issues that otolaryngologists face. The literature is replete with speculation, based largely on theory rather than on data, that topical quinolones might lead to serious ecologic changes in the ear. The biggest concern is with pediatric patients because resistance patterns in children markedly affect adults in many ways. The alleged pathogenic consequences are fungal and methicillin-resistant Staphylococcus aureus infections.

Antibiotic prescribing patterns

Dr. Scott Manning: According to a U.S. database--the National Ambulatory Care Medical Survey, 1997-1999--63 % of all adults who presented to a primary care physician for treatment of an upper respiratory infection received an antibiotic) The highest percentage of prescriptions was written for patients with otitis media or sinusitis, and the lowest for patients with a common cold. Macrolides were the most commonly prescribed antibiotics. Quinolones accounted for approximately 7% of these prescriptions, but this rate is increasing in the United States, especially for the treatment of sinusitis. There was also a surprisingly high rate of antibiotic prescription for patients who had been diagnosed with a viral illness.

According to an Italian pharmacy database, more than 50% of children younger than 15 years received a prescription for an antibiotic in any given year. (2) Of those, only 3.9% were topical antibiotics, and most of them were ophthalmics. Broad-spectrum cephalosporins were the most commonly prescribed agents in the younger children, while macrolide antibiotics were more common in older children.

With regard to ophthalmologic disease, Pseudomonas aeruginosa is the most common cause of bacterial keratitis in patients with contact lenses. (3) Quinolones have largely replaced the aminoglycosides as a topical therapy for keratitis during the past 10 years, and they are largely successful. An increase in reported case series of resistance to gram-negative bacteria and S aureus has been noted. (4,5) Granted, these data are not derived from prospective studies, but these observational reports are becoming more frequent.

In patients with acute otitis media through tympanostomy tubes (AOMT), high quinolone levels are achieved in the otorrhea fluid, some concentration in the middle ear fluid, and variable levels in the middle ear mucosa. (6) No significant systemic absorption is seen. Ototopical quinolones are so effective in treating AOMT that systemic therapy is rarely needed. Not only is systemic therapy unnecessary, it increases the risk of bacterial resistance.

Quinolone pharmacology

Prof. Therese Ovesen: In discussing how the quinolones influence microorganisms and their environment, we must begin with an understanding of the interactions between microorganisms and the environment regardless of the presence or absence of drug intervention.

Quinolones are synthetic derivatives of nalidixic acid, which was discovered during the purification of the anti-malaria agent chloroquine. Nalidixic acid is active against gram-negative bacteria. Because it is concentrated in urine, it is used to treat urinary tract infections.

The quinolones are very stable; in fact, some are almost nondegradable. They exert their bactericidal effect by inhibiting nucleic acid synthesis and ultimately killing the bacterial cell.

The pharmacokinetic properties of the quinolones include good penetration into tissues and cells, a high degree of effectiveness when taken orally, and a relatively low degree of toxicity. Metabolic properties differ among the various quinolones. Only 6 to 12% of ciprofloxacin and ofloxacin is metabolized, compared with approximately 50% of moxifloxacin. Approximately 40 to 60% of ciprofloxacin, 70 to 90% of ofloxacin, and 20% of moxifloxacin is excreted unchanged in urine.

Dr. Zorik Spektor: With regard to pharmacokinetics, Ozagar et al conducted a study of the effects of ototopical ciprofloxacin and gentamicin on hearing in two groups of patients with chronic otitis media. (7) They found no toxicity-induced hearing loss in either group. In a surprising finding, liquid chromatography did not detect ciprofloxacin in plasma. Force et al also failed to detect ciprofloxacin in plasma by liquid chromatography in a study of children with otorrhea associated with tympanostomy tube placement. (6) However, there are questions about the sophistication of the detection methods in these two studies. We conducted a study of the pharmacokinetic effects of ciprofloxacin/dexamethasone, and we had no difficulty measuring plasma ciprofloxacin levels by validated high-performance liquid chromatography/tandem mass spectrometry. (8)

Normal ecology in the healthy patient

Prof. Ovesen: Normal flora is present in the ear canal, oral cavity, and nasopharynx. In healthy humans, the mastoid area, the middle ear cleft, and the eustachian tube are sterile.

Gram-positive organisms account for 96% of the bacteria recovered from the healthy ear. Although Staphylococcus species are not uncommon, isolation of S aureus in the healthy ear is quite rare, a fact that supports its role as a pathogen. The same is true of the gram-negative P aeruginosa.

The environment of the nasopharynx is much more complex than that of the ear because it changes according to the season, with age, and with viral colonization. The normal flora may include streptococci and staphylococci among the gram-positive organisms, and Haemophilus influenzae, Neisseria species, and Moraxella species among the gram-negatives. The potential pathogens are streptococci, H influenzae, and Moraxella catarrhalis. An intriguing point here is the phenomenon of a "healthy carder." In Denmark, almost one-third of adults harbor hemolytic streptococci, but they are quite healthy. Also, small children often harbor Haemophilus bacteria, the type of which changes every 3 months, and they, too, are generally asymptomatic carriers.

Isolates in chronic ear disease

Prof. Ovesen: Quinolones are effective against several gram-negative species, as well as S aureus and streptococci. The two most common pathogens in cases of otitis externa and chronic suppurative otitis media (CSOM) are S aureus and P aeruginosa.

Dr. Harvey Coates: In Japan, Ito et al found that S aureus was a dominant organism in cases of chronic otitis media, chronic sinusitis, and paranasal mucopyoceles. (9) In Taiwan, Hwang et al studied 161 cases of CSOM and found that methicillin-susceptible S aureus and methicillin-resistant S aureus (MRSA) were dominant bacteria--accounting for 30.5 and 13% of isolates, respectively. (10) Overall, S aureus was seen in 43.5% of cases, P aeruginosa in 28.8%, coagulase-negative staphylococci in 7.3 %, and Enterobacter species in 3.4%.

Dr. Ann Edmunds: The top five bacterial pathogens implicated in AOMT are Streptococcus pneumoniae (19% of all cases), H influenzae (15%), S aureus (14%), P aeruginosa (13%), and Staphylococcus epidermidis (11%). (11) Gram-positive bacteria are isolated in 61% of cases, gram-negatives in 36%, and yeast in 5%.

Mechanism of quinolone resistance

Prof. Ovesen: The mechanism by which bacteria develop resistance to quinolones is chromosome-mediated. Resistance requires only a single mutation in the code for DNA gyrase. Recently, a plasmid-mediated transfer of resistance has been suggested. Spontaneous mutations resulting in quinolone resistance occur in approximately 1 of 100 million bacteria.

Dr. Manning: One mutation secondary to exposure to an antibiotic often leads to only low-level resistance. High-level resistance usually occurs secondary to a multistep mutation that is related to prolonged or repeated courses of antibiotics. The clinical therapeutic lesson is that short-term, high-concentration, targeted antibiotic courses minimize the chance of resistance.

There are two kinds of horizontal transmission: plasmid bacteria-to-bacteria transmission and, clinically, patient-to-patient transmission.

Blondeau et al proposed an interesting concept called the mutant prevention concentration, which supports the advantages of higher concentrations whenever possible. (12)

The chief advantage of antiinfective topical therapy is complete eradication of bacteria, which reduces the likelihood of a single or multistep mutation.

Dr. Coates: The increase in quinolone resistance can be attributed to the misuse--specifically prolonged use and overuse----of the systemic form.

Dr. Edmunds: The risk of antibiotic resistance is greater with systemic antibiotics than with topicals because many different sites in the body are exposed to systemics. Topical preparations, on the other hand, deliver a higher concentration of antibiotic to the site of infection in the middle ear, resulting in less systemic absorption, less alteration of the flora (particularly in the nasopharynx), and less risk of resistance.

Prof. Ovesen: Can the quinolones affect the susceptibility patterns of colonizing bacteria? In patients with otitis of the external ear canal, between 2 and 4.5% of S aureus isolates demonstrate resistance, meaning that the minimum inhibitory concentration (MIC) is elevated. By way of comparison, resistance rates to S aureus in other parts of the body range from 1 to 90%. The percentage of quintlone-resistant Pseudomonas isolates in the external ear canal ranges from 0.1 to 33%; elsewhere in the body, the range is 10 to 50%. Finally, the percentage of quinolone-resistant S epidermidis isolates ranges from 12 to 19% in the external ear canal and from 2 to 31% elsewhere. We do not usually think of S epidermidis as a pathogen, but bacteremia can cause endocarditis. Quinolone resistance may be associated with resistance to other agents. (13,14)

Studies of quinolone treatment for other infections in which swabs were taken from the oral cavity or the nasopharynx showed no convincing emergence of resistance during therapy, whereas some resistance was noted in the lung and gastrointestinal tract. (15-17) However, such studies are rare and ought to be repeated. So although it is possible that the susceptibility patterns of colonizing bacteria can be affected by quinolones, the effect has been documented only with systemic use. It is highly unlikely that this effect occurs with topical use because of the drastically higher local concentrations that are delivered to otherwise healthy patients with community-acquired infections in short treatment courses ([less than or equal to] 10 days).

Are recurrences of ear infections caused by resistant bacteria? To date, there is no evidence to support this. The MIC determined in vitro does not predict ototopical antibiotic activity in vivo. In one study of patients with ear discharge, 10% of patients were found to have quinolone-resistant strains prior to treatment, and most of these patients were cured with quinolone therapy. (18) This is because the definition of "quinolone resistance" is based on systemic rather than topical breakpoints.

What is the possibility that quinolones select for resistant strains in the mastoid cavity, middle ear cleft, and eustachian tube? There are no data that we can examine to answer this question. We usually consider the middle ear cleft to be sterile, but this is not necessarily the case when the tympanic membrane is not intact. Microflora of the ear canal may colonize and/or infect the middle ear.

Is reinfection caused by resistant bacteria? Again, there is no evidence that topical quinolone use increases the risk of reinfection. Within the macroenvironment, there is always a risk of contracting resistant strains that are transferred from person to person.

Trends in antibiotic resistance

Dr. Manning: Resistance by gram-negative bacteria, especially Pseudomonas species, has increased during the past 10 years. Currently, approximately 75 % of gram-negative species are sensitive to ciprofloxacin. (19) Although there is cross-resistance, quinolone resistance is more common in patients who have used broad-spectrum cephalosporins.

There is evidence that Spneumoniae resistance to quinolones, although low, is increasing. Between 1995 and 1997, the rate rose from 2.9 to 3.8%. Certainly, quinolones are not a first-line therapy for S pneumoniae infection, but they are being prescribed empirically, especially for patients with otitis.

With the exception of MRSA, S aureus is still very sensitive to quinolones. MRSA is horizontally transmitted from patient to patient, and it is ubiquitous in the community. (20)

Dr. Dohar: MRSA is becoming a more common pathogen in community-acquired respiratory disease, and this increase is absolutely independent of ototopical quinolone use. The MRSA strains isolated from simple, uncomplicated community-acquired eye infections are highly resistant to quinolones. Conversely, in iatrogenically acquired MRSA infection, the reverse is true--that is, there is a much lower incidence of quinolone resistance among isolates. Again, it is systemic use, not topical use, that drives these patterns.

Dr. Coates: In a report of 127 patients with CSOM, Altuntas et al reported that ciprofloxacin resistance was seen in 10% of S aureus isolates, 8.3% of Escherichia coli isolates, 6.2% of Pseudomonas isolates, and 2.9% of Proteus isolates. (21)

In 2003, Jang and Park looked at AOMT in 17 children. (22) They found that 4 of these patients had ciprofloxacin-resistant Pseudomonas infection.

Dr. David Stroman: The only circumstance in which a good correlation exists between quinolone use and the emergence of resistance is in the setting of E coli in the urinary tract. Beyond that, there is no evidence to implicate quinolones in emerging resistance with respect to any other organisms. Quinolone resistance is a chromosomal event; it is not spread from bacteria to bacteria. It is true that on a large scale we see more pretherapy quinolone-resistant organisms than we did 20 years ago. But on an individual patient basis, we do not see such an emergence.

Preventing resistance

Dr. Coates: We can take several measures to reduce quinolone resistance:

* Perform adequate mechanical ear toilet along with suction when indicated, and dry the external ear canal prior to instilling the drops. Among Aboriginal children in Australia, the best way to clean ears is not overly popular with parents, so it is usually done by healthcare workers. They wash the ears with a dilute 0.05% povidine iodine solution, which can wash away any biofilm. After they dry the ears with a tissue spear, they introduce the eardrops. I believe that many of the failures and resistance problems that have been seen in Taiwan and Korea are related to the fact that parents are placing eardrops on top of a pool of pus, and obviously the drops are not penetrating and they are not having any effect at all. This goes on for a period of months on end, and eventually resistance occurs.

* Do not use quinolone drops for more than 28 days; fewer would be better. In our study of 147 Australian Aboriginal children with CSOM (the NACCHO study), we stopped at 14 days. (23) We achieved very good results, and we observed no resistance.

* If otorrhea persists, consider the presence of other pathologies, particularly cholesteatoma. Among Australian Aboriginal children who experience long-standing otorrhea and perforations by the age of 10 years, the incidence of cholesteatoma is quite high: 10%.

Fungal infections

Dr. Manning: Otolaryngologists uniformly believe that it is important to change the environment of the ear through aural toilet to enhance drug delivery, as well as to prevent dermatitis and fungal infections. Primary care physicians must learn to swab ears and perform tragal pumping.

Otomycosis is probably a secondary infectious dermatitis that occurs when the environment becomes favorable for fungal growth, rather than a primary infection. There have been a few anecdotal reports--only letters--of what has been described as fungal "infection" with increasing quinolone use. (24,25) But we do not know if these are actually infections. Vennewald et al wrote that fungi are part of the normal flora and that a change in the environment will result in a secondary dermatitis. (26) In Japan, Suzuki et al conducted a prospective study of 294 patients with CSOM who underwent quinolone therapy with a follow-up as long as 4 weeks. (27) They found no increase in the rate of recovery of fungal organisms.

Dr. Dohar: Those authors specifically looked for fungus with both potassium hydroxide and fungal cultures, and they found no increased incidence of fungal isolation compared with cultures at entry after 4 weeks of treatment with a neutral quinolone and drainage, both of which are conducive to isolating fungal growth. These data do not support the idea that topical quinolones lead to treatment failure from fungi.

Dr. Manning: From a clinical perspective, antibiotic therapy may create pressure for bacterial resistance development. High-concentration topical therapy is better than low-concentration systemic therapy for minimizing resistance. Obviously, in an age of increasing bacterial resistance, we need a lower threshold for culturing ear infections and for ongoing surveillance.

Dr. Dohar: It is likely that the very same spectrum of fungal disease that has been described in sinusitis exists in otitis. Saprophytic colonization occurs, wherein there is very little inflammatory host response to the saprophyte. Grossly fungal hyphae in clumps are the equivalent of mycetoma. Allergic fungal otitis also exists, and it may require desensitization immunotherapy, debridement, and azole-derivative systemic therapy to cure.

Invasive nonfulminant fungal otitis with secondary osteitis proven by radionucleotide studies in an immunocompetent host is rarely seen. No cause-and-effect relationship with topical quinolone treatment has been noted. Finally, invasive fungal otitis in immunocompromised hosts often leads to death.

Prof. Michael Hawke: Visible fungal hyphae are diagnostic of Aspergillus species. No structural elements are visible in otomycosis caused by Candida species. In order for Aspergillus to grow, there must be some "food"--that is, material present to support that growth. Usually it is keratin, but it can be other debris. I do not believe that this represents a treatment failure. It is more likely that it represents a phenomenon that occurs when the normal microbiologic flora of the external ear canal is altered. There happen to be fungi present, some foreign material left in the ear canal on which they will grow, and a suppression of the normal "healthy" bacterial flora.

Dr. Dohar: It is more likely that this change occurs as a result of the disease itself rather than its treatment (i.e., topical quinolone therapy). If we compare normal physiologic ear canal pH with the pH in a draining ear, the pH increases above the 7.0 neutral point. Alkaline pH is conducive to saprophytic fungal overgrowth. The disease itself is clearly a factor--probably the main factor. It is rare in the acute draining ear that fungi are isolated by traditional culture techniques. In studies of ofloxacin otic solution, the isolation rate in AOMT at entry was 2%. (28) It is fair to conclude that the isolation rate of fungus is extremely low in acute otorrhea. It does increase as the chronicity of the disease increases and as patients continue to show signs and symptoms and continue to be treated. But it is naive to ascribe a cause-and-effect relationship to the treatment when in fact the cause is the disease. The same kind of debate is taking place with respect to ototoxicity and eardrops. Is it chronic otitis that causes hearing loss and disequilibrium, or is it aminoglycoside therapy?

Dr. Edmunds: We also see secondary overgrowth by resident fungal elements. Weber et al reviewed the literature and found three studies of fungal overgrowth. (29)

Several other studies of fungal infection are of note:

* Clayton et al treated 139 draining ears with either topical aluminum acetate or topical gentamicin. (30) They found only a few cases of yeast overgrowth.

* Miro conducted a comparison trial of ciprofloxacin and neomycin/polymyxin B/hydrocortisone in 232 patients with CSOM. (31) Again, he found very few cases of fungal invasion.

* Suzuki and Baba showed that the detection of fungal species did not increase in a cohort of patients treated for CSOM with ofloxacin for up to 4 weeks. (32)

* In a study of 60 patients with CSOM, Aslan et al found that 3 % of patients had fungal involvement at study's end. (33) Earlier we noted that fungal isolation in AOMT is rare. These studies demonstrate that fungal isolation is likewise uncommon in CSOM, and its incidence does not rise during or after ototopical quinolone therapy.

* Tutkun et al compared ototopical ciprofloxacin with gentamicin in 44 patients with CSOM. (34) Of the 24 patients in the ciprofloxacin group, 21 (88%) were cured, compared with only 6 of 20 (30%) in the gentamicin group. The 3 patients in the ciprofloxacin group in whom treatment failed had positive cultures for Candida albicans.

Dr. Dohar: To summarize, we have agreed that:

* There does not appear to be any good evidence to support the idea that administering ototopical quinolones to the middle ear significantly alters the nasopharyngeal flora.

* Topical quinolones are very effective, and their potential to lead to increased resistance appears to be very low. Surveillance of their influence on microflora, of the interaction between pathogens and "nonpathogens," and of the effects of repeated courses of therapy is of paramount importance. Mechanisms of resistance and the attendant changes in the macroenvironment that they effect must be monitored at both genetic and molecular levels.

* What we see in the ENT literature with regard to quinolone resistance is merely a manifestation of the systemic trends that we have seen with MRSA infection across the board. It would be difficult to prove that an ototopical quinolone contributes to resistance when most of the implicated pathogens are quinolone-resistant prior to any exposure to ototopical quinolones.

* The role of fungal pathogens in middle ear disease is still unclear, and more study needs to be done.

* We do not know if the appearance of fungi is the result of disease, ototopical quinolone use, or another completely unrelated host factor, but it is most likely the disease.

* We have no evidence that secondary fungal infections occur in ears that are treated for up to 4 weeks with continuous topical quinolone therapy.

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