Are topical quinolones safe for middle ear use in children?

Safety is more important than efficacy, a concept originally expressed as, "First, do no harm." The purported safety issues that surround the use of topical fluoroquinolones are the systemic effects of its absorption and its effects on the ecology of the ear canal, middle ear, and nasopharynx.

Systemic effects

Systemic blood levels of ototopical quinolones have not been shown to be a problem in any way. Spektor et al administered 4 drops of 0.3% ciprofloxacin/dexamethasone otic solution to children and adolescents who were undergoing tympanostomy tube placement. (1) They found that the mean serum drug level was only 1.2 ng/m1 30 to 60 minutes after administration and that the drug was completely undetectable 6 to 8 hours after administration. Similarly, Claros et al administered 0.2% ciprofloxacin drops to 30 children for 7 to 10 days and found no detectable levels at post-therapy follow-up. (2) To put this into perspective, in one of the early studies of oral ciprofloxacin, Campoli-Richards et al reported that ingestion of a 250-mg tablet resulted in a mean serum level of more than 1,000 ng/ml. (3)

The federal Food and Drug Administration has still not approved quinolones for respiratory infections in children. This is in striking contrast to the situation in adults. The concerns that have been raised about systemic quinolone use in children have pertained to safety, not efficacy. Some of these concerns, such as joint arthropathy, have been allayed by experience with thousands of cases of compassionate use, and others remain unanswered. The data on ototopical use strongly support their safety.

Resistance

Since 2000, several studies, most of them small, have been published in which authors have expressed concerns about emerging resistance to topical quinolones. The purportedly resistant strains have included community-acquired methicillin-resistant Staphylococcus aureus (MRSA) (4,5) and ciprofloxacin-resistant Pseudomonas spp. (6,7) But the methodology of these studies invalidates any conclusion that topical quinolones are a serious risk factor for resistance.

This is not to say that topical antibiotics do not lead to resistance, because such a statement is incomplete. What is clear is that ototopical quinolone use is not likely to contribute to overall bacterial resistance rates for the following three reasons:

* Local concentrations are extremely high--on the order of 1,000-fold above typical middle ear concentrations achieved by way of systemic use.

* Treatment courses are relatively short--generally 7 to 10 days.

* The percentage of patients who receive ototopical quinolones is exceedingly small relative to the total denominator of patients who are exposed to antibiotics--and even relative to only systemic antibiotics from the quinolone class.

Ecologic impact of topical quinolones

At the end of the day, what's the ecologic impact of ototopical quinolone use on the external ear canal, the middle ear cleft, and the nasopharynx?

External ear canal. There is no question that ototopical agents that are used to treat middle ear infections have the potential to impact the nondiseased ecology of the ear canal. They are easily delivered into the external ear canal. They have excellent activity against the normal canal flora and are able to eradicate them, thus setting the stage for replacement with alternative strains.

Although several authors have suggested that topical quinolones lead to secondary infections with MRSA and yeast, the current data show only a temporal relationship, not a cause-and-effect relationship.

Pseudomonas aeruginosa originates in the external ear canal, to which it can readily adhere. It enters the middle ear by "twitching motility" or some other method of movement once the tympanic membrane is perforated. Its passage is greatly facilitated when an existing middle ear exudate caused by another bacterial species drains through the tube. In such a scenario, according to Kenna et al, P aeruginosa may gain access to the middle ear through a tube or perforation by incorporating itself with the existing exudate and "swimming upstream." (8)

Middle ear cleft. Quinolone penetration into the middle ear has been documented. Ohyama et al administered a single dose (adults: 0.5 ml; children: 0.25 ml) of 0.3% ofloxacin otic solution to 38 patients, aged 3 to 81 years, who had chronic suppurative otitis media and a perforated eardrum. (9) Although serum drug levels were low, as noted previously, sampling of the middle ear mucosa 30 minutes following administration revealed drug concentrations ranging from 388.8 to 2,849.8 [micro]g/g; the value at the high end is close to the total concentration of the drug itself.

With regard to the middle ear cleft, direct pharmacokinetic studies of the mastoid and eustachian tube have not been performed. However, imaging studies have shown that all compartments of the middle ear cleft are uniformly involved as a "field infection." Therefore, the drug likely distributes, except in rare exceptions such as a blocked aditus ad antrum.

Nasopharynx. We have virtually no published data on the nasopharynx. Tragal pumping studies have documented penetration of fluorescent material into the nasopharynx as detected by a Wood's light. Delivered in minimal concentrations, a quinolone would not be expected to invoke a first-level gene mutation. But studies are certainly needed.

In summary, there's no evidence that topical quinolones have an ecologic impact or directly contribute to community-acquired resistance.

Joseph E. Dohar, MD, MS, FAAP, FACS 

References

(1.) Spektor Z, Jasek MC, Dahlin D, et al. Pharmacokinetics of topical Ciprodex otic suspension in pediatric and adolescent patients after tympanostomy tube surgery. Presented as a poster at the 19th Annual Meeting of the American Society of Pediatric Otolaryngology; May 2-3, 2004; Phoenix.

(2.) Claros P, Sabater F, Claros A Jr., Claros A. [Determination of plasma ciprofloxacin levels in children treated with 0.2% topical ciprofloxacin for tympanic perforation]. Acta Otorrinolaringol Esp 2000;51:97-9.

(3.) Campoli-Richards DM, Monk JP, Price A, et al. Ciprofloxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 1988;35:373-447.

(4.) Hartnick CJ, Shott S, Willging JP, Myer CM III. Methicillin-resistant Staphylococcus aureus otorrhea after tympanostomy tube placement: An emerging concern. Arch Otolaryngol Head Neck Surg 2000; 126:1440-3.

(5.) Al-Shawwa BA, Wegner D. Trimethoprim-sulfamethoxazole plus topical antibiotics as therapy for acute otitis media with otorrhea caused by community-acquired methicillin-resistant Staphylococcus aureus in children. Arch Otolaryngol Head Neck Surg 2005;131: 782-4.

(6.) Jang CH, Park SY. Emergence of ciprofloxacin-resistant pseudomonas in pediatric otitis media. Int J Pediatr Otorhinolaryngol 2003;67:313-16.

(7.) Jang CH, Park SY. Emergence of ciprofloxacin-resistant pseudomonas in chronic suppurative otitis media. Clin Otolaryngol Allied Sci 2004;29:321-3.

(8.) Kenna MA, White G, Wadowsky RD, et al. Bacteriology of otorrhea: Polymerase chain reaction versus cultures. In: Lim DJ, Bluestone CD, Casselbrant ML, et al, eds. Proceedings of the Sixth International Symposium on Recent Advances in Otitis Media. Toronto: B.C. Decker; 1996:428-30.

(9.) 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; 125:337-40.