Updated recommendations caution about use of systemic fluoroquinolones

November 2006

The Red Book Committee in the September Pediatrics has updated recommendations for the use of fluoroquinolones for pediatric patients.

Although initially this class of drugs was not approved by the FDA for patients younger than 18, subsequently there have been exceptions made for certain specific indications. The recommendation of the committee appears to be directed more at restraining use, about half a million prescriptions are written annually for these drugs, than for broadening their indications or in any way encouraging additional use.

The main concern with the use of fluoroquinolones in children is the potential for skeletal injury. This is based primarily on animal studies in which joint cartilage damage occurred in puppies that had received fluoroquinolones.

If half a million doses are prescribed for those younger than age 18 which have not resulted in a slew of lawsuits, one might reasonably ask how great is the risk.

There have been a number of retrospective reviews and statements attesting to the safety of fluoroquinolones in children.

Much has been published about their use in children with cystic fibrosis where use has been common and for long periods of time.

The statement also cites studies in which resistance developed fairly quickly. It is difficult to assess musculoskeletal complaints in this population as they occur even in the absence of fluoroquinolones. In a poster which appeared at the Infectious Diseases Society of America Meeting held last month in Toronto, a comparative study of more than 2,000 children treated for a variety of indications cited that only four had musculoskeletal complaints in the fluoroquinolones group, none of which was permanent and there was no effect noted on growth of these children (Abstract LB 27, p241).

It is frequently cited by the proponents of fluoroquinolones that nalidixic acid has been in use for years and there have been no reports of joint injury. It should be pointed out that this drug is a quinolone but not a fluoroquinolone.

Fluoroquinolones have a unique mechanism of action and modifications have increased their bacterial spectrum. Resistance is emerging and this is probably a major reason for restricting their use. As documented in the report, resistance is directly related to use. There is concern that authorizing the use of this class of drugs for respiratory infections and ear infections in children probably would result in a more rapid emergence of resistance. The fact of the matter is that there are alternatives. Although the more recent generation of these drugs require two mutations in the bacterial gyrases rather than a single one for resistance, there are other mechanisms by which the bacteria have developed resistance, e.g. efflux pumps or porin channels.

Have I prescribed fluoroquinolones myself? Yes, but in situations that are exceptions to the “do not use in children” rule. These drugs can be administered orally and are quite effective against Pseudomonas.

We did use them in children who were HIV-infected who had ears that were chronically draining pus-containing Pseudomonas. We actually rotated this drug with carbenicillin and amoxicillin-clavulinate in an effort to minimize the chance of resistance. This regimen clearly decreased drainage. One of the uses identified by the committee is for the treatment of “chronic suppurative otitis media or malignant otitis externa caused by pseudomonas.” This is not a license to use these drugs for recurrent or unresponsive otitis and certainly not for initial treatment of otitis.

Ciprofloxacin, the only drug in this class licensed for pediatric use is not a great choice for pneumococcus. Some of the later generations of fluoroquinolones have more activity against Gram-positive organisms, e.g. pneumococcus. The committee cites the two open label non-comparative clinical trials of gatifloxacin, which is not approved for use in the United States. They note that neither of the two studies clearly defined otitis media or included a control group.

The other situation in which we used fluoroquinolones with great trepidation was in neonatal intensive care residents who had acquired multiresistant organisms for which there were no other options. This was clearly a situation where our backs were to the wall. The treatment of organisms for which there is no other drug is an appropriate exception.

Pseudomonas may be a difficult organism to treat. Ciprofloxacin has the advantage of oral administration so it has been useful in patients with cystic fibrosis who have had an acute flare and in patients with resistant E. coli or Pseudomonas urinary tract infections. In evaluating sensitivity data for UTI, it is important to remember that data are relative to achievable blood levels and that urinary levels may exceed these many fold. However, the acidity of urine may impair the effectiveness of many antimicrobials.

Osteochondritis resulting from penetrating wounds do no require ciprofloxacin. The critical factor in management is adequate surgical debridement of the wound. This in contrast to Pseudomonas osteomyelitis, which does require therapy, and usually hospitalization, which enables one to choose other antimicrobials.

One of the other uses mentioned is the use of these drugs in the treatment of bacterial diarrhea. Certainly ciprofloxacin has become a popular drug to pack when going to places where this is a problem.

Some pediatric travel consultants recommend fluoroquinolones although there is rarely an indication for treating diarrhea in the United States with antimicrobials. Treatment tends to increase the likelihood of chronic carriage of Salmonella and increase its duration. It is difficult to withhold therapy from an acutely febrile child with shigella especially if accompanied by a seizure. Therapy has been shown to shorten the course of this illness, which in any case is self-limited. By the time the sensitivities come back from the lab, the child’s clinical condition will have improved. Shigella resistant to conventional therapy is not uncommon in the United States. (MMWR. 2006;55(39);1068-1071).

The committee lists several other instances in which fluoroquinolones may be considered, including non-tuberculous mycobacterial infections, exposure to aerosolized anthrax, severe allergy to other antibiotics and several other instances.

The committee very clearly provides guidelines for the use of fluoroquinolones. It is unclear how many patients who receive these drugs will have to be observed before we will have a definitive picture of their safety. Other than the indications given, there does not seem to be a urgent need for these drugs.