Antibiotic considerations in the treatment of AOM and sinusitis

October 2003

This month’s Pharmacology Consult coincides with the special October issue on otitis media and sinusitis. Despite the commonality of antibiotic use in treating acute otitis media (AOM) and sinusitis, their treatment remains quite controversial.

Although the published literature abounds with information on these subjects, a significant amount of information is still lacking. This month’s column will review major issues confronting the use of antibiotics in these common infections.

In decreasing order of prevalence, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are the most common bacterial causes of AOM and sinusitis. S. pneumoniae is an important pathogen not only because of its likelihood of causing infection, but also because it is the least likely to cause infection that resolves without the use of antibiotics (20%).

The primary mechanism whereby these organisms become resistant to amoxicillin and other ß-lactam antibiotics (penicillins and cephalosporins) also differs. S. pneumoniae may alter its antibiotic binding sites (penicillin-binding proteins, PBPs) conferring some degree of resistance to amoxicillin. These pathogens are referred to as drug-resistant S. pneumoniae (DRSP) and may display intermediate resistance (nonsusceptibility) or full resistance. H. influenzae and M. catarrhalis display resistance to ß-lactams primarily through the production of ß-lactamase enzymes, which disrupt the antibiotic chemical structure.

Several considerations become important when choosing an antibiotic for treatment. Prior to this discussion, however, is the issue of the necessity of antibiotic use. It is the opinion of many that because antibiotics provide only modest benefit in AOM and because of the relatively high spontaneous resolution, “watchful waiting” is an appropriate treatment strategy in some patients (eg, children older than 2 years of age with uncomplicated AOM). The use and benefit of antibiotics in the treatment of sinusitis is more accepted. What is still controversial is the overdiagnosis of sinusitis — resulting in inappropriate treatment. This is highlighted by the fact that the most appropriate means to diagnose AOM and sinusitis remain very controversial.

Once the decision is made to treat with antibiotics, additional factors are considered: antimicrobial activity toward the pathogens (including resistant pathogens), resistance patterns in the patient’s community, age of the patient, recent antibiotic use, day care attendance, published literature support and recommendations by expert panels, dosage form, compliance issues (including taste of liquids), cost and patient allergies.

Pathogen sensitivity patterns

Of all the antibiotics commonly used in the treatment of AOM and sinusitis, amoxicillin remains the most active overall toward S. pneumoniae. This becomes complicated, however, by the increasing resistance of S. pneumoniae toward penicillin, amoxicillin and other ß-lactams. Several large susceptibility studies have recently been published, reflecting the increasing prevalence of DRSP. A study published this year of over 2,400 isolates (from adults) found an overall rate of penicillin nonsusceptibility of 37% (Jacobs). Another study evaluated over 1,500 isolates obtained during 1999-2000, 447 of which were recovered from children 5 years of age or younger (Doern). The isolates from children displayed a 42.6% rate of nonsusceptibility toward penicillin. These and other susceptibility studies have also evaluated risk factors for harboring resistant S. pneumoniae: isolates obtained from children (especially under 2 years of age) and isolates obtained from middle ear and sinus fluids are more likely to display resistance toward penicillin. Susceptibility studies have also revealed that S. pneumoniae pathogens nonsusceptible toward penicillin are more likely to display resistance toward other antibiotics as well. Resistance rates toward macrolide antibiotics (including azithromycin [Zithromax, Pfizer]) have been reported by several studies to be approximately 25%. This rate is important because this resistance cannot be overcome by increased dosages, as can be with ß-lactam antibiotics. Recently published national susceptibility studies have shown ß-lactamase production by H. influenzae and M. catarrhalis to be 35% and over 90%, respectively.

Susceptibility studies have also evaluated in vitro antimicrobial activities of various cephalosporins, macrolides and other antibiotics used in treating AOM and sinusitis. Overall, the cephalosporins with the best activity toward S. pneumoniae include cefdinir (Omnicef, Parke-Davis), cefuroxime axetil (Ceftin, GlaxoSmithKline), cefpodoxime (Vantin, Pharmacia) and ceftriaxone (Rocephin, Roche). Although these cephalosporins have demonstrated the best overall activity toward S. pneumoniae (other than amoxicillin), some susceptibility studies have revealed resistance rates of 15% to 25%. Other antibiotics, such as trimethoprim-sulfamethoxazole and the macrolides, have generally demonstrated significantly lower rates of activity toward S. pneumoniae. Susceptibility studies of H. influenzae and M. catarrhalis have shown that amoxicillin-clavulanate (Augmentin, GSK), cefuroxime axetil, cefpodoxime and cefdinir similarly generally demonstrated the best in vitro activity toward these pathogens. While information gleaned from these susceptibility studies is useful, its limitations are important to note.

Many susceptibility studies include pathogens from adults, and thus are not reflective of the pediatric population. Perhaps most important, however, is that in vitro (ie, minimum inhibitory concentrations, MIC) data provide no information on the course and pharmacodynamic/pharmacokinetic activities of antimicrobials.

Of the antibiotics commercially available to clinicians to treat AOM and sinusitis, two principles can be applied to their antimicrobial activity. The time that the antibiotic concentration at the site of infection exceeds the MIC (T>MIC) of the pathogen characterizes the effectiveness of the b-lactam antibiotics (amoxicillin, cephalosporins), erythromycin and clarithromycin (Biaxin, Abbott) (time-dependent). This principle also applies to clindamycin, which may be used to treat AOM and sinusitis in specific circumstances. Studies have shown that a T>MIC of 40% to 50% of the dosing interval is necessary for adequate bacterial killing and clinical efficacy. This forms the principle of increased dosages of amoxicillin and amoxicillin-clavulanate: as the MIC of S. pneumoniae increases, increased dosages are necessary to maintain an adequate T>MIC. For azithromycin, an azilide antibiotic (often referred to as a macrolide), the parameter characterizing its antimicrobial activity is the 24-hour AUC/MIC ratio (area-under-the-curve) (concentration vs. time). PD/PK data from pharmacokinetic studies of peak plasma concentrations and elimination rates, and middle ear fluid and sinus fluid concentrations, can then be applied to in vitro MIC data to develop PD/PK breakpoints, predicting the susceptibility and likely clinical efficacy of antibiotics. Some susceptibility studies have applied PD/PK data to further describe antibiotics’ antimicrobial activity toward the major pathogens of AOM and sinusitis. Much of this data, however, comes from adults.

Data from susceptibility studies applying PD/PK breakpoints reveal that cefuroxime axetil, cefpodoxime, cefdinir and ceftriaxone (Rocephin, Roche) have the best activity of the cephalosporin antibiotics toward S. pneumoniae. One study concluded that cefuroxime axetil, cefpodoxime and cefprozil (Cefzil, Bristol-Meyer Squibb) would reach PD/PK breakpoints for intermediate-nonsusceptible DRSP (Mason). Ceftriaxone was not evaluated in this study. PD/PK data similarly applied to studies evaluating H. influenzae and M. catarrhalis susceptibilities demonstrated that cefuroxime axetil, ceftriaxone and cefdinir had the best activity. Azithromycin and clarithromycin, while demonstrating good in vitro activity toward H. influenzae and M. catarrhalis, do not demonstrate good PD/PK breakpoint activity toward H. influenzae. This relates to the high intracellular but low serum concentrations of these antibiotics.

It is important to point out that the antibiotics demonstrated to have the best overall activity (MIC and PD/PK) toward S. pneumoniae (including DRSP), H. influenzae and M. catarrhalis are amoxicillin and amoxicillin-clavulanate. Amoxicillin is not stable to ß-lactamase producing H. influenzae and M. catarrhalis, while amoxicillin-clavulanate is. Augmentin ES suspension is indicated for the treatment of AOM when DRSP is suspected or known to be an infecting pathogen. It is important to recognize that the ratio of amoxicillin to clavulanate is higher (14:1) in this product than other Augmentin products (7:1 for the 200 mg and 400 mg per 5 ml products). This higher ratio allows a higher dose of amoxicillin (90 mg/kg/day) to be given without the administration of a clavulante dose exceeding 10 mg/kg/day. Exceeding this clavulante dose is more likely to result in diarrhea. Dosing the older Augmentin products at 90 mg/kg/day results in administration of clavulanate doses exceeding 10 mg/kg/day. Accordingly, Augmentin ES should not be dosed less than 90 mg/kg/day, for lower doses will provide a lower clavulanate dose which may not effectively treat ß-lactamase producing pathogens.

Expert panel recommendations

Because of the commonality, controversy and importance of AOM and sinusitis, several expert panels have convened and published recommendations on their treatment. The Drug-resistant Streptococcus pneumoniae Therapeutic Working Group published its recommendations in 1999. Amoxicillin was recommended as the antibiotic of first choice, with cefuroxime axetil, ceftriaxone and amoxicillin-clavulanate as alternative agents most likely to be effective. Increased doses of amoxicillin and amoxicillin-clavulante are recommended for patients more likely to be infected with DRSP. Guidelines published in 2001 by the AAP on the treatment of sinusitis also recommend that amoxicillin be considered first-line therapy. Higher doses of amoxicillin or amoxicillin-clavulanate are recommended for patients who fail standard-dose amoxicillin, have recently (within three months) received an antibiotic, are more severely ill, or attend day care. Alternative antibiotics recommended include cefdinir, cefuroxime axetil or cefpodoxime. Consensus recommendations by Hoberman on the treatment of AOM similarly state that amoxicillin remains the initial antibiotic of choice, but the authors suggest that amoxicillin-clavulanate and ceftriaxone only be considered as alternative agents, because other previously recommended antibiotics, such as cefuroxime axetil, have lost some activity toward S. pneumoniae. The 2003 Red Book lists cefdinir, cefuroxime axetil, ceftriaxone, and amoxicillin-clavulanate as alternative agents after amoxicillin for S. pneumoniae.

Despite the amount of published information on the treatment of otitis media and sinusitis, the most effective pharmacotherapy for these infections remains unproven and controversial. Although numerous clinical trials evaluating antibiotics in the treatment of AOM are available, many of these have been critiqued as poorly designed. Numerous study design flaws, such as lack of adequate patient numbers and inappropriate diagnostic and inclusion/exclusion criteria, have led to the “Pollyanna phenomenon,” where inadequate study methodology leads to inflated assessments of study drug effectiveness. Thus, the available published clinical trials provide very little evidence for comparative antibiotic efficacy. While in vitro data provide additional useful information, limitations with these data also exist. Susceptibility studies often include only limited numbers of pathogens from pediatric populations, and it is known that antimicrobial susceptibilities often differ in children. While local susceptibility data may be helpful, some experts caution their usefulness is limited because the susceptibilities may not differentiate between pediatric and adults patients, nor body site sources of tested isolates.

Applying pharmacodynamic and pharmacokinetic principles provides more useful information. Amoxicillin continues to be recommended as the first-line antibiotic when treating AOM and sinusitis because it provides the best in vitro and PD/PK activity toward S. pneumoniae, including DRSP. Risk factors for infection caused by DRSP are well defined and include patient age of 2 years or less, day care attendance or recent (within three months) antibiotic use. Children with these risk factors are more likely to benefit from high-dose amoxicillin or amoxicillin-clavulanate, as increased doses are more likely to provide antibiotic concentrations in the middle ear or sinuses above the MIC of the pathogen for 40% to 50% of the dosing interval. For the three most prevalent bacterial pathogens, amoxicillin-clavulanate provides the best PD/PK activity overall. Of the remaining antibiotics for AOM, existing in vitro and PD/PK data and expert panel recommendations support a relative few, including cefuroxime axetil, cefpodoxime proxetil, cefdinir and ceftriaxone. For patients with a history of a hypersensitivity reaction to amoxicillin, the macrolides can be used, although they may be less active toward the bacterial pathogens. It is important for clinicians to differentiate between non-allergic reactions associated with amoxicillin and true hypersensitivity reactions, as labeling a patient as “penicillin allergic” significantly limits the choice of antibiotics most likely to be effective. Lastly, and perhaps most important, is the “judicious use” of antibiotics in treating AOM. Although appropriate diagnosis remains controversial, published guidelines are available to assist clinicians in guiding decisions on when to prescribe antibiotics.

For more information:

• Jacobs MR. The Alexander Project 1998-2000: susceptibility of pathogens isolated from community-acquired respiratory tract infection to commonly used antimicrobial agents. J Antimicrob Chemother. 2003;52:229-46.
• Doern GV. Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in the United States during 1999-2000, including a comparison of resistance rates since 1994-1995. Antimicrob Agents Chemother. 2001;45: 1721-1729.
• Mason EA. Streptococcus pneumoniae in the USA: in vitro susceptibility and pharmacodynamic analysis. J Antimicrob Chemother. 2000;45:623-31.
• Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26:1-12.
• Dowell SF, Schwartz B, O’Brien KL, Rosenstein N. Otitis media, pharyngitis, acute sinusitis, cough illness/bronchitis, upper respiratory tract infections, the common cold – principles of judicious use of antimicrobial agents. Pediatrics. 1998;101(supplement):165-84.
• American Academy of Pediatrics. Clinical practice guideline: management of sinusitis. Pediatrics. 2001;108:798-808.
• Dowell SF. Acute otitis media: management and surveillance in an era of pneumococcal resistance – a report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatr Infect Dis J. 1999;18:1-9.
• Hoberman A. Treatment of acute otitis media consensus recommendations. Clin Pediatr. 2002;41:373-90.
• Wald ER. Acute otitis media: more trouble with the evidence. Pediatr Infect Dis J. 2003;22:103-4.