Moraxella catarrhalis

Authors: Mark Lacy, M.D., M.A., Justin L. Berk, M.D., M.B.A., M.P.H., Steven L. Berk, M.D.

Monograph
Tables
What's New
Reviews
History

Microbiology

During the 1960s and early 1970s Moraxella catarrhalis was classified as Neisseria catarrhalis--a nonpathogenic inhabitant of the upper respiratory tract. In 1970, Neisseria catarrhalis was reclassified as a member of the genus Branhamella. A heightened appreciation for Branhamella catarrhalis as a true pathogen occurred during the 1970s. Presently, Branhamella catarrhalis has been delegated to the genus Moraxella and has been renamed Moraxella catarrhalis.

M. catarrhalis on gram stain is a gram-negative diplococcus with a tendency to resist decolorizing (83). The size of the organism varies; it is often larger than the meningococcus or gonococcus. The flat sides of the organism abut against each other. At times, the resemblance of a sputum gram stain from a patient with M. catarrhalis bronchitis to an urethral smear from a patient with gonorrhea is striking. On blood agar, the organism forms small, opaque, gray-white colonies, 1-3mm in diameter, that are circular and non-hemolytic. They can be pushed over the surface of the agar like a hockey puck on ice.

EPIDEMIOLOGY

M. catarrhalis colonizes the nasopharynx of up to 7% of adults and 30% of children (83) M. catarrhalis has been implicated in a diverse array of pediatric and adult infections. Colonization rates may vary by geography, living conditions, tobacco smoke exposure, hygiene, and other factors. Populations vaccinated against pneumococcus have proportionately higher colonization rates with non-typeable Haemophlus inlfunezae and M. catarrhalis compared to non-vaccinated groups (93). Other studies have shown no consistent changes in M. cattarhalis colonization after implementation of the newer 7-valent pneumococcal conjugate vaccine (PCV-7) (109). M. catarrhalis is the third most common bacterial agent in pediatric acute otitis media and maxillary sinusitis – surpassed only by Streptococcus pneumoniae and Haemophilus influenzae (25). In adult patients, M. catarrhalis is responsible for acute exacerbations of chronic bronchitis and bronchopneumonia in the elderly and immune compromised (41). Bacteremia with and without endocarditis (47), septic arthritis (18, 56) meningitis (68, 33), conjunctivitis (14, 50), and acute urethritis (26,61) have been less commonly associated with M. catarrhalis infection.

CLINICAL MANIFESTATIONS

The clinical presentations of bronchitis, otitis media, sinusitis and pneumonia are not substantially different from these syndromes caused by H. influenzae and S. pneumoniae. Moraxella is the 3rd most common of cause acute otitis media in children and may manifest with less erythema and distortion of the tympanic membrane than infections due to Streptococcus pneumoniae (105). Since overlap can occur among pathogens, etiologic diagnosis cannot be made on clinical signs alone. In fact, acute otitis media due to Moraxella is more commonly associated with mixed-pathogen infections than other causes and is less likely to be associated with tympanic membrane perforation or mastoiditis ((94)).

LABORATORY DIAGNOSIS

M. catarrhalis typically is oxidase positive and fails to ferment glucose, maltose, sucrose and lactose. Only Neisseria flavescens (among species that may be recovered from the same site) shares these biochemical characteristics and M. catarrhalis may be distinguished by its reduction of nitrates, its lack of colony pigmentation and its production of deoxyribonuclease (83). Hydrolysis of DNA and tributyrin are valuable differentiating tests for M. catarrhalis.

PATHOGENESIS

Colonization of the oro-nasopharynx best explains the ability of this organism to produce sinusitis, otitis media, and lower respiratory tract infection. Several studies have suggested that M. catarrhalis exhibits a preferential attachment to the oropharyngeal epithelial cells of patients with chronic lung disease when compared to control subjects, that adherence increases in winter months, and that β-lactamase producing bacteria show increased propensity to be adherent (83). However, the organism is not particularly virulent and the status of the host is important in pathogenesis. COPD is the most consistently reported underlying illness associated with M. catarrhalis respiratory infection. Hager et al (41) reviewed the published literature on M. catarrhalis respiratory infections (both bronchitis and pneumonia) prior to 1987 (429 cases) and found the mean age of 340 patients whose age was given to be 64.8 years of age. Acquisition of infection was nosocomial in 49% of patients in whom this information could be ascertained. The mean duration of lower respiratory tract colonization with a particular strain of M. catarrhalis is one month, relatively short compared to other pathogens (101). About half the time, M. catarrhalis-related exacerbations are related to acquisition of a new strain (107). Seventy-seven percent of patients had used tobacco and over 50% of patients had a diagnosis of chronic obstructive lung disease. Of one-hundred and sixty-six patients who could be evaluated for diseases or therapies known to compromise the immune system, sixty-three were receiving corticosteroid therapy, six had diabetes mellitus, 13 had hematologic malignancies, 18 had undefined malignancies, and 5 abused alcohol. Eighteen other patients had miscellaneous conditions, including chronic renal failure, decreased levels of gamma-globulins, AIDS, collagen-vascular disease and neutropenia.

Underlying immunoglobulin deficiency is an interesting though quantitatively less important risk factor for M. catarrhalis infection (83). Cases reported in association with AIDS (83) may represent the indirect effect of HIV infection on B cell function. Children with a specific Toll-like receptor 4 polymorphism (Asp229Gly) were shown to have an increased risk of repeated M. catarrhalis colonization and higher bacterial load. This polymorphism is proven to cause an impaired response to lipopolysaccharide from gram-negative bacteria (113).

M. catarrhalis colonization may play a role in susceptibility to lower respiratory tract infections. Neonatal airway colonization with pathogens including S. pnuemoniae, H. influenzae, and M. catarrhalis is associated with an increased risk of pneumonia and bronchiolitis in early life (112). Bacterial colonization may also contribute to other common pediatric clinicl presentations. In one study, pre-school aged children with persistent wheezing resistant to inhaled corticosteroid therapy were shown to have bacterial infection of the bronchial tree. Pathogens identified via bronchoalevolar lavage in this population consistent of H.influenzae, S. pnuemoniae, and M. catarrhalis (95).

The outer membrane protein OlpA has been shown to play a role in the pathophysiology of M. catarrhalis. Bernard et al. demonstrated that this outer membrane protein binds Factor H, an important complement regulator. Moreover, in the absence of the OlpA protein, M. cattarhalis resistance dramatically decreased. Thus, OlpA’s inhibition of the alternative complement pathway significantly contributes to the pathogen’s virulence (Bernard et al. 2014).

M. catarrhalis forms biofilms, a phenomenon associated with reduced susceptibility to antimicrobial agents and host defenses. While a pathogenetic role is plausible in cases of recurrent or chronic otitis media, the clinical consequences of biofilm formation are uncertain (97).

Further discussion of the molecular mechanisms of M. catarrhalis have been comprehensively discussed (98).

SUSCEPTIBILITY IN VITRO AND IN VIVO

As appreciation of the pathogenicity of M. catarrhalis increased, investigations revealed production of a chro-mosomally mediated β-lactamase. In 1977 β-lactamase-producing strains of M. catarrhalis were recovered in Sweden, France, and England (60, 66, 69). Review of earlier strains from the Centers for Disease Control, Atlanta, Georgia revealed initial β-lactamase-producing strains only as far back as 1976 (85). Further investigations revealed that β-lactamase producing strains have spread rapidly throughout the world. In a worldwide study of resistance prevalence among the three most important respiratory pathogens, Hoban et al found a high and stable rate for Moraxella catarrhalis β-lactamase production ranging from 94% in the United States to 99% in Europe reported in 1999 (43). Similar prevalence rate were seen among over 300 clinical isolates in Taiwan; β-lactamase production was documented in nearly 98% of strains (108).

The β-lactamases associated with M. catarrhalis are unique among β-lactamase classes defined by Richmond and Sykes (72). M. catarrhalis produces two enzymes, BRO-1 and BRO-2, which hydrolyze penicillin, ampicillin, methicillin, and cefaclor. These enzymes have much more activity against penicillinase-susceptible penicillins than against cephalosporins (60), but resistance to second generation cephalosporins was detected in over 8% of isolates in Taiwan (108). Since these β-lactamases are strongly membrane-associated and are present in small amounts, their activity is limited and easily neutralized by β-lactamase inhibitors (27, 32). BRO-1 is present in approximately 90% of β-lactamase-producing isolates, with BRO-2 present in the remaining 10% (15, 31, 64). BRO-1-producing isolates are more resistant to ampicillin than BRO-2 producers (38, 58). BRO-1 presence is also associated with reduced susceptibility to clarithromycin and other β-lactams antibiotics (106)). BRO-1 production levels are also generally double or triple those of BRO-2.

Resistance to non-β-lactam antimicrobials has also been reported, but specific mechanisms have not been well characterized. Inherent resistance to vancomycin (2, 81), trimethoprim (1), and clindamycin (27, 87) has been documented. The first case of quinolone-resistant M. catarrhalis in the United Sates was reported in 1998 from a 22-year-old patient with Bruton’s agammaglobulinemia. The organism was markedly resistant with MICs of 1.5->32 μg/mL to several marketed fluoroquinolones. The patient was successfully treated with ampicillin/sulbactam and rifampin intravenously followed by amoxicillin/clavulanic acid and rifampin orally (24). Resistance to tetracycline and erythromycin was reported initially in 1983 by Kallings (49). While, development of resistance to erythromycin and tetracycline has been comparatively slow, resistance patterns are geographically variable. For example, isolates tested in Taiwan indicate M. catarrhalis resistance to trimethoprim-sulfamethoxazole and tetrayclines may be as high 32% and nearly 33%, respectively, with regional variations in rates (108). Mutations in ribosomal proteins confer high-level macrolide resistance among M. catarrhalis strains studied in Japan though such strains were only seen in 2.2% of nearly 600 isolates (99).

Recently, resistance to complement-mediated killing was identified as a virulence factor of M. catarrhalis (44, 48). M. catarrhalis isolates from patients manifesting clinical disease were more likely to be serum resistant than were colonizing strains.

The heightened appreciation of M. catarrhalis as pathogen coupled with the organism’s recent and progressive β-lactamase production has made vigilant monitoring of antibiotic susceptibility essential. Due to the high incidence of β-lactamase production, testing for β-lactamase activity should be routine particularly since the prevalence of these strains continues to rise (108).

Susceptibility testing for M. catarrhalis is medium and inoculum dependent. Carefully standardized media and methodologies must be used when comparing susceptibility data to ensure accurate results. Broth microdilution is considered a "gold standard" in susceptibility testing. The in vitro activity of various antimicrobial agents against M. catarrhalis is expressed in MICs. Table 1 summarizes MIC data. MICs are a single piece of information that must be interpreted in conjunction with other factors such as the achievable concentration of an antimicrobial at the site of infection, host factors, necessity for bactericidal activity, and breakpoint criteria to arrive at a sound therapeutic decision. It is tempting to equate in vitro potency of an antimicrobial agent with the clinical response rate. In truth, susceptibility in vitro does not predict a clinically favorable outcome, although resistance in vitro generally does predict clinical failure.

Although many excellent studies have compared MICs of antimicrobial agents, fewer studies have addressed the bactericidal activity of these drugs against M. catarrhalis. Determination of an antimicrobial agent’s bactericidal activity against a particular organism is problematic. Issues such as antibiotic tolerance, growth phase, antibiotic carryover, and degradation rates can all affect results (81).

Single Drug

Penicillin

Studies by Barbar and Waterforter in 1962 revealed M. catarrhalis to be highly sensitive to penicillin V. By 1983, a widening range of MICs for penicillin V was reported for both β-lactamase producers and non-β-lactamase producers (10, 49). MICs varied from less than 0.125 to 8 mg/L for non-β-lactamase producers. MICs for β-lactamase-producing strains ranged from 1 to more than 16 mg/L. Most recently, a study of community-acquired respiratory isolates from 15 centers in Europe and the United States (6) revealed 83% penicillin re?sistance, with an MIC breakpoint of 0.25 mg/L: 92% of U.S. isolates were resistant, compared with 79.4% of European isolates. All β-lactamase-producing strains had MICs above 0.25 mg/L, consistent with resistance. Of interest, 83% of β-lactamase-negative isolates from Europe were resistant, while all U.S. isolates, had MICs below 0.06 mg/L and were uniformly sensitive.

Ampicillin/Amoxicillin

In general, ampicillin has greater in vitro activity against β-lactamase-producing M. catarrhalis than penicillin. An MIC range of 0.005 to 0.5 mg/L for β-lactamase (-) strains and an MIC range of 1 to 4 mg/L for β-lactamase (+) strains has been reported (10, 49). A wide range of MICS for ampicillin has been reported with both β-lactamase (-) and β-lactamase (+) strains. Careful scrutiny is necessary when evaluating ampicillin MICs in β-lactamase (+) strains with regard to achievable serum levels of ampicillin. Ampicillin MICs in β-lactamase (+) strains were innoculum dependent (52). Interpretation of antimicrobial susceptibility may also depend upon changing MIC break?points. An incidence of 56% resistance to ampicillin in 100 strains of M. catarrhalis was documented by disk-diffusion testing. These same isolates showed 95% resistance with the broth microdi?lution technique. These discrepancies were reconciled with changes in breakpoint criteria from the 1990 NCCLS tables to 1992 NCCLS tables.

Ampicillin MICGM for BRO-1 producers were 25 times that for nonproducers of β-lactamase, whereas BRO-2 producers were only 4 times higher than nonproducers (38). An ampicillin MIC range of 0.06 to more than 8 mg/L was found for M. catarrhalis and an MIC90 above 8 mg/L. Berk and Kalbfleisch (6) observed 55.9% amoxicillin resistance in 818 study isolates. Amoxicillin resistance was higher in U.S. isolates (73%) than in European isolates (49%). The European MICGM was 0.44 mg/L in comparison to the U.S. MICGM of 0.98 mg/L. Nonproducers of β-lactamase from Europe had MICs of amoxicillin ranging from 0.06 to 1.0 mg/L. Five strains were resistant to amoxicillin with MICs of 0.5 mg/L. U.S. nonproducing strains were uniformly sensitive with MICs of 0.06 mg/L.

Cephalosporins

Most studies have shown that β-lactamase production by M. catarrhalis confers only a modest effect on in vitro antibiotic susceptibilities to cephalosporins. Isolates with BRO-1 enzyme production are less susceptible to cephems than are BRO-2 and nonproducing isolates. Twofold increase in MICs have been found for β-lactamase producers versus nonproducers (5, 37). A similar relationship between enzyme production and waning cephalosporin susceptibility was noted by Berk and Kalbfleisch (6). MICs for cefaclor, cefuroxime, and ceftriaxone for β-lactamase producers were twice those for nonproducers.

No substantial difference in antibiotic susceptibility to loracarbef between BRO-1 and BRO?-2 producers was found (29). M. catarrhalis BRO-1 producers had two- to fourfold increased MICs for cefixime, cefuroxime, cephalexin, and cefaclor; BRO-2 production had a minimal effect on MIC interpretations (63). Two- to fourfold higher MICs were documented for cefaclor, cefixime, loracarbef, and cefetamet for BRO-1 producers compared with BRO-2 producers and nonproducers (38); this study also suggested that cefetamet and cefaclor were least affected by BRO-1 enzyme production. Cefixime had smaller differences in MICs for β-lactamase producers and nonpro-ducers (6). In vitro studies of BRO-1 and BRO-2 producers revealed that cefaclor was hydrolyzed as rapidly as penicillin and amoxicillin, while cefixime was a poor substrate (46). Cefixime was 3 to 10 times more active against M. catarrhalis than loracarbef, cefaclor, and cefetamet (38). Cefixime inhibited 90% of β-lactamase-producing and non-β-lactamase-producing strains of M. catarrhalis at less than 1 mg/L (79). Cefixime exhibited greater in vitro activity against M. catarrhalis than cefaclor 4% of isolates were resistant to cefaclor, and 10% showed intermediate susceptibility (79). The bactericidal activity of cefaclor was assessed against 10 β-lactamase-producing strains of M. catarrhalis; an MIC range of 8 to 64 mg/L with an MIC90 of 16 mg/L was reported for cefaclor (54). No bactericidal activity was noted with cefaclor at 5 h, and no appreciable killing occurred at 24 h. A time kill study using 30 β-lactamase (+) isolates of M. catarrhalis found early bactericidal activity with cefixime (7). Bacterial regrowth occurred overnight with cefaclor at its Cmax. Prompt hydrolysis of cefaclor by the β-lactamase of M. catarrhalis probably accounts for this observation (7). Serum bactericidal activity of cefuroxime axetil, cefetamet pivoxil, and ceftibuten was evaluated against 10 strains of M. catarrhalis; cefuroxime axetil possessed the greatest serum bactericidal activity against M. catarrhalis, with 80% killing at a titer of 1:8 or above after 2 hours (87). Canadian strains remain susceptible to cefuroxime but MIC 50 and MIC 90 were among the highest of commonly-prescribed empiric antibiotics for respiratory tract infections (91). Cefetamet pivoxil and ceftibufen provided 60% killing at a titer of 1:8 or above after 2 h. A similar study with clarithromycin and cefaclor revealed 10% killing of M. catarrhalis at a titer of 1:8 after 2 h with cefaclor; no activity was detected with cefaclor at 6 h (55). The in vitro activity of cefdinir was evaluated in 700 samples from patients with bacteremia; of those 45 were Moraxella catarrhallis isolates. The MIC 90 was 0.12 and 0.06 μg/ml for β-lactamase positive and β-lactamase negative organisms respectively (9). Ceftaroline, an agent generally used for MRSA skin and skin structure infections and approved for treatment of community-acquired pneumonia, has potent in-vitro activity against Moraxella catarrhalis (96). Based on the AWARE ceftaroline surveillance Program in 2008-2010, M. catarrhalis are very susceptible (MIC 50 0.06 μg/ml, MIC 90 0.12 μg/ml) regardless of β-lactamase production (103).

Macrolides

Erythromycin resistance was initially reported from Sweden in 1983 (49). A similar trend was found in New Zealand (77), Netherlands (23) and the U.S. (12). A 3.6%, incidence of erythromycin resistance was found in 305 U.K. isolates in 1991 (70). Comparable results were found in a study of 413 M. catarrhalis isolates from England and Scotland (37). Sub-sequent reports found no resistant strains in more than 450 isolates studied (63, 78, 79, 80). Of the 818 isolates tested by Berk and Kalbfleish (6), none exhibited erythromycin resistance. Eight strains from Europe had intermediate susceptibility to erythromycin and MICs above 0.5 mg/ L. No in vitrobactericidal activity for erythromycin or erythromycin combined with sulfisoxazole was found in one study although a bacteriostatic effect was observed (54).

The in vitro activity of roxithromycin was studied in 188 clinical isolates of M. catarrhalis (78), and showed an MIC range of 0.06 to 0.25 mg/L and an MIC90of 0.25 mg/L for roxithromycin, while an MIC90 of 1 mg/L was found for 17 isolates of M. catarrhalis (42).

The sensitivity of 223 strains of M. catarrhalis in the United Kingdom to clarithromycin; 94.9% of β-lactamase (-) strains were judged sensitive to clarithromycin while 97.9% of β-lactamase (+) strains were sensitive (45). Similar percentages were found for erythromycin. Macrolide and azalide agents have considerable activity again 55 β-lactamase (+) and (-) strains of M. catarrhalis (5). European and U.S. isolates of M. catarrhalis had an MIC90 of 0.12 mg/L of for clarithromycin, with only one isolate of intermediate susceptibility (MIC = 4 mg/L) (6). Azithromycin MIC90 was 0.06 mg/L, with no resistant isolates noted. The serum bactericidal activity of clarithromycin against 10 isolates of M. catarrhalis showed that clarithromycin exhibited some activity, with approximately 30% of M. catarrhalis isolates dying at a titer of 1:8 at 2 h; only 20% killing was noted at 6 h (55).

Tetracyclines

Tettracycline resistance was initially reported in Swedish isolates by Kallings et al. (49). By 1988, tetracycline resistance has increased to I5% in the Netherlands (23), and 43% in China (90). Tetracycline-resistant isolates were also recovered in the United States by 1988 (12). Wallace et al. (84) identified the Tet B resistance determinant in two resistant strains of M. catarrhalis but found in vitro transfer of this determinant problematic. The slow spread of tetracycline resistance may best be explained by this finding.

An antimicrobial sensitivity study of 305 M. catarrhalis isolates found less than 4% resistance to tetracycline (70). An MIC range of 0.25 to more than 8 mg/L for tetracycline and an MIC90 of 1mg/L was reported in one study (78). An MIC90 of 0.25 mg/L was found in another study (84). Berk and Kalbfleisch (6) found all 818 isolates M. catarrhalis to be highly susceptible to doxycycline. Only four European isolates had MlCs above 0.5 mg/L.

Fluoroquinolones

Quinolones have considerable respiratory tissue penetration and are known to exhibit a postantibiotic effect, which make them efficacious in the treatment of respiratory tract infections. Ball and Tillotson (3) reviewed 37 published clinical trials of ciprofloxacin treatment in patients with lower respiratory tract infections; 74 patients with M. catarrhalis lower respiratory tract infections were treated with ciprofloxacin, with an eradication percentage of 96%. The 22 published cases of bronchitis revealed an eradication percentage of 94.5% for ciprofloxacin.

Ciprofloxacin and ofloxacin had lower MICs against all 46 M. catarrhalis isolates (71.7% β-lactamase producers) than nine other commonly used agents (80). An MIC90 of 0.12 mg/L for ofloxacin and an MIC90 of 0.06 mg/L for ciprofloxacin was reported (80).

Although an MIC90 of 0.015 mg/L was found for ciprofloxacin (84), most MIC90s for ciprofloxacin have generally been 0.06 mg/L or less. Berk and Kalbfleisch (6) found all M. catarrhalis isolates in their centers sensitive to ciprofloxacin (MIC90 = 0.06 mg/L). One U.S. isolate had intermediate sensitivity to ofloxacin (MIC = 4 mg/L). Ofloxacin had an MIC90 of 0.06 mg/L as well. Of 70 isolates clinical isolates collected in Tokyo, Japan recently 5 exhibited elevated MIC’s to fluoroquinolones, conferring low-level resistance. None of the patients harboring these strains had received fluoroquinolones in the preceding 6 months (114).

A highly ciprofloxacin-resistant strain of M. catarrhalis was isolated from the sputum of a patient who received six courses of oral ciprofloxacin over a 6-month period (19). Ciprofloxacin MIC by E-Test (AB Biodisk, Sweden) was 8 mg/L. MICs by agar dilution were 4 mg/L for ciprofloxacin, 8 mg/L for norfloxacin, and 4 mg/L for ofloxacin. The mechanism of resistance is yet unknown. Possible explanations include decreased permeability to quinolones, decreased affinity of DNA gyrase for quinolones, or active efflux of the antimicrobial agent (19).

Fluoroquinolones have favorable in vitro bactericidal activity against M. catarrhalis (8). Concentration-dependent killing was observed, with 24-h bactericidal activity noted for both ciprofloxacin and ofloxacin. Krasemann et al. (53) also found bactericidal activity with ciprofloxacin at 0.25 mg/L (Cmax/8) against β-lactamase (+) strains of M. catarrhalis.

Combination Drugs

Amoxicillin/Clavulanate

The β-lactamase activity of M. catarrhalis is counteracted by β-lactamase inhibitors such as sulbactam and clavulanic acid (1, 27, 65). Testing β-lactamase producers for ampicillin susceptibility in the presence of clavulanic acid resulted in significantly lower MICs (2). Both BRO-1 and BRO-2 producers of β-lactamase were inhibited by low concentrations of clavulanic acid (17). A study of 375 M. catarrhalis isolates from England and Scotland in 1991 found MICs of amoxicillin/clavulanate ranging from 0.008 to 0.25 mg/L for β-lactamase producers and from 0.008 to 0.06 mg/L for nonproducers, while others found similar results (MIC ranges, < 0.03-0.06 for nonproducers and < 0.03-0.25 mg/L for β-lactamase producers) (5, 37). Studies by Struelens et al. (80) and Powell et al. (70) found no M. catarrhalis strains resistant to amoxicillin/clavulanate in a total of 351 isolates tested. Berk and Kalbfleisch tested 818 M. catarrhalis strains from Western Europe and the United States and found all susceptible to amoxicillin/clavulanate as well (6). The MIC90 of amoxicillin/clavulanate was quite low (0.12 mg/L). A time killing study performed on five β-lactamase producers reported MICs of amoxicillin/clavulanate of 0.03 to 0.12 mg/L (89).

In vitro bactericidal activity of amoxicillin/clavulanate for 30 β-lactamase (+) strains of M. catarrhalis yielded an MIC90 of 0.5 mg/L for amoxicillin/clavulanate (range. 0.06-0.5 mg/L) (7). Rapid bactericidal activity (< 24 h) was found for amoxicillin/clavulanate against M. catarrhalis. Bactericidal activity takes on particular rele?vance when treating immunocompromised patients or patients with deep-seated infectious processes such as endocarditis, osteomyelitis, meningitis, and bacteremia.

Trimethoprim/Sulfamethoxazole or Cotrimazole

Despite the inherent resistance of M. catarrhalis to trimethoprim, most isolates are sensitive to trimethoprim in combination with sulfamethoxazole (2, 28, 81). Resistance to the combination of trimethoprim and sulfamethoxazole (TMP/SMX) was reported in New Zealand (77) and Spain (74). Wallace et al. (84) reported an MIC90 of 0.25 mg/L for TMP/SMX and a MIC90 4.0 mg/L for sulfisoxazole. An MIC range of 0.5:0.025 to >8:0.4 mg/L was found for sulfamethoxazole-trimethoprim (19:1) (78). An MIC90 above 8:0.4 mg/L was found for the combination. Uniform resistance to trimethoprim (MICs, 2-128 mg/L) was found for 413 clinical isolates of M. catarrhalis. Sulfamethoxazole MICs were 0.06 to 128 mg/L with a breakpoint of 32 mg/L or above. Some 6.5% of M. catarrhalis isolates were resistant to 32 mg/L or less of sulfamethoxazole in combination with trimethoprim. In contrast, Riley et al. (73) detected no M. catarrhalisisolates requiring more than 32 mg/L of sulfamethoxazole for inhibition. Humphreys et al. (45) found 62% of 223 M. catarrhalis strains sensitive to cotrimazole. Berk and Kalbfleisch found all isolates susceptible to cotrimazole (MIC90 = 0.5 mg/L) (6). In contrast, as noted above, up to 1/3 of isolates in Taiwan were found resistant to cotrimazole. A trend toward rising MICs of cotrimazole has been noted as well as sporadic resistance.

Antimicrobial Resistance

The relatively high MICs of amoxicillin for β-lactamase (-) isolates of M. catarrhalis suggest additional modes of resistance necessitating further study. β-lactamase production by M. catarrhalis has a limited effect on the in vitro susceptibility to oral or parenteral cephalosporins. In general, second- and third-generation cephalosporin resistance is unusual in M. catarrhalis. A trend toward cefaclor resistance may be in progress with intermediate susceptibility of M. catarrhalis strains being reported in different areas. Studies assessing serum bactericidal activity failed to reveal a bactericidal activity of cefaclor (7, 54, 56). Resistance to erythromycin and tetracycline have been reported, but to date, spread has been slow. With increasing use of newer macrolides in the United States, further progression of M. catarrhalis resistance to these agents may be forthcoming.

The effect of selective antibiotic pressure on development of resistance is shown in a highly ciprofloxacin resistant strain of M. catarrhalis (19). To date fluoroquinolones have very low MICs against M. catarrhalis isolates, but this could change with further fluoroquinolone use.

ANTIMICROBIAL THERAPY

Drug of Choice

The β-lactamase stable cephalosporins or amoxicillin-clavulanic acid are generally the drugs of choice. Various oral and parenteral therapeutic agents are available for treatment of M. catarrhalis infection. Table 2 lists adult doses for common infections caused by M. catarrhalis; Table 3 lists pediatric doses.

The prevalence of β-lactamase-producing strains of M. catarrhalis approaching 100% in some U.S. centers, should draw attention to the clinical evidence regarding treatment failures with penicillin and ampicillin therapy. Empirical use of penicillin, ampicillin, or amoxicillin is not advised in treating presumed M. catarrhalis infections. The progressive spread of resistance among other respiratory pathogens such as S. pneumoniae and H. influenzae also makes empirical use of these agents obsolete. In summary, β-lactamase-producing strains of M. catarrhalis should not be treated with penicillin, ampicillin, or amoxicillin regardless of MICs suggesting susceptibility.

Specific Infections

Upper Respiratory Tract Infection

M. catarrhalis is a recognized pathogen in pediatric upper respiratory infections such as otitis media, sinusitis, and pharyngitis. Treatment is generally empirical and usually includes oral medications (which may be available in liquid formulation) for 10 days. Second-and third-generation cephalosporins, trimethoprim-sulfamethoxazole, and amoxicillin/clavulanate are considered first-line agents. Erythromycin and the newer macrolides and azalides have considerable activity against M. catarrhalis but questionable performance against H. influenzae. Selection of the optimal antimicrobial agent must take into account other possible pathogens, since infections may be polymicrobial and acceptable material for culture may not be readily available. Tetracyclines and fluoroquinolones are not recommended for treatment in children because of their potential for adverse reactions. Recent studies comparing the clinical efficacy of a single intramuscular dose of ceftriaxone with 7- to 10-day courses of oral antimicrobial therapy for acute otitis media have shown comparable outcomes (4, 13, 40, 82). Single-dose parenteral therapy may be advantageous when vomiting may cause suboptimal absorption of oral formulations or poor compliance is anticipated.

Lower Respiratory Tract Infection

Lower respiratory tract infections may involve acute exacerbations of tracheobronchitis or pneumonia in patients with chronic respiratory disease and various immunologic derangements such as long-term steroid usage, alcoholism, hypogammaglobulinemia, and neutropenia. Bacteremia associated with M. catarrhalis pneumonia is rare (111). Mixed infection with other respiratory pathogens such as S. pneumoniae and H. influenzae are common. The diagnosis of lower respiratory infection due to M. catarrhalis may be made on the basis of gram stain and culture of expectorated sputum. These evaluations may be problematic in patients with chronic bronchitis and in the very young or old. A documented M. catarrhalis lower respiratory infection may be treated with second-generation cephalosporins, trimethoprim-sulfamethoxazole, erythromycin, β-lactamase inhibitor combinations (ampicillin/sulbactam or amoxicillin/clavulanate), or tetracyclines as first-line agents. Empirical treatment prior to culture confirmation of M. catarrhalis must cover other possible pathogens and generally includes broad ?spectrum agents such as second and third-generation cephalosporins. The duration of therapy has generally been 10 to 14 days, bur more recent studies have focused on shorter courses of therapy.

A five day course of oral moxifloxacin was compared with a seven day course of co-amoxiclav in a non-blinded randomized trial of 575 patients with acute exacerbation of chronic bronchitis (AECB). The success rate defined as resolution or improvement of symptoms, and no further antibacterial therapy necessary at 14 days, was 96.2% for moxifloxacin and 91.6% for co-amoxiclav. In this study, Moraxella catarrhalis accounted for 18.6% of the total evaluable cases (76). Grepafloxacin, 5 day and 10 day courses, were compared to a 10 day course of clarithromycin in 805 patients with acute bacterial exacerbations of chronic bronchitis. Clinical success rates were comparable for the two grepafloxacin regimens and superior to clarithromycin. Twelve percent of the isolates were M. catarrhalis (55). A three day course of oral azithromycin 500 mg once daily performed equally to a 10 day course of clarithromycin patients with acute exacerbation of chronic bronchitis (110)).

Bacteremia

The clinical features of M. catarrhalis bacteremia vary some?what from the pediatric to adult population and from the immunocompetent to the immunodeficient host. Most patients have underlying disease and associated respiratory tract infections. Bacteremia may be present in normal hosts (particularly children) with otitis media and sinusitis. Selection of antimicrobial therapy depends upon the patient’s clinical presentation and immune status. Neutropenic patients should receive broad-spectrum agents as empirical parenteral therapy to cover Gram-positive and Gram-negative pathogens. Immunocompetent patients may receive parenteral second- or third--generation cephalosporins or ampicillin/sulbactam. Fluoroquinolones could be used as second-line options for patients allergic to penicillin or β-lactam antibiotics and in streamlining therapy from parenteral to oral formulations. Prompt antibiotic therapy should be initiated whenever M. catarrhalis is isolated from blood. M. catarrhalis may have significant pathogenicity even in an immunocompetent host. The recommended duration of therapy for bacteremia without associated endocarditis is 14 days.

Bacteremia with endocarditis usually produces a continuous bacteremia with numerous positive blood cultures. Endocarditis due to M. catarrhalis is a rare entity and there is limited clinical experience in treating this serious and life-threatening infection. Therapeutic decisions are best guided by in vitro susceptibility testing and determination of β-lactamase activity. Empirical therapy may be necessary while awaiting in vitro susceptibility testing results and should consist of β-lactamase-stable antimicrobial agents with bactericidal activity. Second and third-generation cephalosporins are attractive options since more experience has been gained recently in using these agents in the treatment of endocarditis (36). The most recently reported M. catarrhalis endocarditis (67) was treated with a parenteral broad-spectrum cephalosporin with defervescence within 48 h and had a favorable clinical outcome. Treatment options for patients sensitive to penicillin and other β-lactam antibiotics are best guided by in vitro susceptibility testing. Possible options include aminoglycosides, fluoroquinolones, erythromycin, and chloramphenicol. Fluoroquinolones and aminoglycosides are reasonable options for combination therapy since these agents exert a postantibiotic effect and are bactericidal. Experience with the use of fluoroquinolones and erythromycin in endocarditis is limited. Fluoroquinolones should only be used when established treatments are not possible or have failed.

Meningitis

M. catarrhalis meningitis has been reported only sporadically since 1908. Questions have been raised regarding the possible misidentification of M. catarrhalisin the cerebrospinal fluid in the early cases. Neisseria meningitidis shares many microbiologic similarities with M. catarrhalis. It is possible, however, that the paucity of cases since that time may reflect a natural change in the spectrum of this disease. Due to the small number of clinically documented cases of M. catarrhalis meningitis, recommendations regarding therapy should be drawn primarily from in vitro susceptibility data. This is best illustrated in the recent report of a case of neonatal meningitis in which the isolate was sensitive only to ceftazidime, amikacin, netilmicin, and erythromycin (22). Previous patients have been treated with combinations of various agents such as, penicillin, chloramphenicol, and sulfa. The fact that most M. catarrhalis isolates are presently β-lactamase producers suggests use of β-lactamase-stable antimicrobial agents. The recent recommendations for empirical use of a third-generation cephalosporin in combination with vancomycin for bacterial meningitis in which penicillin-resistant S. pneumoniae is suspected should provide reasonable coverage for M. catarrhalis. Third-generation cephalosporins have excellent central nervous system (CNS) penetration and favorable efficacy against M. catarrhalis, while vancomycin has no activity against this organism. Treatment options for patients allergic to β-lactam antimicrobials are chloramphenicol and trimethoprim-sulfamethoxazole. Tetracyclines and fluoroquinolones have contraindications in pediatric patients, where most M. catarrhalis meningitis has been documented. Fluoroquinolones also have variable CNS penetration and should only be considered when more-accepted therapy has been futile.

Bone and Joint Infection

M. catarrhalis has been implicated in vertebral osteomyelitis (71) and septic arthritis (18, 62) on rare occasion. Empirical coverage with a second- or third-generation cephalosporin is reasonable unless gram stains of the infected material suggest staphylococcus. Fluoroquinolones are also reasonable therapeutic options in adults, particularly when streamlining from intravenous to oral therapy or when intravenous access is problematic.

Eye Infection

M. catarrhalis has been reported as an etiologic agent in ophthalmia neonatorum (39), adult conjunctivitis (14, 50) and keratitis (486). Treatment of ocular infections such as conjunctivitis and keratitis is usually initiated while awaiting culture. Gram stain of conjunctival secretions or corneal scrapings direct empirical therapy. Ideally, antimicrobial agents are applied topically in concentrated formulations for enhanced penetration. Subconjunctival injection, continuous lavage, or parenteral therapy may be used when keratitis is present.

Parenteral therapy is usually necessary when deep corneal ulcers pose a threat of perforation. Parenteral second-and third-generation cephalosporins and aminoglycosides are effective options. Topical therapies are not judged on the basis of MIC determinations, which apply to the achievable serum levels of antimicrobial agents. Therapeutic options should, however, have bactericidal activity for M. catarrhalis, limited toxicity to ocular tissues, and a low risk of emergence of resistance. Topical aminoglycosides, erythromycin, and tetracycline can be used. Topical fluoroquinolones are generally reserved for severe conjunctivitis. Topical therapy is usually applied every 2 to 4 h for 7 to 10 days.

Periocular infection with M. catarrhalis has been reported in a patient with pediatric bacteremia with preseptal cellulitis (75). Parenteral therapy with a second- or third-generation cephalosporin, trimethoprim-sulfamethoxazole, or chloramphenicol should he initiated in the pediatric population. Tetracycline or fluoroquinolones could be used as well in adults. Antimicrobial therapy may be further refined when the results of susceptibility and β-lactamase testing are available.

Peritonitis Associated with Continuous Ambulatory Peritoneal Dialysis

M. catarrhalis has been associated with bacterial peritonitis in patients receiving continuous ambulatory peritoneal dialysis (CAPD) (16, 20, 21, 59). Therapeutic decisions for M. catarrhalis peritonitis are best directed by antimicrobial susceptibility testing results and determination of β-lactamase production. The intraperitoneal route is preferred for CAPD patients, and second- and third-generation cephalosporins are well tolerated. Aminoglycosides and trimethoprim-sulfamethoxazole are also acceptable options, especially for patients with β-lactam allergy. Initial and maintenance doses should he adjusted to maintain an antimicrobial concentration above the MIC for M. catarrhalis for the duration of the dosing interval. The duration of intraperitoneal therapy usually ranges from 10 to 21 days and depends upon a functioning catheter. Systemic therapy should be initiated if the intraperitoneal route is not available.

Empirical Use

In clinical situations in which M. catarrhalis is a pathogen, bacterial cultures may be difficult to obtain (i.e., tympanocentesis, transtracheal aspirate, or sinus aspirates). Therapeutic intervention may be empirical, particularly in the ambulatory setting. Treatment decisions will be based upon the severity of the infection, likelihood of resistance in the suspected pathogens, and clinician awareness and understanding of antibiotic resistance.

Selecting an antibiotic for empirical use invokes consideration of M. catarrhalis sensitivity data as well as data for S. pneumoniae and H. influenzae. Constraints on therapy are imposed by drug-resistant S. pneumoniae and H. influenzae. Once microbiologic confirmation and sensitivity profiles are available, use of a narrower-spectrum agent may be possible.

The choice of oral or parenteral therapy depends on the severity of illness and the patient’s immune status and ability to retain oral medications. Special consideration should be given to the bactericidal activity of different therapeutic options when immunosuppression, deep-seated infection, or the potential for bacteremia or meningitis exists.

ADJUNCTIVE THERAPY

In patients with COPD and infectious exacerbation of bronchitis or pneumonia, it is important to continue concomitant aggressive treatment of the underlying lung disease with bronchodilators, steroids if indicated, supplemental oxygen, with standard supportive measures.

ENDPOINTS FOR MONITORING THERAPY

With the common infectious syndromes of bronchitis, otitis, sinusitis, subjective patient improvement along with decreased cough, fever, sputum production are the usual end points for treatment.

VACCINES

There are no vaccines commercially available. Research continues to seek novel targets for vaccine development (102).

PREVENTION OR INFECTION CONTROL MEASURES

Clinicians presently face a challenging era with rapid emergence of antibiotic-resistant bacteria. Prudent use of antibiotics in the managed-care environment with formulary restrictions must be balanced with the delivery of safe and effective therapy without risk to the patient. Optimal therapy involves prompt identification of the pathogen whenever possible, targeted therapy based on antibiotic susceptibility studies, and adequate doses and duration of treatment. Anecdotal reports suggest M. catarrhalis may be transmissible from patient to patient (104,100)). Containment of hospital outbreaks may thus entail adoption of droplet and possibly contact precautions.

COMMENTS

Other concerns regarding the indirect pathogenic potential of M. catarrhalis warrant mention as well. Brook (11) and others have postulated that β-lactamase production by M. catarrhalis may prevent eradication of other bacteria such as H. influenzae and group A streptococci because of inactivation of penicillinase-susceptible penicillins. Yamada et al. (88) developed a simple agar double-layer method to evaluate the influence of β-lactamase-producing organisms such as M. catarrhalis on the disk susceptibility of other pathogens to various antibiotics. While evaluating S. pneumoniae, Streptococcus pyogenes, and H. influenzae, Yamada et al. found reduced inhibition zones for various drugs in the presence of β-lactamase-producing M. catarrhalis.

REFERENCES

1. Ahmad F. McLeod DT, Croughan MJ, Calder MA. Antimicrobial susceptibility of Branhamella isolates from bronchopulmonary infections. Antimicrob Agents Chemother 1984;26: 424-425. [PubMed]

2. Alvarez S, Jones M, Holtsclaw-Berk S, Guarderas J, Berk SL. In vitro susceptibilities and β- lactamase production of 53 clinical isolates of Branhamella catarrhalis. Antimicrob Agents Chemother 1985;27:646-647. [PubMed]

3. Ball AP, Tillotson GS. Lower respiratory tract infection therapy--the role of ciprofloxacin. J Int Med Res 1995;23:315-327. [PubMed]

4. Barnett ED, Teele DW, Klein JO, Cabral HJ, Kharasch SJ, and the Greater Boston Otitis Media Study Group. Comparison of ceftriaxone and trimethoprim-sulfamethoxazole for acute otitis media Pediatrics 1997;99:23-28. [PubMed]

5. Barry AL. In vitro potency of nine orally administered antimicrobial agents against three respiratory tract pathogens Eur J Clin Microbiol Infect Dis 1992;11:867-869. [PubMed]

6. Berk SL, Kalbfleisch JH. Antibiotic susceptibility patterns of community acquired respiratory isolates of Moraxella catarrhalis in Western Europe and in the USA. J Antimicrob Chemother 1996;38(Suppl A):85-96. [PubMed]

7. Bingen E, Bourgeois F, Chardon H, Doit C, Lambert-echovsky, N. Killing kinetics of five orally administered antibiotics at clinically achievable concentrations againstMoraxella catarrhalis. Eur J Clin Microbiol Infect Dis 1992;11:923-926. [PubMed]

8. Bourgeois F, Bingen E. Killing kinetics of five fluroquinolones against Moraxella catarrhalis at clinically achievable concentrations. J Antimicrob Chemother 1994;33:364- 365. [PubMed]

9. Briggs BM, Jones RN, Erwin ME, Barrett MS, Johnson DM. In vitro activity evaluations of cefdinir (FK482, CI983 and PD 134393). Diagn Microbiol Infect Dis 1991;14:425-434. [PubMed]

10. Brorson JE, Larsson P, Zackrisson G. Antibiotic susceptibility of bacteria commonly isolated from the upper respiratory tract. Infection 1983;11:287-288. [PubMed]

11. Brook I. Pathogenicity of Branhamella catarrhalis in respiratory tract infections. Immunol Allergy Pract 1988;10:342-348.

12. Brown BA, Wallace RJ Jr, Flanagan CW, Wilson RW, Luman JI, Redditt SD. Tetracycline and erythromycin resistance among clinical isolates of Branhamella catarrhalis. Antimicrob Agents and Chemother 1989;33:1631-1633. [PubMed]

13. Chamberlain JM, Boenning DA, Ochsenschlager DW, Klein BL. Single dose ceftriaxone versus 10 days of ceclor for otitis media. Clin Pediatr 1994;33:642-646. [PubMed]

14. Chin AT. Branhamella catarrhalis conjunctivitis. Can Med Assoc J 1983;129:922-926. [PubMed]

15. Christensen JJ, Keiding J, Bruun B. Antimicrobial susceptibility and β-lactamase characterization of Branhamella catarrhalis iso1ates from 1983/1984 and 1988. APMIS 1990;98:1039-1044. [PubMed]

16. Contreras MR, Ash SR, Swick SD, Grutzner J. Peritonitis due to Moraxella (Branhamella) catarrhalis in a diabetic patient receiving peritoneal dialysis. South Med J 1993;86:589-590. [PubMed]

17. Cooper CE, Slocombe B, White AR. Effect of low concentration of clavulanic acid on the in-vitro activity of amoxicillin against β-lactamase producing Branhamella catarrhalis and Hemophilus influenzae. J Antimicrob Chemother 1990;26:371-380. [PubMed]

18. Craig DB, Wehrle PA. Branhamella catarrhalis septic arthritis J Rheumatol 1983;10:985- 986. [PubMed]

19. Cunliffe NA, Emmanuel FX, Thomson CJ. Lower respiratory tract infection due to ciprofloxacin resistant Moraxella catarrhalis. J Antimicrob Chemother 1995;36:273-274. [PubMed]

20. Dadone C, Redaelli B. Branhamella catarrhalis peritonitis in CAPD: an avoidable complication? Peritoneal Dial Int 1991;11: 185. [PubMed]

21. Damani NN, Chin AT. Branhamella catarrhalis peritonitis in a continuous ambulatory peritoneal dialysis patient. Nephron 1987;45:160-161. [PubMed]

22. Daoud A, Abuekteish F, Masaadeh H. Neonatal meningitis due to Moraxella catarrhalis and review of the literature. Ann Trop Paediatr 1996;16:199-201. [PubMed]

23. Davies BI, Maesen FP. The epidemiology of respiratory tract pathogens in Southern Netherlands. Eur Respir J 1988;1: 415-420. [PubMed]

24. DiPersio JR, Jones RN, Barrett T, Doern GV, Pfaller MA. Fluoroquinolone-resistant Moraxella catarrhalis in a patient with pneumonia: report from the SENTRY antimicrobial s Surveillance program (1998). Diagn Mircobiol Infect Dis 1998;32:131-135 [PubMed] . [PubMed]

25. Doern GV. Branhamella catarrhalis--an emerging human pathogen. Diagn Microbiol Infect Dis 1986;4:191-201. [PubMed]

26. Doern GV, Gantz NM. Isolation of Branhamella (Neisseria) catarrhalis from men with urethritis. Sex Transm Dis 1982;9: 202-204. [PubMed]

27. Doern GV, Siebers KG, Hallick LM, Morse SA. Antibiotic susceptibility of beta-lactamase- producing strains of Branhamella (Neisseria) catarrhalis. Antimicrob Agents and Chemother 1980;17:24-29. [PubMed]

28. Doern GV, Tubert TA. In vitro activities of 39 antimicrobial agents for Branhamella catarrhalis and comparison of results of different quantitative susceptibility test methods. Antimicrob Agents and Chemother 1988;32:259-261. [PubMed]

29. Doern GV, Vautour R, Parker D, Tubert T, Torres B. In vitro activity of loracarbef (LY163892) a new oral carbacephem antimicrobial agent, against respiratory isolates of Haemophilus influenzae and Moraxella catarrhalis. Antimicro Agents Chemother 1991;35:1504-1507 [PubMed] .[PubMed]

30. Dubois J, St.-Pierre C. In vitro activity of ABT-773 versus macroliodes and quinolones against resistant respiratory tract pathogens. Diagnost Micro and Inf Dis 2001;40:35-40. [PubMed]

31. Eliasson I, Kamme C, Vang M. Waley SG. Characterization of cell-bound papain-soluble beta-lactamases in Bro-1 and Bro-2 producing strains of Moraxella(Branhamella) catarrhalis and Moraxella nonliquifaciens. Eur J Clin Microbiol Infect Dis 1992;11:313- 321. [PubMed]

32. Farmer T, Reading C. Beta-lactamases of Branhamella catarrhalis and their inhibition by clavulanic acid. Antimicrob Agents and Chemother 1982;21:506-508. [PubMed]

33. Feigin RD, San Joaquin V, Middelkamp JN. Purpura fulminans associated with Neisseria catarrhalis septicemia and meningitis. Pediatrics 1969;44:120-123. [PubMed]

34. Felmingham D, Zhanel G, HobanD. Activity of the ketolide antibacterial telithromycin against typical community-acquired respiratory pathogens. J Antimicrob Chem 2001;48:T1,33-42 [PubMed]

35. Forsgren A, Walder M. Antimicrobial susceptibility of bacterial isolates in south Sweden including a 13 year follow-up study of some respiratory tract pathogens. APMIS 1994;102(3):227-235. [PubMed]

36. Francioli PB. Ceftriaxone and outpatient treatment of infective endocarditis. In: Wilson WR, Steckelberg JM, eds. Infectious disease clinics of North America. Philadelphia: WB Saunders 1993;7:97-115. [PubMed]

37. Fung CP, Powell M, Seymour A, Yuan T, Williams JD. The antimicrobial susceptibility of Moraxella catarrhalis isolated in England and Scotland in 1991. J Antimicrob Chemother 1992;30:47-55. [PubMed]

38. Fung CP, Yeo SF. Livermore DM. Susceptibility of Moraxella catarrhalis isolates to β- lactamase antibiotics in relation to β-lactamase pattern. J Antimicrob Chemother 1994;33:215-222. [PubMed]

39. Garvey RJ, Reed TA. Ophthalmia neonatorum due to Branhamella (Neisseria) catarrhalis. Case reports. Br J Vener Dis 1981;57:346. [PubMed]

40. Gehanno P, Taillebe M, Denis P, Jacquet P, Hoareau J, Gojon D, Pascarel J, Kosowski A. Short-course cefotaxime compared with five-day co-amoxyclav in acute otitis media in children. J Antimicrob Chemother 1990;26(Suppl A):29-36. [PubMed]

41. Hager H, Verghese A, Alvarez S, Berk SL. Branhamella catarrhalis respiratory infections. Rev Infec Dis 1987;9:1140-1149. [PubMed]

42. Hardy DJ, Hensey DM, Beyer JM, Vojtko C, McDonald EJ, Fernandes PB. Comparative in vitro activities of new 14-, 15-, and 16- membered macrolides. Antimicrob Agents Chemother 1988;32:1710-1719 [PubMed] . [PubMed]

43. Hoban DJ, Doern GV, Fluit AC, Roussel-Delvallez M, Jones RN. Worlwide prevalence of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in the SENTRY antimicrobial surveillance program, 1997-1999. Clin Inf Dis 2001;32 (Suppl 2): S81-93 [PubMed]

44. Hol C, Verduin CM, Van Dijke EE, Verhoef J, Fleer A, Van DijkH. Complement resistance is a virulence factor of Branhamella (Moraxella) catarrhalis. FEMS lmmunol Med Microbiol 1995; 11:207-211. [PubMed]

45. Humphreys JE. Smith EG, Coles SJ. A clarithromycin sensitivity survey in the United Kingdom using Stokes' method. J Antimicrob Chemother 1993;32:341-342 [PubMed] . [PubMed]

46. Ikeda F, Yokota Y, Mine Y, Yamada T. Characterization of BRO enzymes and beta- lactamase transfer of Moraxella (Branhamella) catarrhalis isolated in Japan. Chemotherapy 1993;39: 88-95. [PubMed]

47. Ioannidis JP, Worthington M, Griffiths JK, Snydman DR. Spectrum and significance of bacteremia due to Moraxella catarrhalis. Clin Infect Dis 1995;21:390-397 [PubMed] . [PubMed]

48. Jordan KL, Berk SH, Berk SL. A comparison of serum bactericidal activity and phenotypic characteristics of bacteremia pneumonia-causing strains. and colonizing strains of Branhamella catarrhalis. Am J Med 1990;88(Suppl 5A):28S-32S. [PubMed]

49. Kallings I. Sensitivity of Branhamella catarrhalis to oral antibiotics. Drugs 1986:31(Suppl 3):17-22. [PubMed]

50. Kawakami Y, Segawa K, Kanai M. A case of acute catarrhal conjunctivitis due to Branhamella catarrhalis. Microbiol Immunol 1983;27:641-643. [PubMed]

51. Kibsey PC, Rennie RP. Rushton JE. Disk diffusion versus broth micro dilution susceptibility testing of Haemophilus species and Moraxella catarrhalis using seven oral antimicrobial agents: application of updated susceptibility guidelines of the National Committee for Clinical Laboratory Standards. J Clin Microbiol 1994;32:2786-2790. [PubMed]

52. Kovatch AL, Wald ER, Michaels RH. β-lactamase producing Branhamella catarrhalis causing otitis media in children. J Pediatr 1983;102:261-264. [PubMed]

53. Krasemann C, Rohrig M, Cullman B. Bactericidal kinetics of ciprofioxacin and β-lactams against strains of Branhamella catarrhalis and Haemophilus infiuenzae. Eur J Clin Microbiol Infect Dis 1990;10(Suppl S):356-357.

54. Lambert-Zechovsky N, Mariani-Kurkdjian P, Doit C, Bourgeois F, Bingen E. In vitro bactericidal activity of four oral antibiotics against pathogens responsible for acute otitis media in children. J Hosp Infect 1992;22(Suppl A):89-97. [PubMed]

55. Langan CE, Zuck P, Vogel F, McIvor A, Pierzchala W, Smakal M, Staley H, Marr C. Randomized, double blind study of short course (5 day) grepafloxacin versus 10 day clarithromycin in patients with acute bacterial exacerbations of chronic bronchitis. J Antimicrob Chem 1999;44:515-523. [PubMed]

56. Lemmen SW, Anding K, Engels I, Daschner FD. Bactericidal activity of clarithromycin and ceclor against Streptococcus pneumoniae and Moraxella catarrhalis in healthy volunteers. J Antimicrob Chemother 1994;33:673-674. [PubMed]

57. Lemmen SW, Hauer T, Anding K, Engels I, Daschner FD. Serum bactericidal activity against Moraxella catarrhalis and Streptococcus pneumoniae after administration of four oral cephalosporins in health volunteers. J Antimicrob Chemother 1995;35:233-235. [PubMed]

58. Luman I, Wilson RW, Wallace RJ Jr, Nash DR. Disk diffusion susceptibility of Branhamella catarrhalis and relationship of β-lactam zone size to β-lactamase production. Antimicrob Agents Chemother 1986;30:774-776. [PubMed]

59. MacArthur RD. Branhamella catarrhalis peritonitis in two continuous ambulatory dialysis patients. Peritoneal Dial Int 1990; 10:169-171. [PubMed]

60. Malmvall BE, Brorsson JE, Johnsson J. In vitro sensitivity to penicillin V and beta- lactamase production of Branhamella catarrhalis. J Antimicrob Chemother 1977;3:374-375. [PubMed]

61. McCague JJ, McCague NJ, Altman CC. Neisseria catarrhalis urethritis: a case report. J Urol 1976;115:471. [PubMed]

62. Melendez PR, Johnson RH. Bacteremia and septic arthritis caused by Moraxella catarrhalis. Rev Infect Dis 13(3):428-429. [PubMed]

63. Nash DR, Flanagan C, Steele LC, Wallace RJ Jr. Comparison of the activity of cefixime and activities of other oral antibiotics against adult clinical isolates ofMoraxella (Branhamella) catarrhalis containing BRO-1 and BRO-2 and Haemophilus influenza. Antimicrob Agents Chemother 1991;35:192-4. [PubMed]

64. Nash DR, Wallace RJ Jr, Steingrube VA, Shurin PA. Isoelectric focusing of beta-lactamases from sputum and middle ear isolates of Branhamella catarrhalisrecovered in the United States. Drugs 1986;31(Suppl 3):48-54. [PubMed]

65. Ninane G, Joly J, Kraytman M, Piot P. Bronchopulmonary infection due to β-lactamase producing Branhamella catarrhalis treated with amoxycillin/clavulanic-acid. Lancet 1978;(8083): 257. [PubMed]

66. Percival A, Corkill JE, Rowlands J, Sykes RB. Pathogenicity of and beta-lactamase production of Branhamella (Neisseria) catarrhalis. Lancet 1977;(8049)1175.[PubMed]

67. Periyakoil V, Krasner C, Moraxella catarrhalis bacteremia as a cause of erythema nodosum. Clin Infect Dis 1996;23:650-651. [PubMed]

68. Pfister LE, Gallagher MV, Potterfield TG, Brown DW. Neisseria catarrhalis bacteremia with meningitis. JAMA 1965;193:399-401. [PubMed]

69. Philippon A, Riou JY, Guibourdenche M, Sotolongo F. Detection, distribution and inhibition of Branhamella catarrhalis β-lactamases. Drugs 1986;31(Suppl 3):64-69.[PubMed]

70. Powell M, McVey D, Kassim MH, Chen HY, Williams JD. Antimicrobial susceptibility of Streptococcus pneumoniae, Haemophilus influenza, and Moraxella(Branhamella) catarrhalis isolated in the UK from sputa. J Antimicrob Chemother 1991;28: 249-259. [PubMed]

71. Prallet B, Lucht F, Alexandre C. Vertebra] osteomyelitis due to Branhamella catarrhalis. Rev Infect Dis 1991;13:769 [PubMed]

72. Richmond MH, Sykes RB. The beta-Iactamases of gram negative bacteria and their physiologic role. Adv Microbiol Physiol 1973;9:31-88. [PubMed]

73. Riley TV, Digiovanni C, Hoyne GF. Susceptibility of Branhamella catarrhalis to sulphamethoxazole and trimethoprim. J Antimicrob Chemother 1987;19:39-43[PubMed]

74. Robledano L, Rivera MJ, Otal I, Gomez-Lus R. Enzymatic modification of amino glycoside antibiotics by Branhamella catarrhalis carrying an R-factor Drugs Exp Clin Res 1989;13(3): 137-143. [PubMed]

75. Rotta AT, Asmar BI. Moraxella catarrhalis bacteremia and pre-septal cellulitis. South Med J 1994;87:541-542. [PubMed]

76. Schaberg T, Ballin I, Huchon G, Bassaris H, Hampel B, Reimnitz P and the AECB study group. A multinational, multicentre, non-blinded, randomized study of moxifloxacin oral tablets compared with co-amoxiclav oral tablets in the treatment of acute exacerbation of chronic bronchitis. J Int Med Res 2001;29:314-328. [PubMed]

77. Slevin NJ, Aitken J, Thornley PE. Clinical and microbiological features of Branhamella catarrhalis bronchopulmonary infections. Lancet 1984;(8380):782- 783.[PubMed]

78. Spencer RC, Wheat PF. In vitro activity of roxithromycin against Moraxella catarrhalis. Diagn Microbiol Infect Dis 1991;15:63S-65S. [PubMed]

79. Stefani S, Pellegrino MB, D' Amico G, Privitera A, Privitera O, Maccarrone G, Russo G, Nicoletti G. In vitro activity of a new broad spectrum beta-lactamase-stable oral cephalosporin, cefixime, in comparison with other drugs, against Haemophilus influenza. Haemophilus parainfluenza, Moraxella catarrhalis and Streptococcus pneumoniae. Chemotherapy 1992;38:36-45. [PubMed]

80. Struelens MJ, Nonhoff C, Llontie M, Delannoy P, Lanis G, Van Pelt H, Serruys E. In vitro activity of commonly used oral antimicrobial agents against community isolates of respiratory pathogens Acta Clin Belg 1991;46:283-289. [PubMed]

81. Sweeney KG, Verghese A, Needham CA. In vitro susceptibilities of isolates from patients with Branhamella catarrhalis pneumonia compared with those of colonizing strains. Antimicrob Agents Chemother 1985;27:499-502. [PubMed]

82. Varsano I, Frydman M, Amir J, Alpert G. Single dose intramuscular dose of ceftriaxone as compared to 7-day amoxicillin therapy for acute otitis media in children: a double-blind clinical trial. Chemotherapy 1988;34(Suppl l):39-46. [PubMed]

83. Verghese A, Berk SL. Moraxella (Branhamella) catarrhalis. Infectious Diseases Clinics of North America 5:September 1991, 523-539. R Wallace, Editor. [PubMed]

84. Wallace RJ Jr, Nash DR, Steingrube V A. Antibiotic susceptibilities and drug resistance in Moraxella (Branhamella) catarrhalis Am J Med 1990:88(Suppl 5A):46S-50S. [PubMed]

85. Wallace RJ Jr, Steingrube VA, Nash DR, Hollis DG, Flanagan CW, Brown BA, et al. BRO β-lactamases of Branhamella catarrhalis and subgenus Moraxella, including evidence for chromosomal β-lactamase transfer by conjugation in B. catarrhalis, M. nonliquefaciens, and M. lacunata. Antimicrob Agents Chemother 1989;33:1845-1854. [PubMed]

86. Wilhelmus KR, Peacock J, Coster DJ. Branhamella keratitis. Br J Ophthalmol 1980;64:892. [PubMed]

87. Winstanley TG, Spencer RC. Moraxella catarrhalis: antibiotic susceptibility with special reference to trimethoprim. J Antimicrob Chemother 1986;18:425-426.[PubMed]

88. Yamada T, Yokota Y, Ikeda F, Mine Y, Kitada T. Antibacterial activity of cefixime against Streptococcus pneumoniae, Streptococcus pyogenes, and Haemophilus influenza in the presence of Moraxella (Branhamella) catarrhalis. Chemotherapy 1992;38: 28-35. [PubMed]

89. Yourassowsky E, Van der Linden MP, Crokaert F. Killing rate and growth rate comparison for newer beta-lactamase stable oral beta-lactams against Streptococcus pneumoniae, Haemophilus influenza and Moraxella catarrhalis. Chemotherapy 1992;38:7-13. [PubMed]

90. Zheng XT, Cao Y. β-lactamase producing Branhamella in Beijing, China Pediatr Infect Dis J 1988;7:744. [PubMed]

91. Bandel T, Whitehead S, Blondel-Hill E, Wagner K, Cheeptham N. Susceptibility of clinical Moraxella catarrhalis isolates in British Columbia to six empirically prescribed antibiotic agents. Can J Infect Dis Med Microbiol, 2014 May;25 (3):155-8.[PubMed]

92. Bernhard S, Fleury C, Su Y-C, et al. Outer membrane protein OlpA contributes to Moraxella catarrhalis serum resistance via interaction with factor H and the alternative pathway. J Infect Dis. 2014;210(8):1306-1310. doi:10.1093/infdis/jiu241.[PubMed]

93. Bock SL, Hedrick J, Harrison CJ, et al. Community-wide vaccination with the heptavalent pneumococcal conjugate significantly alters the microbiology of acute otitis media. Pediatr Infect Dis J 2004;23: 829.[PubMed]

94. Broides A, Dagan R, Greenberg D, et al. Acute otitis media caused by Moraxella catarrhalis: epidemiologic and clinical characteristics. Clin Infect Dis 2009;49:1641.[PubMed]

95. De Schutter I, Dreesman A, Soetens O, et al. In young children, persistent wheezing is associated with bronchial bacterial infection: a retrospective analysis. BMC Pediatr. 2012;12:83. doi:10.1186/1471-2431-12-83.[PubMed]

96. Flamm RK, Sader HS, Farrell DJ, Jones RN. Summary of ceftaroline activity against pathogens in the United States, 2010: report from the Assessing Worldwide Antimicrobial Resistance Evaluation (AWRE) surveillance program. Antimicrob Agents Chemother. 2012 Jun;56 (6):2933-40.[PubMed]

97. Hall-Stoodley, I, Hu E, Gieseke A, et al. Direct detection of bacterial biofilms on the middle-ear mucosa of children with chronic otitis media. JAMA 2006;296:202-11.[PubMed]

98. Hassan F. Molecular Mechanisms of Moraxella catarrhalis-Induced Otitis Media. Current Allergy and Asthma Reports. 2013;13(5):512-517. doi:10.1007/s11882-013-0374-8.[PubMed]

99. Kasai A, Ogihara S, Yamada K, Tanimichi Y, Nishiyama H, Saito R. Prevalence and molecular analysis of macrolide-resistant Moraxella catarrhalis clinical isolates in Japan, following emergence of the highly macrolide-resistant strain NSH1 in 2011. J Med Microbiol 2015 Jul;64 (7):708-13.[PubMed]

100. Masaki H, Asoh N, Kawazoe K, et al. Possible relationship of PFGE patterns of Moraxella cartarrhalis between hospital- and community-acquired respiratory infections in a community hospital. Microbiol Immuno 2003; 47:379.[PubMed]

101. Murphy TF, Brauer AL, Grant BJ, Sthi S. Moraxella catarrhalis in chronic obstructive pulmonary disease: burden of disease and immune response. Am J Respir Crit Care Med 2005;12:195.[PubMed]

102. Otsuka T, Kirkham C, Johnson A, Jones MM, Murphy TF. Substrate binding protein SBP2 of a putative ABC transporter as a novel vaccine antigen of Moraxella catarrhalis. Infect Immun. 2014;82(8):3503-3512. doi:10.1128/IAI.01832-14.[PubMed]

103. Pfaller MA, Farrell DJ, Sader HS, Jones RN. AWARE Ceftaroline Surveillance Program (2008-2010): trends in resistance patterns among Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States. Clin Infect Dis. 2012;55 Suppl 3:S187-S193. doi:10.1093/cid/cis561.[PubMed]

104. Qin L, Masaki H, Gotoh K, Furumoto A, Terada M, Watanabe K, et al. Molecular epidemiological study of Moraxella catarrhalis isolated from nosocomial respiratory infection patients in a community hospital in Japan. Intern Med 2009;48:797-803.[PubMed]

105. Rodriguez W, Schwartz RH. Streptococcus pneumoniae causes otitis medial with higher fever and more redness of tympanic membrane than Haemophilus influenzae or Moraxella catarrhalis. Peditr Infec Dis J 1999;18:942-4.[PubMed]

106. Saito R, Nonaka S, Fujinami Y, et al. The frequency of BRO β-lactamase and its relationship to antimicrobial susceptibility and serum resistance in Moraxella catarrhalis. J Infect Chemother. 2014;20(1):6-8. doi:10.1016/j.jiac.2013.06.003.[PubMed]

107. Sethi S, Evans N, Grant BJ, Murphy T. New strains of bacteria and exacerbations of chronic obstructive pulmonary disease. N Engl J Med 2002;347:465.[PubMed]

108. Shie-Fen Hsua, Yi-Tusng Lin, Te-Le Chen, et al. Antimicrobial resistance of Moraxella catarrhalis isolates in Taiwan. J Microbio, Immunology, Infection 2012; 45:134-140.[PubMed]

109. Spijkerman J, Prevaes SMPJ, van Gils EJM, et al. Long-term effects of pneumococcal conjugate vaccine on nasopharyngeal carriage of S. pneumoniae, S. aureus, H. influenzae and M. catarrhalis. PLoS ONE. 2012;7(6):e39730. doi:10.1371/journal.pone.0039730.[PubMed]

110. Swanson RN, Lainez-Ventosilla A, De Salva MC, Dunne MW, Amsden GW. Once daily azithromycin for 3 days comparted with clarithromycin for 10 days for acute exacerbation of chronic bronchitis: a multicenter, double-blind, randomized study. Treat Respir Med 2005. 4 (1):31-9.[PubMed]

111. Thorsson B, Haraldsdottir V, Kristjansson M. Moraxella catarrhalis bacteraemia. A report on 3 cases and a review of the literature. Scand J Infect Dis. 1998. 30 (2):105-9.[PubMed]

112. Vissing NH, Chawes BLK, Bisgaard H. Increased risk of pneumonia and bronchiolitis after bacterial colonization of the airways as neonates. Am J Respir Crit Care Med. 2013;188(10):1246-1252. doi:10.1164/rccm.201302-0215OC.[PubMed]

113. Vuononvirta J, Peltola V, Mertsola J, He Q. Risk of repeated Moraxella catarrhalis colonization is increased in children with Toll-like receptor 4 Asp299Gly polymorphism. Pediatr Infect Dis J. 2013;32(11):1185-1188. doi:10.1097/INF.0b013e31829e6df2.[PubMed]

114. Yamada K, Saito R. Molecular analysis of low-level fluoroquinolone resistance in clinical isolates of Moraxella catarrhalis. J Med Microbiol. 2014 Aug;63:1066-70.[PubMed]

Tables

Table 1. MIC Distribution of European and U.S. M. catarrhalis Isolates for 1992 and 1993 (n = 818)

Antibiotic	MIC
Antibiotic	0.03	0.06	0.12	0.25	0.5	1	2	4	8	16	32	64
Penicillin	119^a	18^a	2^a	17^b	36^b	160^b	95^b	60^b	85^b	224^b	nt	nt
Amoxicillin	nt	152^a	56^a	153^a	78^b	111^b	126^b	104^b	26^b	4^b	8^b	nt
Amoxicillin/clavulanate	nt	471^a	177^a	154^a	14^a	2^a	0^a	0^a	0^b	0^b	0^b	0^b
Cefaclorb	nt	nt	nt	179^a	267^a	296^a	51^a	16^a	7^a	2^c	0^b	0^b
Cefuroxime	nt	nt	nt	96^a	283^a	226^a	197^a	15^a	1^c	0^b	0^b	0^b
Cefixime	nt	nt	471^a	210^a	136^a	1^a	0^a	0^b	0^b	0^b	0^b	nt
Cefixime Ceftriaxone	nt	nt	458^a	70^a	158^a	122^a	9^a	1^a	0^a	0^c	0^c	0b
Erythromycin	nt	129^a	622^a	48^a	11^a	3^c	2^c	3^c	0^b	0^b	0^b	nt
Clarithromycin	nt	728^a	72^a	8^a	3^a	3^a	3^a	1^c	0^b	0^b	0^b	nt
Azithromycin	nt	795^a	13^a	2^a	6^a	1^a	0^c	0^b	0^b	0^b	0^b	nt
Doxycycline	nt	nt	nt	810^a	4^a	3^a	1^a	0^a	0^c	0^b	0^b	nt
Chloramphenicol	nt	nt	nt	157^a	615^a	45^a	1^a	0^a	0^a	0^c	0^b	0^b
Ciprofloxacin	628^a	171^a	15^a	3^a	0^a	1^a	0^a	0^b	0^b	0^b	nt	nt
Ofloxacin	49^a	305^a	445^a	15^a	3^a	0^a	0^a	1^c	0^b	0^b	nt	nt
Cotrimoxazole	nt	nt	nt	nt	796^a	176^a	4^a	1^c	0^b	0^b	0^b	0^b

^aSensitive; ^bResistant; ^cIntermediate; nt = not tested

Table 2. Adult Doses

Agents	Route	Dose	Infection	Frequency	Duration (Days)	Pregnancy Category
Cefprozil p.o. Cefuroxime axetil p.o. Cefuroxime i.v.	p.o. p.o. i.v.	500 mg 250-500 mg³ 750 mg-1.5 g ^3/4/5	Bronchitis/sinusitis Bronchitis/sinusitis/pneumonia³ Pneumonia³/bacteremia⁴/ Bone & joint⁵	q. 12 h q. 12 h q. 8 h	10-14^b 10-14^b 10-14^b	B B B
Cefixime Cefpodoxime Ceftriaxone	p.o. p.o. i.v. or i.m.	400 mg 200 mg 1-2 g max;2 g q. 12 h ⁶	Bronchitis/sinusitis/pneumonia Bronchitis/sinusitis/pneumonia Pneumonia/meningitis⁶/Bone & joint	q. 24 h q. 12 h q. 12-24 h	10-14^b 10-14^b 10-14^b	B B B
Amoxicillin/clavulanate Ampicillin/sulbactam Trimethoprim/ Sulfamethoxazole TMP/SMX Erythromycin	p.o. i.v./i.m. p.o. i.v.³ p.o.	250-500 mg³ 1.5-3.0 g 1 DS tab 5 mg/kg i.v. (TMP) 250 mg/333^a mg/500 mg	Bronchitis/sinusitis/pneumonia³ Pneumonia Bronchitis/sinusitis Pneumonia³ Bronchitis/sinusitis/pneumonia	q. 8 h q. 6 h q. 12 h q. 6 h q. 6/8/12 h^a	10-14 10-14 10-14 10-14	B B Caution Contraindicated At term B estolate contraindicated
Erythromycin Clarithromycin Azithromycin	i.v.³ p.o. p.o.	500 mg-1 gm 250 mg-500 mg 500 mg day 1/250 mg day 2-5	Pneumonia³ Bronchitis/sinusitis/pneumonia Bronchitis/sinusitis	q. 6 h q. 12 h q. 24 h	10-14 10-14 5	B C/contraindicated B
Azithromycin	i.v.³	500 mg	Pneumonia³	q. 24 h (2-5)	7-10 total i.v./p.o.	B
Ciprofloxacin	p.o./i.v.	500-750 mg p.o./400 mg i.v.	Bronchitis/sinusitis/pneumonia/ bacteremia/bone & joint	q. 12 h	10-14^b	C/contraindicated
Ofloxacin	p.o./i.v.	400 mg p.o./ 400 mg i.v.	Bronchitis/sinusitis/pneumonia/ bacteremia/bone & joint	q. 12 h	10-14^b	C/contraindicated
Levofloxacin	p.o./i.v.	500 mg p.o./ 500 mg i.v.	Bronchitis/sinusitis/pneumonia/ bactermia/bone & joint	q. 24 h	10-14^b	C/contraindicated
Tetracycline	p.o.	250-500 mg	Bronchitis/sinusitis	q. 6 h	10-14	Contraindicated
Doxycycline	p.o.	200 mg 1^st day/ 100 mg q. day	Bronchitis/sinusitis/pneumonia	q. 12-24 h	10-14	Contraindicated
Doxycycline	i.v.	100 mg	Pneumonia	q. 12 h	10-14	Contraindicated
Chloramphenicol	i.v.	100 mg/kg/d7	Meningitis⁷	q. 6 h	10-14^b	Caution- especially at term
Chloramphenicol	i.v.	50 mg-75 mg/kg/day	Bacteremia/pneumonia	q. 6 h	10-14^b	Caution- Especially at term

^aPreparation dependent.

^bBone infections and bacteremia with associated endocarditis require longer therapy.

Table 3. Pediatric Doses

Agents	Route	Dose		Frequency	Duration
Cefprozil	p.o.	30 mg/kg q. d¹,	Acute otitis media¹/pharyngitis/ sinusitis/bronchitis	q. 12 h	10-14 days^a
Cefuroxime axetil	p.o.	30 mg/kg q. d¹, 15 mg/kg q. d.²	Acute otitis media¹/pharyngitis/ sinusitis/bronchitis	q. 12 h	10-14 days^a
Cefuroxime axetil	p.o.	30-40 mg/kg/day¹/ 20 mg/kg/day²	Acute otitis media¹/pharyngitis² sinusitis/bronchitis/pneumonia	q. 12 h	10-14 days^a
> Cefuroxime	> i.v.	100-150 mg/kg day^5/6	> Pneumonia⁴/bacteremia⁵/ bone & joint⁶	> q. 8 h	> 10-14 days^a
Cefixime	p.o.	8 mg/kg/day¹	Acute otitis media¹/pharyngitis sinusitis/bronchitis/pneumonia	q. 24 h	10-14 days^a
Cefpodoxime	p.o.	10 mg/kg/day¹ (NTE 400 mg/day¹)	Acute otitis media¹/pharyngitis sinusitis/bronchitis/pneumonia	q. 12 h	10-14 days^a
Ceftriaxone	i.v. or IM	50 mg/kg to 75-100 mg/kg/day^7b	Acute otitis media¹/bronchitis/ pneumonia/meningitis⁷ bacteremia/bone & joint	Single dose¹ to 12 h⁷	10s
Amoxicillin/clavulanate	p.o.	40/6.4-20/6. 4 mg/kg/day	Acute otitis media¹/bronchitis/ pneumonia/pharyngitis/sinusitis	q. 8 h	10-14 days^a
> Ampicillin/sulbactam	> i.v. or i.m. Not Recommended If < 12 years of age	25-50 mg/kg q6^o 50-100 mg/kg⁷q6	> Pneumonia⁴/meningitis⁷/ bacteremia⁵/bone & joint⁶	> q. 6 h	> 10-14 days^a
Trimethoprim/ sulfamethoxazole	p.o. i.v. ^4/6/7	8 mg/kg/day (TMP)¹ 5 mg/kg q. 6 h (TMP)	Acute otitis media¹/bronchitis/ pneumonia⁴	q. 12 h	10-14 days
TMP/SMX Erythro-sulfisoxazole	p.o.	40 mg/kg/day¹	Meningitis⁷/bacteremia⁶/sinusitis Acute otitis media¹/bronchitis/ pneumonia/pharyngitis/sinusitis	q. 6 h q. 6-8 h	10-14 days 10-14 days
> Erythromycin	> p.o.	30-40 mg/kg/day	> Acute otitis media¹/bronchitis/ Pneumonia/pharyngitis/sinusitis	> q. 6/8/12 h	> 10-14 days
Erythromycin	i.v.	15-40 mg/kg.day	Pneumonia⁴	q. 6 h	10-14 days
Clarithromycin	p.o.	7.5 mg/kg/day	Acute otitis media¹/bronchitis/ Pneumonia/pharyngitis/sinusitis	q. 12 h (NTE 500 mg dose)	10-14 days
Azithromycin	p.o.	10 mg/kg/day, then 5 mg/kg/day 2-5 days	Acute otitis media¹/bronchitis pneumonia/sinusitis/pharyngitis	q. 24 h	5 days dosing
Chloramphenicol	i.v.	50-75 mg/kg/day	Bacteremia	q. 6 h	10-14 days^a
Chloramphenicol	i.v.	100 mg/kg/day⁷	Meningitis⁷	q. 6 h	10-14 days^a