Effect of amoxicillin and co-amoxiclav on the aerobic and anaerobic nasopharyngeal flora

Itzhak Brook,* and Alan E. Gober

Department of Pediatrics, Georgetown University School of Medicine, Washington, DC, USA


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The effects of co-amoxiclav (AMC) and amoxicillin (AMX) therapy on the nasopharyngeal flora of children with acute otitis media (AOM) were compared. Nasopharyngeal culture for aerobic and anaerobic bacteria were obtained before therapy and 2–4 days after completion of antimicrobial therapy in 25 patients treated with either antibiotic. After therapy, 16 (64%) of the 25 patients treated with AMX and 23 (92%) of the 25 patients treated with AMC were considered clinically cured. Polymicrobial aerobic–anaerobic flora were present in all instances. A significant reduction in the number of both aerobic and anaerobic isolates occurred after therapy in those treated with AMX (177 isolates versus 133, P< 0.005) and AMC (172 isolates versus 60, P< 0.001). However, the number of all isolates recovered after therapy in those treated with AMC was significantly lower (60 isolates) than in those treated with AMX (133 isolates, P < 0.001). The recovery of known aerobic pathogens (e.g. Streptococcus pneumoniae, Staphylococcus aureus, ß-haemolytic streptococci, Haemophilus species and Moraxella catarrhalis) and penicillin-resistant bacteria after therapy was lower in the AMC group than in the AMX group (P < 0.005). This study illustrates the greater ability of AMC, compared with AMX, to reduce the number of potential nasopharyngeal pathogens and penicillin-resistant bacteria in children with AOM.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The nasopharynx of normal children is generally colonized by relatively non-pathogenic aerobic and anaerobic organisms. Carriage of potential respiratory pathogens such as Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis is significantly higher in children prone to otitis media and in the general population of young children during respiratory illness.1

Administration of antimicrobial agents can affect the composition of the nasopharyngeal bacterial flora.2 Elimination of potential pathogens may reduce the risk of subsequent respiratory tract infection.

This study was designed to compare the effects of co-amoxiclav (AMC) and amoxicillin (AMX) on the nasopharyngeal flora of children with acute otitis media (AOM). AMC is a broad-spectrum antimicrobial effective against aerobic and anaerobic ß-lactamase-producing bacteria (BLPB), whereas AMX is a narrower-spectrum antibiotic.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Children diagnosed with AOM and treated with either AMC or AMX were included in the study. The first 25 patients who had received AMC and the first 25 who had received AMX, and had completed their course of therapy, were monitored for cultures as outlined below. No randomization of antimicrobial agents was done. The choice of antimicrobial was made by the examining physician at his discretion. The age of patients was similar in the two groups and ranged from 9 months to 5 years (mean: 2 years, 6 months), and 32 were male. Those who had received antimicrobial therapy in the previous 3 months, those who had attended day care and those with an underlying illness or facial anomalies were excluded from the study.

Nasopharyngeal cultures were obtained before therapy and on a follow-up visit 2–4 days after completion of 10 days of antimicrobial therapy. These were obtained with calcium alginate swabs that were immediately plated on to media supportive of the growth of aerobic and anaerobic bacteria. The collectors of cultures and the microbiologist were blinded to the patients' therapy. Specimens were processed semi-quantitatively, and organisms were identified and ß-lactamase production determined as described previously.3 All isolates of S. pneumoniae were screened for penicillin susceptibility with a 1 µg oxacillin disc by the Kirby–Bauer disc diffusion method. Resistance was confirmed by microdilution cation-supplemented Mueller– Hinton broth plus 5% lysed and centrifuged horse blood, as recommended by the NCCLS.4 Intermediate resistance to penicillin was defined as an MIC of 0.1–1.0 mg/L, and high resistance to penicillin was defined as MICs of >=2.0 mg/L.

Patients received either AMC or AMX 45 mg/kg/day divided into two doses. Both drugs were administered for 10 days. Compliance with therapy was assessed using a dosage card and by inspecting unused medicine after completion of treatment. Patients who failed to take more than two doses or who failed to return their medicine bottles and dosage cards were excluded from the study. Patients were evaluated clinically 2–4 days after completion of therapy. Patients were considered clinically cured if their clinical symptoms of acute infection were no longer present and the tympanic membrane inflammation had subsided. Statistical significance was calculated using the {chi}2 test.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
After therapy, 16 (64%) of the patients treated with AMX and 23 (92%) of those treated with AMC were considered clinically cured (P < 0.01). Persistence of middle-ear fluid without inflammation was present in 10 (40%) of those treated with AMX and eight (32%) of those treated with AMC.

Polymicrobial aerobic–anaerobic flora were present in all instances. The most commonly recovered aerobic species in both therapy groups were {alpha}-haemolytic and non-haemolytic streptococci, S. pneumoniae, ß-haemolytic streptococci, H. influenzae, Staphylococcus aureus and M. catarrhalis. The most commonly recovered anaerobic species in all groups were Peptostreptococcus, Prevotella and Fusobacterium (Tables 1 and 2GoGo).


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Table 1. Aerobic and facultative organisms isolated from the nasopharynx of 50 children with AOM
 

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Table 2. Anaerobic bacteria isolated from the nasopharynx of 50 children with AOM
 
A significant reduction in the number of the different isolates occurred after therapy in those treated with AMX (177 versus 133, P < 0.005) and AMC (172 versus 60, P < 0.001). However, the number of isolates recovered after therapy was significantly lower in those treated with AMC (60) than in those treated with AMX (113) (P < 0.001) (Tables 1 and 2GoGo).

The recovery of potential pathogenic organisms (e.g. S. pneumoniae, S. aureus, ß-haemolytic streptococci, Haemophilus species and M. catarrhalis) and penicillin-resistant bacteria after therapy was lower in the AMC group than in the AMX group (P < 0.005).

Thirty-three potential pathogens (1.32 isolates per specimen) were recovered from 19 (76%) of the AMX-treated patients before therapy, compared with 27 (1.08 isolates per specimen) recovered from 15 (60%) patients after therapy (P > 0.5). Thirty potential pathogens (1.2 isolates per specimen) were isolated from 18 (72%) of the AMC-treated patients before therapy, and eight (0.32 isolates per specimen) were recovered from five (20%) patients after therapy (P < 0.005).

Forty-three penicillin-resistant bacteria were isolated from 21 (84%) of the AMX-treated children before therapy (Tables 1 and 2GoGo), including three penicillin-resistant S. pneumoniae and 40 BLPB. After therapy, 37 penicillin-resistant organisms were recovered from 20 (80%) patients, including two S. pneumoniae and 35 BLPB (P > 0.05). Forty-one penicillin-resistant bacteria were recovered from 23 (92%) of the AMC-treated patients before therapy, including three penicillin-resistant S. pneumoniae and 38 BLPB. After therapy, 11 penicillin-resistant organisms were recovered from seven (28%) patients, including two S. pneumoniae and nine BLPB (P > 0.005).

Adverse effects were noted in six patients: diarrhoea (more than three watery stools in 24 h) was noted in two patients on AMX and in three on AMC, and vomiting was noted in one patient on AMX.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study compared the effects on the nasopharyngeal bacterial flora of two antibiotics, AMX alone or in combination with a ß-lactamase inhibitor (clavulanate). A greater reduction in the number of colonizing species was achieved with AMC. The greater eradication ability of AMC may be due to its ability to eradicate aerobic as well as anaerobic BLPB. These organisms may not only cause infection (i.e. H. influenzae, M. catarrhalis) but also ‘shield’ penicillin-susceptible or penicillin intermediately resistant pathogens (i.e. S. pneumoniae) from antimicrobial activity.5 Eradication of nasopharyngeal pathogens may have a beneficial effect, as it may prevent recurrent infection.2

Even though increasing the dose of AMX is recommended for the treatment of AOM due to penicillinresistant S. pneumoniae,6 this may not be sufficient to reduce the colonization of the oropharynx and the adenoids3 by this organism, where it may be protected by the presence of BLPB. In fact, in our study, AMX reduced the number of S. pneumoniae isolates from eight to seven, whereas AMC reduced it from seven to two. The persistence of colonization by S. pneumoniae may allow for later re-infection of the middle ear and reoccurrence of AOM.

The phenomenon of ‘shielding’ was demonstrated in vitro as well as in vivo and is one of the explanations for the failure of penicillin in the treatment of group A streptococcal tonsillitis.5 AMC was found to be superior to penicillin in the therapy of acute episodes of recurrent tonsillitis after penicillin failure and in prevention of recurrent infection.7 ß-Lactamase activity was detected in various upper respiratory tract infected sites. These include middle ear, sinus cavity and tonsillar tissue.5 Actual enzyme activity in the ear fluid was detected in aspirates of >70% of patients with otitis media who were infected with BLPB. These included all those who were infected with ß-lactamase-producing H. influenzae and three-quarters of those infected with M. catarrhalis.8

Further evidence of the ‘shielding’ effect of ß-lactamase comes from a study that investigated ß-lactamase activity in middle-ear aspirates obtained from 12 children with AOM who failed to respond to oral AMX therapy.9 BLPB were recovered in all 19 culture-positive aspirates, and ß-lactamase activity was detected in 17 of the 19 (89%) culturepositive aspirates, indicating that the enzyme might not only protect the BLPB but also shield AMX-susceptible organisms. AMX was not detected or was present in lower concentrations in the middle-ear aspirates with BLPB, and non-BLPB were able to survive alongside BLPB in the face of AMX therapy in eight instances.

Recently, Könönen et al.10 reported an increased recovery rate of nasopharyngeal anaerobes during AOM episodes. The significance of these anaerobes in the pathogenesis of AOM is uncertain, and we await further studies. However, if these organisms play a role in the pathogenesis of AOM, reducing their number may contribute to recovery and prevent recurrences. The ability to reduce the number of nasopharyngeal anaerobes in patients with AOM may be beneficial, as over half of the pigmented Prevotella and Fusobacterium species can produce ß-lactamase.2

This study demonstrates the greater ability of AMC, compared with AMX, to reduce the number of potential AOM pathogens and BLPB. Further long-term studies are warranted to explore whether such therapy can reduce the failure and recurrence rate of AOM and how quickly recolonization of the nasopharynx occurs after therapy.


    Notes
 
* Correspondence address. PO Box 70412, Chevy Chase, MD 20813-0412, USA. Tel: +1-301-295-2698; Fax: +1-646-390-2494; E-mail: ib6{at}georgetown.edu Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1 . Faden, H., Waz, M. J., Bernstein, J. M., Brodsky, L., Stamlevich, J. & Ogra, P. L. (1991). Nasopharyngeal flora in the first three years of life in normal and otitis-prone children. Annals of Otolarynology, Rhinology and Laryngology 100, 612–5.

2 . Dagan, R., Leibovitz, E., Cheletz, G., Lieberman, A. & Poray, N. (2001). Antibiotic treatment in acute otitis media promotes superinfection with resistant Streptococcus pneumoniae carried before initiation of treatment. Journal of Infectious Diseases 183, 880–6.[ISI][Medline]

3 . Brook, I., Shah, K. & Jackson, W. (2000). Microbiology of healthy and diseased adenoids. Laryngoscope 110, 994–9.[ISI][Medline]

4 . National Committee for Clinical Laboratory Standards. (1994). Performance Standards for Antimicrobial Susceptibility Testing: 4th International Supplement. M7-A3. NCCLS, Villanova, PA.

5 . Brook, I. (2001). The role of beta-lactamase producing bacteria and bacterial interference in streptococcal tonsillitis. International Journal of Antimicrobial Agents 17, 439–42.[ISI][Medline]

6 . Dowell, S. F., Butler, J. C., Giebink, G. S., Jacobs, M. R., Jernigan, D., Musher, D. M. et al. (1999). Acute otitis media: management and surveillance in an era of pneumococcal resistance—a report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatric and Infectious Disease Journal 18, 1–9.

7 . Kaplan, E. L. & Johnson, D. R. (1988). Eradication of group A streptococci from the upper respiratory tract by amoxicillin with clavulanate after oral penicillin V treatment failure. Journal of Pediatrics 113, 400–3.[ISI][Medline]

8 . Brook, I. & Yocum, P. (1989). Quantitative bacterial cultures and beta-lactamase activity in chronic suppurative otitis media. Annals of Otolarynology, Rhinology and Laryngology 98, 293–7.

9 . Brook, I. (1995). Bacteriology and beta-lactamase activity in ear aspirates of acute otitis media that failed amoxicillin therapy. Pediatric and Infectious Disease Journal 14, 805–8.

10 . Könönen, E., Kanervo, A., Pryk, A., Takala, A., Syrjänen, R. & Jousimies-Somer, H. (1999). Anaerobes in the nasopharynx during acute otitis media episodes in infancy. Anaerobe 5, 237–9.[ISI]

Received 21 August 2001; returned 5 November 2001; revised 5 December 2001; accepted 17 December 2001