The role of beta-lactamase-producing-bacteria in mixed infections
BMC Infectious Diseases volume 9, Article number: 202 (2009)
Beta-lactamase-producing bacteria (BLPB) can play an important role in polymicrobial infections. They can have a direct pathogenic impact in causing the infection as well as an indirect effect through their ability to produce the enzyme beta-lactamase. BLPB may not only survive penicillin therapy but can also, as was demonstrated in in vitro and in vivo studies, protect other penicillin-susceptible bacteria from penicillin by releasing the free enzyme into their environment. This phenomenon occurs in upper respiratory tract, skin, soft tissue, surgical and other infections. The clinical, in vitro, and in vivo evidence supporting the role of these organisms in the increased failure rate of penicillin in eradication of these infections and the implication of that increased rate on the management of infections is discussed.
Penicillins have been the agents of choice for the therapy of avariety of bacterial infections. However, within the past sixtyyears, an increased resistance to these drugs has been noted. Inaddition to bacteria long known to resistant penicillin, such as Staphylococcus aureus and Enterobacteriaceae, other previously susceptible organisms became increasingly resistant due to several mechanisms including the production of the enzyme beta-lactamase (BL). These include aerobic and facultative bacteria such as Haemophilus influenzae, Moraxella catarrhalis, as well as anaerobic Gram-negative bacilli (AGNB, i.e. Bacteroides fragilis group, pigmented Prevotella and Porphyromonas, Prevotella bivia, and Prevotella disiens) and Fusobacterium spp.) [1–3].
Beta-lactamase-producing bacteria (BLPB) may have an important clinical role in infections. These organisms can be pathogenic in causing the infection as well as have an indirect effect through their ability to produce the enzyme BL into their environment. BLPB may not only survive penicillin therapy but also may protect other penicillin-susceptible bacteria from penicillins by releasing the free enzyme into their environment (Figure 1).
In vivo and in vitro studies have demonstrated this phenomenon. Animal studies demonstrated the ability of the enzyme BL to influence polymicrobial infections. BL producing of AGNB protected a penicillin-sensitive Fusobacterium necrophorum  and Group A beta hemolytic streptococci (GABHS)  from penicillin therapy in mice. Clindamycin or the combination of penicillin and clavulanate (a BL inhibitor), which are active against both GABHS and AGNB, were effective in eradicating the infection . An increase in resistance of GABHS to penicillin was found when it was co-inoculated with S. aureus , Haemophilus parainfluenzae , or B. fragilis .
Several studies demonstrate the activity of the enzyme BL in polymicrobial infections. Penicillins were degraded by purulent exudates obtained from abscesses [11, 12] and in experimental B. fragilis infection .
The presence of BL in clinical specimens was reported in abscesses and mixed infections. These include abdominal infections , empyema , cerebrospinal specimens , abscesses , ear aspirates of acute and chronic ear infections [17, 18], and aspirates of acutely and chronically inflamed maxillary sinuses. Many of these infections had failed beta lactam therapies and required surgical drainage to enhance cure .
The isolation of penicillin-susceptible bacteria mixed with BLPB in patients who have failed to respond to penicillin or cephalosporin therapy suggests the ability of BLPB to protect a penicillin-susceptible or cephalosporin-susceptible organism from the activity of those drugs.
The emergence of oral BLPB was shown to be associated with the administration of penicillin therapy . The selection of BLPB following antimicrobial therapy may account for many of the clinical failures that occur after penicillin therapy . BLPB were recovered in 75 (40%) of 185 children with orofacial and respiratory infections who failed to respond to penicillin .
Aerobic and anaerobic BLPB may play a role in penicillin failure to eradicate GABHS tonsillitis [8, 9, 21–31]. It is plausible that these BLPB can protect GABHS from penicillin by inactivation of the antibiotic. (Figure 1) BLPB were recovered in 37 of 50 tonsils (74%) removed from children who failed penicillin therapy. These observations were confirmed by Reilly et al. , Chagollan et al. , and Tuner and Nord . Assays of the free enzyme in the tissues demonstrated its presence in 33 of 39 (85%) tonsils that harbored BLPB .
BLPB emerged in the oropharynx promptly following penicillin therapy [32–34]. BLPB were isolated in 3 of 21 (14%) of children prior to penicillin therapy, and in 10 of 21 (48%) following one course of penicillin . In a study of 26 children who were treated with penicillin for seven days 11% harbored BLPB prior to the thearpy which increased to 45% at the conclusion of the treatment, and the incidence was 27% three months later . These organisms were also isolated from household contacts of children repeatedly treated with penicillin, suggesting their possible transfer within a family .
Chemoprophylaxis of 20 children with recurrent otitis media with amoxicillin increased the recovery rate of BLPB from 20% to 100% after six month . No change occurred in the recovery of BLPB in a group of 20 children who received sulfisoxazole.
An association has been noted between the presence of BLPB even prior to therapy of acute GABHS tonsillitis and the outcome of 10-day oral penicillin therapy . Of 98 children with acute GABHS tonsillitis, 36 failed to respond to therapy. Prior to therapy, 18 isolates of BLPB were detected in 16 (26%) of those cured and following therapy 30 such organisms were recovered in 19 (31%) of these children. In contrast, prior to therapy, 40 BLPB were recovered from 25 (69%) of the children who failed, and following therapy, 62 such organisms were found in 31 (86%) of the children in that group.
A high levels of BL in saliva reflects colonization with many BLPB . Previous antimicrobial therapy can select for resistant bacterial strains that could persist in the nasopharynx to re-emerge in new ear and sinus infection .
The presence of BLPB in mixed infection warrants administration of drugs that will be effective in eradication of BLPB as well as the other pathogens. The high failure rate of penicillin therapy associated with the recovery of BLPB in a growing number of cases of mixed aerobic-anaerobic infections highlights the importance of this therapeutic approach [21, 22].
An infection in which this therapeutic approach has been successful is recurrent tonsillitis [39–51]. Antimicrobials active against aerobic and anaerobic BLPB as well as GABHS were more effective in the eradication of this infection and even prevented elective tonsillectomy  compared to penicillin. These include lincomycin [39–42], clindamycin [43–48], and amoxicillin/clavulanate .
BLPB colonized over 83% of the adenoids in children with chronic adeno-tonsillitis  which may explain the persistence of many pathogens including Streptococcus pneumoniae. The total number of potential pathogens and BLPB were lower in those treated with amoxicillin/clavulante or clindamycin [54, 55] Similarly amoxicillin/clavulante was superior to amoxicillin in achieving clinical cure (92% vs 64%) and reducing the number of potential nasopharyngeal pathogens including S. pneumoniae and BLPB in children with acute otitis media .
Two studies illustrated the superiority of clindamycin to penicillin in the treatment of lung abscesses [57, 58]. This was postulated to be due to its ability to eradicate the anaerobic BLPB present in lung abscess.
Antimicrobials effective against anaerobic BLPB (ticarcillin/clavulanate or clindamycin with ceftazidime) were superior to an agent without such coverage (ceftriaxone) in the therapy of aspiration or tracheostomy-associated pneumonia in 57 children .
The above studies illustrate that the successful management of polymicrobial infections is enhanced by directing antimicrobial therapy at the eradication of both aerobic and anaerobic BLPB. This approach is also useful in management infections such as tonsillitis where BLPB are part of the normal flora at the infection site and is often employed it the treatment of other infections at all body sites. Some of these are polymicrobial where one of the pathogens is a BLPB while in others the role of the BLPB as a primary pathogen is unclear (i. e. tonsillitis).
Although beta lactam antibiotics are still the mainstay in treatment of numerous infections, agents effective against BLPB should be considered in the treatment of those who failed these agents. Since BLPB can spread within the community as well as the hospital efforts should be made to reduce the spread.33 However, further studies are warranted to critically investigate these modalities.
Beta lactamase producing bacteria
group A Beta hemolytic bacteria.
Doern GV: Resistance among problem respiratory pathogens in pediatrics. Pediatr Infect Dis J. 1995, 14: 420-3. 10.1097/00006454-199505001-00003.
Richter SS, Brueggemann AB, Huynh HK, Rhomberg PR, Wingert EM, Flamm R, Doern GV: A 1997-1998 national surveillance study: Moraxella catarrhalis and Haemophilus influenzae antimicrobial resistance in 34 US institutions. Int J Antimicrob Agents. 1999, 13: 99-107. 10.1016/S0924-8579(99)00112-0.
Brook I, Calhoun L, Yocum P: Beta-lactamase-producing isolates of Bacteroides species from children. Antimicrob Agents Chemother. 1980, 18: 264-6.
Brook I: The role of beta-lactamase-producing bacteria in the persistence of streptococcal tonsillar infection. Rev Inf Dis. 1984, 6: 601-7.
Hackman AS, Wilkins TD: In vivo protection of Fusobacterium necrophorum from penicillin by Bacteroides fragilis. Antimicrob Agents Chemother. 1975, 7: 698-703.
Brook I, Pazzaglia G, Coolbaugh JC, Walker RI: In vivo protection of group A beta-hemolytic streptococci by beta-lactamase producing Bacteroides species. J Antimicrob Chemother. 1983, 12: 599-606. 10.1093/jac/12.6.599.
Brook I, Pazzaglia G, Coolbaugh JC, Walker RI: In vivo protection of penicillin susceptible Bacteroides melaninogenicus from penicillin by facultative bacteria which produce beta-lactamase. Can J Microbiol. 1984, 30: 98-104. 10.1139/m84-017.
Simon HM, Sakai W: Staphylococcal anatagosim to penicillin group therapy of hemolytic streptococcal pharyngeal infection: Effect of oxacillin. Pediatrics. 1963, 31: 463-9.
Scheifele DW, Fussell SJ: Frequency of ampicillin resistant Haemophilus parainfluenzae in children. J Infect Dis. 1981, 143: 495-8.
Brook I, Yocum P: In vitro protection of group A beta-hemolytic streptococci from penicillin and cephalothin by Bacteroides fragilis. Chemother. 1983, 29: 18-23. 10.1159/000238168.
De Louvois J, Hurley R: Inactivation of penicillin by purulent exudates. Br Med J. 1977, 2: 998-1000. 10.1136/bmj.1.6067.998.
Masuda G, Tomioka S: Possible beta-lactamase activities detectable in infective clinical specimens. J Antibiot (Tokyo). 1977, 30: 1093-7.
O'Keefe JP, Tally FP, Barza M, Gorbach SL: Inactivation of penicillin-G during experimental infection with Bacteroides fragilis. J Infect Dis. 1978, 137: 437-42.
Bryant RE, Rashad AL, Mazza JA, Hammond D: Beta-lactamase activity in human plus. J Infect Dis. 1980, 142: 594-601.
Boughton WH: Rapid detection in spinal fluid of beta-lactamase produced by ampicillin-resistant Haemophilus influenzae. J Clin Microbiol. 1982, 15: 1167-8.
Brook I: Presence of beta-lactamase-producing bacteria and beta-lactamase activity in abscesses. Am J Clin Pathol. 1986, 86: 97-101.
Brook I: Quantitative cultures and beta-lactamase activity in chronic suppurative otitis media. Ann Otol Rhinol Laryngol. 1989, 98: 293-7.
Brook I, Yocum P: Bacteriology and beta-lactamase activity in ear aspirates of acute otitis media that failed amoxicillin therapy. Pediatr Infect Dis J. 1995, 14: 805-8. 10.1097/00006454-199509000-00015.
Brook I, Yocum P, Frazier EH: Bacteriology and beta-lactamase activity in acute and chronic maxillary sinusitis. Arch Otolaryngol Head Neck Surg. 1996, 122: 418-22.
Brook I, Gober AE: Monthly changes in the rate of recovery of penicillin-resistant organisms from children. Pediatr Infect Dis J. 1997, 16: 255-7. 10.1097/00006454-199702000-00020.
Heimdahl A, Von Konow L, Nord CE: Isolations of beta-lactamase-producing Bacteroides strains associated with clinical failures with penicillin treatment of human orofacial infections. Arch Oral Biol. 1980, 25: 288-92. 10.1016/0003-9969(80)90102-8.
Brook I: Beta-lactamase-producing bacteria recovered after clinical failures with various penicillin therapy. Arch Otolaryngol. 1984, 110: 228-31.
Tomeh MO, Starr SE, McGowan JE: Ampicillin-resistant Haemophilus Influenzae type b infection. JAMA. 1974, 229: 295-10.1001/jama.229.3.295.
Jacobs MR: Worldwide trends in antimicrobial resistance among common respiratory tract pathogens in children. Pediatr Infect DisJ. 2003, 22 (8 Suppl): S109-19. 10.1097/00006454-200308001-00002.
Kovatch AL, Wald ER, Michaels RH: Beta-lactamase-producing Branhamella catarrhalis causing otitis media in children. J Pediatr. 1983, 102: 260-3.
Brook I, Yocum P, Friedman EM: Aerobic and anaerobic flora recovered from tonsils of children with recurrent tonsillitis. Ann Otol Rhinol Laryngol. 1981, 90: 261-3.
Brook I, Yocum P: Bacteriology of chronic tonsillitis in young adults. Arch Otolaryngol. 1984, 110: 803-5.
Brook I, Yocum P: Quantitative measurement of beta-lactamase levels in tonsils of children with recurrent tonsillitis. Acta Otolaryngol Scand. 1984, 98: 456-9.
Reilly S, Timmis P, Beeden AG, Willis AT: Possible role of the anaerobe in tonsillitis. J Clin Path. 1981, 34: 542-7. 10.1136/jcp.34.5.542.
Chagollan JR, Macias JR, Gil JS: Flora indigena de las amigalas. Investigacion Medical Internacional. 1984, 11: 36-43.
Tuner K, Nord CE: Beta lactamase-producing microorganisms in recurrent tonsillitis. Scand J Infect Dis Suppl. 1983, 39: 83-5.
Tuner K, Nord CE: Emergence of beta-lactamase producing microorganisms in the tonsils during penicillin treatment. Eur J Clin Microb. 1986, 5: 399-404. 10.1007/BF02075694.
Brook I, Gober AE: Emergence of beta-lactamase-producing aerobic and anaerobic bacteria in the oropharynx of children following penicillin chemotherapy. Clin Pediatr. 1984, 23: 338-41. 10.1177/000992288402300608.
Brook I: Emergence and persistence of β-lactamase-producing bacteria in the oropharynx following penicillin treatment. Arch Otolaryngol Head Neck Surg. 1988, 114: 667-670.
Brook I, Gober AE: Prophylaxis with amoxicillin or sulfisoxazole for otitis media: effect on the recovery of penicillin-resistant bacteria from children. Clin Infect Dis. 1996, 22: 143-5.
Brook I: Role of beta-lactamase-producing bacteria in penicillin failure to eradicate group A streptococci. Pediatr Infect Dis. 1985, 4: 491-5. 10.1097/00006454-198509000-00010.
Roos K, Grahn E, Holn SE: Evaluation of beta-lactamase activity and microbial interference in treatment failures of acute streptococcal tonsillitis. Scand J Infect Dis. 1986, 18: 313-8. 10.3109/00365548609032342.
Brook I, Gober AE: Resistance to antimicrobials used for the therapy of otitis and sinusitis effect of previous antimicrobial therapy and smoking. Ann Otol Rhinol Laryngol. 1999, 108: 645-7.
Breese BB, Disney FA, Talpey WB: Beta-hemolytic streptococcal illness: Comparison of lincomycin, ampicillin and potassium penicillin-G in treatment. Am J Dis Child. 1966, 112: 21-7.
Breese BB, Disney FA, Talpey WB, et al: Beta-hemolytic streptococcal infection:Comparison of penicillin and lincomycin in the treatment of recurrent infections or the carrier state. Am J Dis Child. 1969, 117: 147-52.
Randolph MF, DeHaan RM: A comparison of lincomycin and penicillin in the treatment of group A streptococcal infections:Speculation on the "L" forms as a mechanism of recurrence. Del Med J. 1969, 41: 51-62.
Howie VM, Plousard JH: Treatment of group A streptococcal pharyngitis in children:Comparison of lincomycin and penicillin G given orally and benzathine penicillin G given intramuscularly. Am J Dis Child. 1971, 121: 477-
Randolph MF, Redys JJ, Hibbard EW: Streptococcal pharyngitis III. Streptococcal recurrence rates following therapy with penicillin or with clindamycin (7-chlorlincomycin). Del Med J. 1970, 42: 87-92.
Stillerman M, Isenberg HD, Facklan RR: Streptococcal pharyngitis therapy:Comparison of clindamycin palmitate and potassium phenoxymethyl penicillin. Antimicrob Agents Chemother. 1973, 4: 516-20.
Massell BF: Prophylaxis of streptococcal infection and rheumatic fever: A comparison of orally administered clindamycin and penicillin. JAMA. 1979, 241: 1589-94. 10.1001/jama.241.15.1589.
Brook I, Leyva F: The treatment of the carrier state of group A beta-hemolytic streptococci with clindamycin. Chemother. 1981, 27: 360-7. 10.1159/000238005.
Brook I, Hirokawa R: Treatment of patients with recurrent tonsillitis due to group A beta-hemolytic streptococci: A prospective randomized study comparing penicillin, erythromycin and clindamycin. Clin Pediatr. 1985, 24: 331-6. 10.1177/000992288502400606.
Orrling A, Stjernquist-Desatnik A, Schalen C: Clindamycin in recurrent group A streptococcal pharyngotonsillitis--an alternative to tonsillectomy?. Acta Otolaryngol. 1997, 117: 618-22. 10.3109/00016489709113448.
Chaudhary S, Bilinsky SA, Hennessy JL, Soler SM, Wallace SE, Schacht CM, Bisno AL: Penicillin V and rifampin for the treatment of group A streptococcal pharyngitis: A randomized trial of 10 days penicillin vs 10 days penicillin with rifampin during the final 4 days of therapy. J Pediatr. 1985, 106: 481-6. 10.1016/S0022-3476(85)80687-9.
Tanz RR, Shulman ST, Barthel MJ, Willert C, Yogev R: Penicillin plus rifampin eradicate pharayngeal carrier of group A streptococci. J Pediatr. 1985, 106: 876-880. 10.1016/S0022-3476(85)80229-8.
Tanz RR, Poncher JR, Corydon KE, Kabat K, Yogev R, Shulman ST: Clindamycin treatment of chronic pharyngeal carriage of group A streptococci. J Pediatr. 1991, 119: 123-8. 10.1016/S0022-3476(05)81052-2.
Brook I: Treatment of patients with acute recurrent tonsillitis due to group A beta-haemolytic streptococci: a prospective randomized study comparing penicillin and amoxycillin/clavulanate potassium. J Antimicrob Chemother. 1989, 24: 227-33. 10.1093/jac/24.2.227.
Brook I, Shah K, Jackson W: Microbiology of Healthy and Diseased Adenoids. Laryngoscope. 2000, 110: 994-999. 10.1097/00005537-200006000-00021.
Brook I, Shah K: Effect of amoxycillin with or without clavulanate on adenoid bacterial flora. J Antimicrob Chemother. 2001, 48: 269-73. 10.1093/jac/48.2.269.
Brook I, Shah K: Effect of amoxicillin or clindamycin on the adenoids bacterial flora. Otolaryngol Head Neck Surg. 2003, 129: 5-10. 10.1016/S0194-5998(03)00522-9.
Brook I, Gober AE: Effect of amoxicillin and co-amoxiclav on the aerobic and anaerobic nasopharyngeal flora. J Antimicrob Chemother. 2002, 49: 689-92. 10.1093/jac/49.4.689.
Levison ME, Mangura CT, Lorber B, Abrutyn E, Pesanti EL, Levy RS, MacGregor RR, Schwartz AR: Clindamycin compared with penicillin for the treatment of anaerobic lung abscess. Ann Int Med. 1983, 98: 466-471.
Gudiol F, Manresa F, Pallares R, Dorca J, Rufi G, Boada J, Ariza X, Casanova A, Viladrich PF: Clindamycin vs penicillin for anaerobic lung infections. High rate of penicillin failures associated with penicillin-resistant Bacteroides melaninogenicus. Arch Intern Med. 1990, 150: 2525-9. 10.1001/archinte.150.12.2525.
Brook I: Treatment of aspiration or tracheostomy-associated pneumonia in neurologically impaired children: effect of antimicrobials effective against anaerobic bacteria. Int J Pediatr Otorhinolaryngol. 1996, 35: 171-7. 10.1016/0165-5876(96)01332-8.
The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/9/202/prepub
The authors declare that they have no competing interests.
Authors’ original submitted files for images
Below are the links to the authors’ original submitted files for images.
About this article
Cite this article
Brook, I. The role of beta-lactamase-producing-bacteria in mixed infections. BMC Infect Dis 9, 202 (2009). https://doi.org/10.1186/1471-2334-9-202