Curr Infect Dis Rep (2010) 12:110117
DOI 10.1007/s11908-010-0081-8
-LactamaseProducing Bacteria in Upper Respiratory
Tract Infections
Itzhak Brook
Published online: 24 February 2010
# Springer Science+Business Media, LLC 2010
Abstract -Lactamaseproducing bacteria (BLPB) can
play an important role in respiratory 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 -lactamase. BLPB not only may survive penicillin
therapy, but as demonstrated by in vitro and in vivo studies,
can also protect other penicillin-susceptible bacteria from
penicillin by releasing the free enzyme into their environ-
ment. 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.
Keywords -lactamase . Penicillin . Anaerobic bacteria .
Haemophilus influenzae . Moraxella catarrhalis .
Staphylococcus aureus
Introduction
Penicillins have been the agents of choice for the therapy of
a variety of bacterial infections. However, within the past
60 years, an increased resistance to these agents has been
noted. In addition to bacteria long known to resistant
penicillin, such as Staphylococcus aureus and Enterobac-
teriaceae, other previously susceptible organisms became
increasingly resistant because of several mechanisms,
I. Brook (*)
Department of Pediatrics,
Georgetown University School of Medicine,
4431 Albemarle Street NW,
Washington, DC 20016, USA
e-mail: ib6@georgetown.edu
including their ability to produce the enzyme -lactamase
(BL). These include aerobic and facultative bacteria such as
Haemophilus influenzae [1], Moraxella catarrhalis [2], as
well as anaerobic gram-negative bacilli (AGNB; eg,
Bacteroides fragilis group, pigmented Prevotella and
Porphyromonas spp) and Fusobacterium spp [3].
-Lactamaseproducing 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. BLPB may not only survive penicillin therapy but also
may protect other penicillin-susceptible bacteria from
penicillins by releasing the enzyme into their environment
(Fig. 1) [4].
This review highlights the importance of BLPB in upper
respiratory tract infections (URTI). The clinical, in vitro,
and in vivo evidence supporting the role of these organisms
in the increased failure rate of penicillin in eradicating these
infections and the implication of that increased rate on the
management of various infections is discussed.
Evidence for Indirect Pathogenicity of BLPB
The production of the enzyme BL is an important
mechanism of indirect pathogenicity of aerobic and
anaerobic bacteria that is especially apparent in polymicro-
bial infection. Not only are the organisms that produce the
enzyme protected from the activity of penicillins, but other
penicillin-susceptible organisms can also be shielded
(Fig. 1). This protection can happen when BL is secreted
into the infected tissues or abscess fluid in sufficient
quantities to break the penicillins -lactam ring before it
can kill the susceptible bacteria. Clinical and laboratory
studies are described that illustrate this phenomena.
Curr Infect Dis Rep (2010) 12:110117
Resistance to -lactam antibiotics
-lactam antibiotics
-lactamase -lactam
producing susceptible
bacteria bacteria
Fig. 1 Protection of -lactamesusceptible bacteria from these anti-
biotics by -lactamaseproducing bacteria
In Vivo and In Vitro Studies
Animal studies demonstrated the ability of the enzyme BL
to influence polymicrobial infections. Hackman and
Wilkins [5] demonstrated that penicillin-resistant strains of
B. fragilis, pigmented Prevotella and Porphyromonas spp,
and Prevotella oralis protected a penicillin-sensitive Fuso-
bacterium necrophorum from penicillin therapy in mice.
Brook et al. [6], using a subcutaneous abscess model in mice,
showed protection of group A -hemolytic streptococci
(GABHS) from penicillin by B. fragilis and Prevotella
melaninogenica. Clindamycin or the combination of penicil-
lin and clavulanic-acid (a BL inhibitor), which are active
against both GABHS and AGNB were effective in eradicat-
ing the infection. Similarly, BL-producing facultative bacte-
ria protected a penicillin-susceptible P. melaninogenica from
penicillin [7].
In vitro studies have also illustrated this phenomenon. A
200-fold increase in resistance of GABHS to penicillin was
observed when it was co-inoculated with S. aureus [8]. An
increase in resistance was also present when GABHS was
grown with Haemophilus parainfluenzae [9]. When mixed
with cultures of B. fragilis, the resistance of GABHS to
penicillin increased 8500-fold [10].
-Lactamase in Clinical Infections
Several studies demonstrate the activity of the enzyme BL in
polymicrobial infections. De Louvois and Hurley [11]
observed degradation of penicillin, ampicillin, and cephalor-
idine by purulent exudates obtained from 4 of 22 patients
with abscesses. Studies by Masuda and Tomioka [12]
111
illustrated BL activity in empyema fluid. Most infections
were polymicrobial and involved both Klebsiella pneumo-
niae and Pseudomonas aeruginosa. OKeefe et al. [13]
found inactivation of penicillin-G in an experimental B.
fragilis infection model in the rabbit peritoneum. These
studies suggest that local infection with BLPB may modify
penicillin contents of abscess fluid by enzymatic degradation.
The presence of the enzyme BL in clinical specimens
was reported by Bryant et al. [14], who studied BL activity
in samples of pus obtained from 12 patients with
polymicrobial intra-abdominal abscess or polymicrobial
empyema. Enzyme activity was noted in 4 of the 11
abscess fluids. Boughton [15], who studied cerebrospinal
specimens detected enzyme activity in all five specimens
that contained BL-producing H. influenzae. No BL was
detected, however, in the 33 specimens that contained non-
BL-producing H. influenzae or in the 234 sterile samples.
We investigated the presence of BLPB and BL activity in
109 abscesses [16]. One hundred BLPB were recovered in 88
(77%) specimens. These included all 28 isolates of B. fragilis
group, 18 of 30 pigmented Prevotella and Porphyromonas
spp, 42 of 43 S. aureus, and 11 of 14 Escherichia coli. BL
activity was detected in 40 (55%) of the purulent specimens.
BL activity was detected in 46 of 88 (55%) ear aspirate
specimens that contained BLPB [16]. BL activity was also
present in ear aspirates of 30 of 38 (79%) children with
chronic otitis media (OM) [17] and in 17 of 19 (89%) ear
aspirates of children with acute OM who failed amoxicillin
(AMX) therapy [18].
Brook et al. [19] determined the bacteriology and BL
activity in aspirates of 10 acutely and 13 chronically
inflamed maxillary sinuses. Four BLPB were isolated in
four specimens (40%) obtained from acutely inflamed
sinuses, and 14 BLPB were recovered from 10 chronically
inflamed sinuses (77%). The predominant BLPBs in acute
sinusitis were H. influenzae, and M. catarrhalis; those in
chronic sinusitis were S. aureus, Prevotella spp, Fusobac-
terium spp, and B. fragilis. BL activity was detected in 12
(three in acute and nine in chronic sinusitis) of the 14
aspirates that contained BLPB (Table 1).
The recovery 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 isolation of BLPB in the oropharynx of patients with
URTI has been noted to be increasing in recent years [20].
These organisms are S. aureus, H. influenzae, M. catarrhalis,
and AGNB. The emergence of BLPB was shown to be
associated with the administration of penicillin therapy.
We investigated the monthly changes in the rate of
recovery of aerobic and anaerobic penicillin-resistant bacteria
in the oropharynx of children [20]. Each month over a period
112
Table 1 Isolates recovered in four sample patients with chronic
sinusitis, their ability to produce -lactamase, and the detection of -
lactamase in sinusitis aspirates
Organism Patient no.
1 2 3 4
Staphylococcus aureus (BL +) + +
Streptococcus pneumoniae + patients that were retreated. Two randomized, single-blind,
Peptostreptococcus spp + +
Propionibacterium acnes + that the recommended doses of either oral penicillin-V or
Fusobacterium spp (BL +) + +
Fusobacterium spp (BL -) + +
Prevotella spp (BL +) + penicillin V and 37% of intramuscular penicillin [27].
Prevotella spp (BL -) + + +
Bacteroides fragilis group (BL +) + +
-lactamase activity (BL +) + + + +
BL -, organism does not produce -lactamase; BL +, organism
produces -lactamase
(Data from Brook et al. [19])
of a year, the first 30 children who presented with URTI
were studied. The highest number of aerobic and anaerobic
BLPB and number of patients with BLPB was noted in April
(60% of patients) and the lowest was in September (13%). A
gradual increase of BLPB and penicillin-resistant Strepto-
coccus pneumoniae occurred from September to April, and a
slow decline took place from April to August. These changes
correlated directly with the intake of -lactam antibiotics.
The study was repeated over the following year with similar
results. The crowding that is more common in the winter
might have also contributed to the spread of BLPB.
Monitoring the local seasonal variation in the rate of BLPB
may be helpful in the empiric choice of antimicrobials.
Judicious use of antimicrobials may control the increase of
BLPB.
Clinical Studies
The selection of BLPB following antimicrobial therapy may
account for many of the clinical failures that occur after
penicillin administration. A report described five adults with
clinical failures after penicillin therapy associated with the
isolation of anaerobic BLPB [21]. In a study of 185 children
with orofacial and respiratory infections who failed to respond
to penicillin, BLPB were recovered in 75 (40%) [22]. The
predominant BLPB were S. aureus, pigmented Prevotella and
Porphyromonas spp, B. fragilis group, and P. oralis.
The URTI in which the phenomenon of indirect
pathogenicity was most thoroughly studied is recurrent
tonsillitis due to GABHS [23]. Penicillin was considered
the drug of choice for the therapy of most URTI because of
the susceptibility of most oral pathogens. The growing
Curr Infect Dis Rep (2010) 12:110117
resistance of oral pathogens, however, has limited the use
of this drug [24, 25].
The frequently reported inability of penicillin to eradi-
cate GABHS is of concern. A clinical study [26] demon-
strated the persistence of GABHS in the pharynx despite
treatment with intramuscular penicillin in 21% of the
patients after the first course of therapy and in 83% of
multicenter antibiotic efficacy trials in children illustrated
intramuscular penicillin failed to eradicate GABHS in
acute-onset pharyngitis in 35% patients treated with oral
Various theories have attempted to explain this penicillin
failure. One explanation is that repeated penicillin admin-
istration results in a shift in the oral microflora with
selection of BL-producing strains of Haemophilus spp, S.
aureus, M. catarrhalis, and AGNB [8, 9, 21, 22, 28, 29]. It
is possible that these BLPB can protect GABHS from
penicillin by inactivation of the antibiotic.
Clinical evidence supporting the ability of a BLPB to
protect a penicillin-susceptible pathogen was first reported
in 1963 [8]. Knudsin and Miller [30] observed a signifi-
cantly higher carrier rate of penicillin-resistant S. aureus in
patients with penicillin treatment failure than in those with
treatment success. In contrast, Quie et al. [31], who did not
use methods for detection of anaerobic BLPB, found no
such correlation. Clinical studies suggested that H. para-
influenzae [9] and M. catarrhalis [32] may also have a role
in penicillin failure.
The role of anaerobic BLPB in persistence of GABHS in
tonsils was suggested by Brook et al. [33-35], who studied
core tonsillar cultures of 50 children suffering from
recurrent tonsillitis. One or two strains of aerobic and/or
anaerobic BLPB were recovered in 74% of the tonsils. The
anaerobic BLPB included strains of B. fragilis group,
pigmented Prevotella and Porphyromonas spp and P.
oralis, whereas the aerobic bacteria were S. aureus,
Haemophilus spp, and M. catarrhalis. These observations
were confirmed by Reilly et al. [36], Chagollan et al. [37],
and Tuner and Nord [38]. Assays of the free enzyme in the
tissues demonstrated its presence in 33 of 39 (85%) tonsils
that harbored BLPB, whereas the enzyme was absent in the
11 tonsils without BLPB [35].
Tuner and Nord [39] and Brook and Gober [40]
demonstrated the rapid emergence of BLPB following
penicillin therapy. Tuner and Nord [39] studied the emer-
gence of BLPB in the oropharynx of 10 healthy volunteers
treated with penicillin for 10 days. A significant increase was
observed in the number of BL-producing strains of Bacter-
oides spp, Fusobacterium nucleatum, and S. aureus. BL
activity in saliva increased significantly in parallel to the
increase of BLPB.
Curr Infect Dis Rep (2010) 12:110117
Brook and Gober [40] isolated BLPB in the nasopharynx
of 3 of 21 (14%) children prior to penicillin therapy, and in
10 of 21 (48%) following one course of penicillin (Table 2).
In a study of 26 children who received therapy with
penicillin for 7 days, 11% harbored BLPB in their
oropharyngeal flora prior to therapy [41]. This increased
to 45% at the conclusion of therapy, and 3 months later the
incidence was 27%. These organisms were also isolated
from household contacts of children repeatedly treated with
penicillin, suggesting their possible transfer within a family.
These data suggest that emergence of BLPB occurs rapidly
in the upper respiratory tract following penicillin therapy
and can spread within the household.
Certain groups of children are at greater risk for
developing penicillin-resistant flora. Administration of
AMX chemoprophylaxis is sometimes used for the preven-
tion of recurrent OM. Although AMX prophylaxis has been
shown to prevent ear infections in susceptible patients,
patients receiving the drug are at risk for developing BLPB
in the nasopharynx.
A study investigated the effect of AMX chemoprophylaxis
on the recovery rate of penicillin-resistant nasopharyngeal
aerobic and anaerobic isolates over a 9-month period [42].
The rate of recovery of BLPB in the oropharynx of 20
children who received AMX or sulfisoxazole chemoprophy-
laxis for 4 to 6 months for OM was investigated monthly.
The major BLPB were H. influenzae, M. catarrhalis, S.
aureus, and AGNB. The recovery rate of all BLPB as well as
penicillin-resistant S. pneumoniae increased in the children
after initiation of AMX chemoprophylaxis. Prior to therapy,
six isolates of BLPB were recovered from four (20%)
children. The number of BLPB increased gradually until all
patients were colonized 5 months into their prophylaxis. Four
to 6 months following discontinuation of prophylaxis, the
number of BLPB declined to colonize only three (15%)
children. No change occurred in the recovery of BLPB in
those receiving sulfisoxazole. These data illustrate the shift in
oropharyngeal flora toward penicillin resistance during AMX
chemoprophylaxis.
Table 2 -Lactamaseproducing isolates recovered from the nasopharynx of children before and after treatment with penicillin and from
untreated (control) patients
Organisms Group 1
Isolates recovered in 21 penicillin-treated children
Before therapy
Gram-negative anaerobic bacteria 23 (0)
Staphylococcus aureus 2 (2)
Total children 3 (14%)
(Data from Brook and Gober [40])
113
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 [43]. Of 98
children, 36 failed to respond to therapy (Table 3). Prior to
therapy, 18 isolates of BLPB were detected in 16 (26%) of
those cured; after 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 after therapy, 62 such organisms
were found in 31 (86%) of the children in that group.
A correlation was also noted between the rate of recovery
of BLPB in healthy children and the rate of AMX failure to
eradicate GABHS tonsillitis [44]. AMX failure rate varied
over the year of the study; it was high between October and
May (22% to 32%), with the exception of April (11%), and
low between June and September (8% to 12%). BLPB were
recovered from 226 of 663 (34%) well children. The rate
was also high between October and May (40%52%), with
the exception of April (23%), and the lowest between June
and September (10%12%). Prior to their treatment, BLPB
were recovered from 26 of the 48 (54%) children who
eventually failed AMX therapy, and from 28 of the 180
(16%) who did not fail (P<0.001). A high failure rate of
penicillins in eradication of GABHS in pharyngotonsillitis
can therefore serve as sensitive indicator for a high
prevalence rate of BLPB in the community.
Roos et al. [45] showed that high levels of BL in saliva
may reflect colonization with many BLPB. These investiga-
tors demonstrated that patients with recurrent GABHS
tonsillitis had detectable amounts of BL in their saliva
compared to patients with uncomplicated courses of tonsillitis.
Previous antimicrobial therapy can select for resistant
bacterial strains including BLPB that could persist in the
nasopharynx to re-emerge in new infection. We evaluated
the antimicrobial susceptibility of the pathogens isolated
from the middle ear of 22 children with OM and from sinus
aspirates of 20 adults with maxillary sinusitis who failed to
respond to antimicrobial therapy, and correlate it with
previous therapy [46]. Resistance to the antimicrobial
Group 2
Isolates recovered in 18 nontreated children
After therapy Baseline Follow-up
26 (8) 23 (8) 20 (0)
4 (3) 1 (1) 2 (1)
10 (48%) 2 (11%) 1 (6%)
114
Table 3 -Lactamaseproducing organisms isolated from tonsillar cultures of 98 children with GABHS tonsillitis before and after penicillin
therapy
Prior to penicillin therapy
Group Aa
(62 patients)
Aerobic and facultative 6 20
Anaerobic 12
Total 18
a
Group AChildren who responded to penicillin therapy, and GABHS was eradicated
b
Group BChildren who did not respond to penicillin therapy, and GABHS persisted in tonsils
GABHSgroup A -hemolytic streptococci
(Data from Brook [43])
agents used was found in 23 of the 47 (49%) isolates that
were found in 20 (48%) of the patients. These included 10
of 15 (67%) isolates of S. pneumoniae, 4 of 14 (29%) H.
influenzae, 4 of 7 (57%) S. aureus, and 5 of 6 (83%) M.
catarrhalis. A statistically significant higher recovery of
resistant organisms was noted in those treated 2 to 6 months
previously, and in those with sinusitis who smoked.
The data presented illustrate the increasing role of BLPB
in mixed infections. The data also demonstrate the rapidity
with which BLPB can appear in patients and spread to other
household members.
Therapeutic Implications of Indirect Pathogenicity
The presence of BLPB in mixed infection warrants
administration of drugs that will be effective in eradicating
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].
This therapeutic approach has been successful in
recurrent tonsillitis [26, 47-63]. Antimicrobials active
against BLPB as well as GABHS were more effective than
penicillin in the eradication of this infection. Smith et al.
[26] illustrated the superiority of dicloxacillin therapy (50%
success rate) compared with penicillin (17% success rate) in
eradicating recurrent GABHS tonsillitis. Several studies
demonstrated the efficacy of lincomycin [47-50] and
clindamycin [51-56, 61], the combination of penicillin plus
rifampin over penicillin alone [57, 58], and clindamycin
over penicillin plus rifampin [59]. The superiority of these
drugs compared with penicillin results from their efficacy
against GABHS as well as AGNB and S. aureus.
Amoxicillin-clavulanate (AMX-C) was also found to be
superior to penicillin in therapy of recurrent tonsillitis [60].
Curr Infect Dis Rep (2010) 12:110117
Following 10 days of penicillin therapy
Group Bb Group Aa Group Bb
(36 patients) (62 patients) (36 patients)
11 30
20 19 32
40 30 62
GABHS was eradicated in 14 of 20 (70%) patients treated
with penicillin, and in all those treated with AMX-C (P<
0.001). In a 1-year follow-up, 11 of 19 patients treated with
penicillin and 2 of 18 patients treated with AMX-C had
recurrent GABHS tonsillitis (P<0.005). The addition of
clavulanate, a BL inhibitor that blocks the enzyme, enables
AMX to eradicate the BLPB.
In a double-blind study, Brook and Hirokawa [55]
compared penicillin with erythromycin and clindamycin
(Table 4). Penicillin therapy resulted in only 2 cures of 15,
erythromycin in 6 of 15, and clindamycin in 14 of 15. Four
patients who received penicillin and two who received
erythromycin required a tonsillectomy. No tonsillectomies
were required in the clindamycin group.
BLPB colonize more than 83% of the adenoids in
children with chronic adenotonsillitis [62]. The presence of
BLPB within the adenoids core may explain the persistence
of many pathogens, including S. pneumoniae, where they
may be shielded from the activity of penicillins. The effect
on the adenoid bacterial flora of 10-day therapy with AMX,
AMX-C [63], or clindamycin [64] prior to adenoidectomy
for recurrent OM was studied. The total number of isolates
and bacteria per gram of tissue were lower in those treated
with any of the antibiotics. However, the number of
potential pathogens and BLPB was lower in those treated
Table 4 Double-blind antibiotic comparison study treating patients
with recurrent GABHS tonsillitis (45 patients)
Antibiotic Clinical cures Tonsillectomies
Penicillin 2/15 4/15
Erythromycin 6/15 2/15
Clindamycin 14/15 0/15
GABHSgroup A -hemolytic streptococci
(Data from Brook and Hirokawa [55])
Curr Infect Dis Rep (2010) 12:110117
with AMXC and clindamycin compared with AMC and
controls (P<0.001).
A similar study evaluated the effects of AMX-C or
AMX therapy on the nasopharyngeal flora of children with
acute OM [65]. Nasopharyngeal cultures were obtained
before therapy and 2 to 4 days after completing antimicro-
bial therapy in 25 patients treated with either antibiotic.
After therapy, 16 (64%) of the patients treated with AMX
and 23 (92%) treated with AMX-C were considered
clinically cured. Polymicrobial aerobic-anaerobic flora was
present in all instances. A significant reduction in the
number of aerobic and anaerobic isolates occurred after
therapy in those treated with AMX (177 isolates vs 133, P<
0.005) and AMX-C (172 isolates vs 60, P < 0.001).
However, the number of all isolates recovered after therapy
in those treated with AMX-C was significantly lower (60
isolates) than in those treated with AMX (133, P<0.001).
The recovery of aerobic pathogens (eg, S. pneumoniae, S.
aureus, GABHS, Haemophilus spp, and M. catarrhalis)
and penicillin-resistant bacteria after therapy was lower in
the AMX-C group than in the AMX group (P<0.005). This
study illustrates the greater ability of AMX-C, compared
with AMX, to reduce the number of potential nasopharyn-
geal pathogens and penicillin-resistant bacteria in children
with acute OM.
The superiority of AMX-C and clindamycin over AMX
in eradicating penicillin susceptible pathogens such as S.
pneumoniae and GABHS may be because of their activity
against aerobic and anaerobic BLPB. The elimination of
both potential pathogenic and nonpathogenic BLPB may be
beneficial, because these organisms might shield
penicillin-susceptible pathogens from penicillins. This
phenomenon might explain the survival of penicillin-
susceptible bacteria (eg, S. pneumoniae) in children treated
with AMX.
Supportive data were also generated from lower respira-
tory tract infections. Two studies compared the efficacy of
clindamycin to penicillin in the therapy of lung abscesses
[66, 67]. Clindamycin was superior to penicillin in treating
the infection. The superiority of clindamycin over penicillin
was postulated to be the result of its ability to eradicate the
BL-producing, AGNB present in lung abscesses.
A retrospective study illustrates the superiority of
antimicrobials effective against BL-producing AGNB com-
pared with an antibiotic without such coverage in the
therapy of aspiration or tracheostomy-associated pneumo-
nia in 57 children [68]. The antimicrobials used were either
ticarcillin-clavulanate or clindamycin, which are effective
against penicillin-resistant anaerobes, or ceftriaxone, which
is less effective against these organisms. In those with
aspiration pneumonia, 8 of 9 (89%) patients who received
ticarcillin-clavulanate and 10 of 11 (91%) who received
clindamycin with or without ceftazidime had a satisfactory
115
clinical and microbiologic response (P<0.05), compared
with 7 of 14 (50%) who received ceftriaxone. In those who
had tracheostomy-associated pneumonia, 5 of 6 (83%) who
received ticarcillin-clavulanate and all 7 (100%) who received
clindamycin with or without ceftazidime responded to therapy
(P<0.05), as opposed to 4 of 10 (40%) who were treated
with ceftriaxone. The duration of fever was longer in those
who received ceftriaxone.
The above studies illustrate that the successful manage-
ment of polymicrobial infections is enhanced by directing
antimicrobial therapy at the eradication of both aerobic and
anaerobic BLPB. This approach is also useful in manage-
ment of infections such as tonsillitis where BLPB are part
of the normal flora at the infection site.
In infections that involve aerobic or facultative gram-
negative organisms, some of which can produce BL, therapy
should also be directed against these bacteria. This can be
achieved by the addition of agents such as an aminoglycoside,
a quinolone, or a third-generation cephalosporin, or by the
administration of agents with a wide spectrum of activity, such
as a carbapenem or the combination of penicillin and a BL
inhibitor (ie, ticarcillin plus clavulanate, piperacillin plus
tazobactam, or ampicillin plus sulbactam).
A study of core and surface tonsillar cultures from 44
children who had tonsillectomy because of recurrent GABHS
tonsillitis found seven (16%) isolates of methicillin-resistant
S. aureus (MRSA) in the cores and two in the surface [69].
Five of the core isolates and the two surface isolates were
also BLPB. Because most of the MRSA (5 of 7) were also
BL producers, their presence could potentially interfere with
the eradication of GABHS by penicillin [4]. MRSA that is
also able to produce BL can survive treatment with -lactam
antibiotics and continue to shield GABHS from penicillins
through the production of the enzyme BL.
The emergence of MRSA in tonsillar [69] and other
respiratory infections [70] may contribute to the difficulty
in eradicating GABHS as well as other non-BLPB
pathogens with penicillins and other antimicrobials that
are ineffective against this organism.
Conclusions
Further studies are needed to explore and ascertain the
efficacy of therapeutic modalities targeting polymicrobial
infections involving BLPB. These include obstetric and
gynecologic, skin and soft tissue, and bone and joint
infections. Newer antibiotics, such as carbapenems and
the newer quinolones, should also be evaluated in these
conditions.
Disclosure No potential conflict of interest relevant to this article
was reported.
116
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streptococci from penicillin and cephalothin by Bacteroides
fragilis. Chemotherapy 1983, 29:1823.
11. De Louvois J, Hurley R: Inactivation of penicillin by purulent
exudates. Br Med J 1977, 2:9981000.
12. Masuda G, Tomioka S: Possible beta-lactamase activities detectable in
infective clinical specimens. J Antibiot (Tokyo) 1977, 30:10931097.
13. OKeefe JP, Tally FP, Barza M, Gorbach SL: Inactivation of
penicillin-G during experimental infection with Bacteroides
fragilis. J Infect Dis 1978, 137:437442.
14. Bryant RE, Rashad AL, Mazza JA, Hammond D: Beta-lactamase
activity in human plus. J Infect Dis 1980, 142:594601.
15. Boughton WH: Rapid detection in spinal fluid of beta-lactamase
produced by ampicillin-resistant Haemophilus influenzae. J Clin
Microbiol 1982, 15:11671168.
16. Brook I: Presence of beta-lactamase-producing bacteria and beta-
lactamase activity in abscesses. Am J Clin Pathol 1986, 86:97
101.
17. Brook I: Quantitative cultures and beta-lactamase activity in
chronic suppurative otitis media. Ann Otol Rhinol Laryngol 1989,
98:293297.
18. 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, 14:805808.
19. Brook I, Yocum P, Frazier EH: Bacteriology and beta-lactamase
activity in acute and chronic maxillary sinusitis. Arch Otolaryngol
Head Neck Surg 1996, 122:418422.
Curr Infect Dis Rep (2010) 12:110117
20. Brook I, Gober AE: Monthly changes in the rate of recovery of
penicillin-resistant organisms from children. Pediatr Infect Dis J
1997, 16:255257.
21. 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, 25:288292.
22. Brook I: Beta-lactamase-producing bacteria recovered after
clinical failures with various penicillin therapy. Arch Otolaryngol
1984, 110:228231.
23. Pichichero ME, Casey JR: Systematic review of factors contrib-
uting to penicillin treatment failure in Streptococcus pyogenes
pharyngitis. Otolaryngol Head Neck Surg 2007, 137:851857. The
explanations for penicillin treatment failure in GABHS tonsillo-
pharyngitis are reviewed in this article. These include carrier state,
lack of compliance, recurrent exposure, in vivo copathogenicity of
BL-producing normal pharyngeal flora, in vivo bacterial coaggre-
gation, poor antibiotic penetration to tonsillopharyngeal tissue, in
vivo eradication of normal protective flora, early initiation of
antibiotic therapy resulting in suppression of an adequate host
immune response, intracellular localization of GABHS, GABHS
tolerance to penicillin, contaminated toothbrushes or orthodontic
appliances, and transmission from the family pet. The authors
concluded that the evidence base to support the proposed
explanations is generally weak by current standards.
24. Livermore DM: Has the era of untreatable infections arrived? J
Antimicrob Chemother 2009, 64(Suppl 1):i29i36.
25. Septimus EJ, Kuper KM: Clinical challenges in addressing
resistance to antimicrobial drugs in the twenty-first century. Clin
Pharmacol Ther 2009, 86:336339.
26. Smith TD, Huskins WC, Kim KS, Kaplan EL: Efficacy of beta-
lactamase-resistant penicillin and influence of penicillin tolerance
in eradicating streptococci from the pharynx after failure of
penicillin therapy for group A streptococcal pharyngitis. J Pediatr
1987, 110:777782.
27. Kaplan EL, Johnson DR: Unexplained reduced microbiological
efficacy of intramuscular benzathine penicillin G and of oral
penicillin V in eradication of group A streptococci from children
with acute pharyngitis. Pediatrics 2001, 108:11801186.
28. Tristram S, Jacobs MR, Appelbaum PC: Antimicrobial resis-
tance in Haemophilus influenzae. Clin Microbiol Rev 2007, 20:
368389.
29. Critchley IA, Brown SD, Traczewski MM, et al.: National and
regional assessment of antimicrobial resistance among community-
acquired respiratory tract pathogens identified in a 20052006 US
Faropenem surveillance study. Antimicrob Agents Chemother 2007,
51:43824389.
30. Knudsin RB, Miller JM: Significance of the Staphylococcus
aureus carrier state in the treatment of disease due to group A
streptococci. N Engl J Med 1964, 271:13951397.
31. Quie PG, Pierce AX, Wannamaker LW: Influence of penicillinase
producing staphylococci on the eradication of group A strepto-
cocci from the upper respiratory tract by penicillin treatment.
Pediatrics 1966, 37:467476.
32. Murphy TF, Parameswaran GI: Moraxella catarrhalis, a human
respiratory tract pathogen. Clin Infect Dis 2009, 49:124131.
33. Brook I, Yocum P, Friedman EM: Aerobic and anaerobic flora
recovered from tonsils of children with recurrent tonsillitis. Ann
Otol Rhinol Laryngol 1981, 90:261263.
34. Brook I, Yocum P: Bacteriology of chronic tonsillitis in young
adults. Arch Otolaryngol 1984, 110:803805.
35. Brook I, Yocum P: Quantitative measurement of beta-lactamase
levels in tonsils of children with recurrent tonsillitis. Acta
Otolaryngol Scand 1984, 98:456459.
36. Reilly S, Timmis P, Beeden AG, Willis AT: Possible role of the
anaerobe in tonsillitis. J Clin Pathol 1981, 34:542547.
Curr Infect Dis Rep (2010) 12:110117
37. Chagollan JR, Macias JR, Gil JS: Flora indigena de las amigalas.
Investigacion Medical Internacional 1984, 11:3643.
38. Tuner K, Nord CE: Beta lactamase-producing microorganisms in
recurrent tonsillitis. Scand J Infect Dis Suppl 1983, 39:8385.
39. Tuner K, Nord CE: Emergence of beta-lactamase producing
microorganisms in the tonsils during penicillin treatment. Eur J
Clin Microb 1986, 5:399404.
40. Brook I, Gober AE: Emergence of beta-lactamase-producing aerobic
and anaerobic bacteria in the oropharynx of children following
penicillin chemotherapy. Clin Pediatr 1984, 23:338341.
41. Brook I: Emergence and persistence of -lactamase-producing
bacteria in the oropharynx following penicillin treatment. Arch
Otolaryngol Head Neck Surg 1988, 114:667670.
42. 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;22:143145.
43. Brook I: Role of beta-lactamase-producing bacteria in penicillin
failure to eradicate group A streptococci. Pediatr Infect Dis 1985,
4:491495.
44. Brook I, Gober AE: Failure to eradicate streptococci and beta-
lactamase producing bacteria. Acta Paediatr 2008, 97:193195.
45. Roos K, Grahn E, Holn SE: Evaluation of beta-lactamase activity
and microbial interference in treatment failures of acute strepto-
coccal tonsillitis. Scand J Infect Dis 1986, 18:313318.
46. 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: 645647.
47. 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, 112:2127.
48. 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, 117:147152.
49. 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, 41:5162.
50. 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.
51. Randolph MF, Redys JJ, Hibbard EW: Streptococcal pharyngitis
III. Streptococcal recurrence rates following therapy with penicil-
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42:8792.
52. Stillerman M, Isenberg HD, Facklan RR: Streptococcal pharyngi-
tis therapy: comparison of clindamycin palmitate and potassium
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4:516520.
53. Massell BF: Prophylaxis of streptococcal infection and rheumatic
fever: a comparison of orally administered clindamycin and
penicillin. JAMA 1979, 241:15891594.
117
54. Brook I, Leyva F: The treatment of the carrier state of group A
beta-hemolytic streptococci with clindamycin. Chemother 1981,
27:360367.
55. Brook I, Hirokawa R: Treatment of patients with recurrent
tonsillitis due to group A beta-hemolytic streptococci: a prospec-
tive randomized study comparing penicillin, erythromycin and
clindamycin. Clin Pediatr 1985, 24:331336.
56. Orrling A, Stjernquist-Desatnik A, Schalen C: Clindamycin in
recurrent group A streptococcal pharyngotonsillitisan alterna-
tive to tonsillectomy? Acta Otolaryngol 1997, 117:618622.
57. Chaudhary S, Bilinsky SA, Hennessy JL, et 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,
106:481486.
58. Tanz RR, Shulman ST, Barthel MJ, et al.: Penicillin plus rifampin
eradicate pharayngeal carrier of group A streptococci. J Pediatr
1985, 106:876880.
59. Tanz RR, Poncher JR, Corydon KE, et al.: Clindamycin treatment
of chronic pharyngeal carriage of group A streptococci. J Pediatr
1991, 119:123128.
60. Brook I: Treatment of patients with acute recurrent tonsillitis due
to group A beta-haemolytic streptococci: a prospective random-
ized study comparing penicillin and amoxycillin/clavulanate
potassium. J Antimicrob Chemother 1989, 24:227233.
61. Foote PA Jr, Brook I: Penicillin and clindamycin therapy in
recurrent tonsillitis. Arch Otolaryngol Head Neck Surg 1989,
115:856859.
62. Brook I, Shah K, Jackson W: Microbiology of healthy and
diseased adenoids. Laryngoscope 2000, 110:994999.
63. Brook I, Shah K: Effect of amoxycillin with or without clavulanate on
adenoid bacterial flora. J Antimicrob Chemother 2001, 48:269273.
64. Brook I, Shah K: Effect of amoxicillin or clindamycin on the adenoids
bacterial flora. Otolaryngol Head Neck Surg 2003, 129:510.
65. Brook I, Gober AE: Effect of amoxicillin and co-amoxiclav on the
aerobic and anaerobic nasopharyngeal flora. J Antimicrob Chemo-
ther 2002, 49:689692.
66. Levison ME, Mangura CT, Lorber B, et al.: Clindamycin
compared with penicillin for the treatment of anaerobic lung
abscess. Ann Int Med 1983, 98:466471.
67. Gudiol F, Manresa F, Pallares R, et al.: Clindamycin vs penicillin
for anaerobic lung infections. High rate of penicillin failures
associated with penicillin-resistant Bacteroides melaninogenicus.
Arch Intern Med 1990, 150:25252529.
68. Brook I: Treatment of aspiration or tracheostomy-associated
pneumonia in neurologically impaired children: effect of anti-
microbials effective against anaerobic bacteria. Int J Pediatr
Otorhinolaryngol 1996, 35:171177.
69. Brook I, Foote PA: Isolation of methicillin resistant Staphylococ-
cus aureus from the surface and core of tonsils in children. Int J
Pediatr Otorhinolaryngol 2006, 70:20992102.
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head and neck infections. J Laryngol Otol 2009, 11:17.
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