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Impact of penicillin-resistant pneumococci
on clinical practice
Donald E Low, Joyce de Azavedo, Allison McGeer
Department of Microbiology, Mount Sinai and Princess Margaret Hospitals and the Canadian Bacterial Diseases Network,
Toronto, Ontario, Canada
Streptococcus pneumoniae is the most common bacterial pathogen causing
mucosal infections, such as otitis media, sinusitis and pneumonia and invasive disease, such as bacteremia and
meningitis. As a result of the dramatic success of the Haemophilus
influenzae type b (Hib) conjugate polysaccharide vaccine
in reducing the incidence of invasive disease due to Hib, the relative importance of invasive disease due to S. pneumoniae has
increased substantially (1). There is also some evidence to suggest that there has recently been an absolute increase
in the incidence of bacteremic pneumococcal disease. (2,3).
Efforts to reduce the morbidity and mortality associated with infections
due to S. pneumoniae
include vaccination to prevent disease and the prompt use of effective antimicrobial agents for treatment. Limitations
in the use and efficacy of vaccines have meant that pneumococci continue to cause substantial morbidity and mortality
despite the availability of effective antimicrobials. The recent rapid emergence of multi-drug resistant pneumococci
threatens to dramatically increase the overall impact of pneumococcal disease. (4,5).
Protection against S.
pneumoniae depends primarily on antibodies against pneumococcal
capsular polysaccharides (PPS). Current vaccines, which contain the PPS of the 23 most common invasive serotypes,
can induce anticapsular antibodies in adults and children of more than 2 years of age. However, these vaccines
continue to be under-utilized, and its value is limited by the fact that its protective efficacy is poorest in
the populations that are at greatest risk. In addition, many of the serotypes commonly causing pediatric infections
are poorly immunogenic in infants and young children.
The reason for the lack of efficacy of the current vaccine is that
polysaccharide vaccine antigens, including PPS, are poorly immunogenic (4). Covalent coupling of the pneumococcal
polysaccharide to a protein appears to be the best method of improving immunogenicity. This approach has worked
well for Hib vaccines. However, the development of conjugate pneumococcal vaccines will be delayed by the need
to produce a highly immunogenic conjugate for each serotype included in the vaccine. Further, even if pneumococcal
conjugate vaccines are effective against invasive infections, they may not provide adequate protection against
mucosal infections, where the majority of pneumococcal morbidity occurs.
The absence of prospects for a fully effective vaccine makes the
rapid emergence of strains of S. pneumoniae with decreased susceptibility to penicillin and other classes of antimicrobials
an extremely serious concern. Penicillin-susceptible pneumococci are those with a penicillin MIC < 0.06 µg/ml.
Strains with decreased susceptibility include intermediate strains, with an MIC between 0.1 and 1 µg/ml and
resistant strains with an MIC > 1µg/ml (6). Following early documentation of penicillin-resistant pneumococcal
infections in Australia and South Africa in the 1960s and 1970s, reports of infections appeared from a wide geographic
area during the 1980s. Since then there has been dramatic increase world-wide, including the United States and
Canada, not only in resistance to penicillin but also in resistance to other antimicrobials (7-9).
Penicillins and cephalosporins act by binding to and inhibiting
the action of bacterial cell wall enzymes called penicillin binding proteins (PBPs). Strains develop resistance
through stepwise alterations to PBPs which produce enzymes with progressively lower affinity for these antimicrobials.
PBP alteration may occur either by introduction of point mutations into PBP genes or by remodeling of PBP genes
with foreign DNA (10). In the latter instance, pneumococci take up foreign DNA from their environment (transformation)
and replace their "penicillin-susceptible" PBP genes with those from closely-related streptococcal species
that by chance produce PBPs with lower affinity for penicillin. In either case, there is a stepwise increase in
resistance to penicillin. Although the effect is most marked for penicillin, the altered PBPs also have decreased
affinity for other ß-lactam antibiotics. Consequently, most penicillin-resistant pneumococci have decreased
susceptibility to the cephalosporins, including third generation cephalosporins (11).
The reasons for the dramatic increase in penicillin resistance in
S. pneumoniae
in North America during the last decade are poorly understood. Prior to 1987, isolates identified from surveillance
studies carried out in the United States and Canada, found rates of high level resistance to penicillin to be 0.02%
and 0%, respectively (12,13). Subsequent studies have found rates of > 5% (14,15). It seems likely that excessive
therapeutic and prophylactic use of antimicrobials provides selective pressure for the emergence of penicillin
resistant S. pneumoniae.
In addition, there is now evidence to suggest that shifts in the type of antimicrobials (for instance, from penicillin
or amoxicillin to the increased use of oral cephalosporins) may be an important contribution to the problem (16).
The development of penicillin resistance in a strain is often associated
with increases in resistance to other classes of antimicrobials (5,14). In surveillance studies carried out across
Canada, we found that as susceptibility decreased to penicillin, resistance to other classes of antimicrobials
increased, including antibiotics no longer in use (i.e. chloramphenicol) (Table 1). It is not known why this occurs,
as penicillin resistance is not on a mobile genetic element which could carry other resistance determinants. Possibly
penicillin-resistance provides some survival advantage for strains which have acquired chromosomal mutations or
conjugative transposons resulting in drug resistance. It may also be true that penicillin-resistant strains have
usually been exposed to other antibiotics, thus increasing selective pressure for the development of concomitant
resistance.
The problem of increasing multi-drug resistance in the pneumococci means that clinicians must know (and keep track
of changes in) the prevalence and susceptibility pattern of resistant isolates in their community and use this
data to reassess their selection of first and second line antimicrobials for each particular type of pneumococcal
infection.
Despite the decreased susceptibility of pneumococci to the ß-lactams,
high-dose penicillin is likely to be effective in patients with non-meningeal bacteremic infections or pneumonia
if the MIC of penicillin is £ 2 µg/ml (17,18) (Table 2). However, patients infected with strains of
pneumococci that are highly resistant to penicillin (MIC >2 µg/m) may not respond (17). Highly penicillin-resistant
isolates may be resistant to extended spectrum penicillins and the cephalosporins. The cephalosporins with greatest
activity are ceftriaxone and cefotaxime. Despite reports of isolates of S.pneumoniae with cefotaxime and ceftriaxone MICs of >8 µg/ml and >4 µg/ml respectively, MICs of <4 µg/ml and <2 µg/ml are more common (11,19,20), and patients with invasive non-meningeal
pneumococcal infection with high-level penicillin resistance can be treated with either cefotaxime or ceftriaxone.
Theoretically, ceftriaxone and vancomycin, for which serum levels can be maintained at >3 x MIC for the entire
duration of a q12h dosing interval, are optimal agents for treatment of these infections (11,21,22).
There have been reports of failures of penicillin, extended-spectrum
cephalosporins, chloramphenicol and vancomycin in pneumococcal meningitis due to organisms with intermediate or
high-level resistance to penicillin or third generation cephalosporins (23-25). As a result, despite an absence
of clinical data, combination therapy has been recommended for this infection (14). Ceftriaxone and vancomycin
have been used successfully as a combination experimentally, even when the strains are ceftriaxone-resistant (26).
The use of dexamethasone in pneumococcal meningitis is controversial (27). Since relatively few patients with pneumococcal
meningitis were included in the large randomized studies of this therapy for bacterial meningitis, no conclusions
can be made regarding its effectiveness. However, preliminary animal studies have found that dexamethasone decreases
the penetration of vancomycin and ceftriaxone into the CSF and delays sterilization (28). This would support the
argument against the use of dexamethasone in the treatment of meningitis due to S.
pneumoniae when the isolate has decreased susceptibility
to penicillin.
The treatment of acute otitis media (AOM) caused by penicillin-resistant
pneumococci is complicated by the poor penetration of most orally administered ß-lactams into the inner ear.
With the exception of amoxicillin, the ß-lactams have reduced activity and some have been associated with
treatment failure (11,29,30). Unfortunately the associated multi-drug resistance limits the use of alternative
agents such as erythromycin, clindamycin and trimethoprim-sulfamethoxazole (14). Because AOM is not a life threatening
infection, may not always be caused by a bacteria, and may resolve spontaneously, the choice of an antimicrobial
for empiric therapy need not provide coverage for every potential resistant pathogen (31). Therefore, amoxicillin
remains the drug of choice for the empiric therapy of AOM. If an isolate is available for susceptibility testing
as a result of tympanocentesis, then therapy can be adjusted according to results of this testing (Table 2).
Second line treatment for AOM which has failed to respond to amoxicillin
should be selected based on common pneumococcal resistance patterns in the geographic area. Refractory AOM may
require tympanocentesis in order to determine its etiology, and tympanotomy and combination oral or parenteral
antimicrobials for therapy (32).
The emergence of multi-drug-resistant pneumococci is an alarming
problem. In order to continue to adequately treat patients with pneumococcal infections, many physicians must change
their prescribing practice for the treatment of common infections. These changes in prescribing practice can only
be appropriately directed by improved surveillance for resistance in pneumococci in all geographic areas. Optimal
protection against the impact of pneumococcal disease will require a concerted effort of physicians, patients and
public health departments to optimize the use of available vaccine and to reduce the selective pressure for the
development of resistance by prudent antimicrobial use in all settings.
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