(Chest. 2000;117:530-541.)
© 2000
American College of Chest Physicians
The Drug-Resistant Pneumococcus*
Clinical Relevance, Therapy, and Prevention
Joseph I. Harwell, MD and
Richard B. Brown, MD, FCCP
*
From the Division of Infectious Diseases, Baystate Medical Center, Springfield, MA; and Tufts University School of Medicine, Boston, MA.
Correspondence to: Richard B. Brown, MD, FCCP, Division of Infectious Diseases, Baystate Medical Center, 759 Chestnut St, Springfield, MA 01199
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Abstract
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Streptococcus pneumoniae has been known for > 100
years as the most important bacterial pathogen of the respiratory tract
in adults and children. In recent years, the pneumococcus has begun to
exhibit increasing resistance to antimicrobial agents. Because of the
huge number of infections caused by this organism, the development of
resistance has changed the approach to many infectious disease
problems, particularly with regard to empiric antibiotic therapy and
prophylaxis. In our review of the antibiotic-resistant pneumococcus, we
review the microbiologic basis for resistance, risk factors for and
clinical relevance of infection by a resistant organism, and infection
control measures.
Key Words: meningitis • otitis media • pneumococcus • pneumonia • resistance
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Introduction
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Streptococcus
pneumoniae has been known for > 100 years as the most
important bacterial pathogen of the respiratory tract in adults and
children. In recent years, the pneumococcus has begun to exhibit
increasing resistance to antimicrobial agents. Because of the huge
number of infections caused by this organism, the development of
resistance has changed the approach to many infectious disease
problems, particularly with regard to empiric antibiotic therapy and
prophylaxis. In our review of the antibiotic-resistant pneumococcus, we
review the microbiologic basis for resistance, risk factors for and
clinical relevance of infection by a resistant organism, and infection
control measures.
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The Pathogen
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The pneumococcus is a Gram-positive coccus that appears
microscopically under favorable growth conditions as pairs or chains.
When grown on blood agar, the organism produces a green halo of
hemolysis (
hemolysis) around each colony. This typical appearance,
a lack of catalase production, and a zone of inhibition around an
optochin disk or solubility in bile salts is sufficient for presumptive
identification of S pneumoniae.1
Each organism is surrounded by a polysaccharide capsule. Antigenic
differences in this capsule separate S pneumoniae into 90
different serotypes. Capsular variability allows different subtypes to
avoid immune detection by antibodies previously generated through
infection or immunization. In the absence of subtype-specific antibody,
the capsule permits the organism to avoid phagocytosis, and therefore
represents an important virulence factor. Some capsular types are less
immunogenic and are more commonly associated with prolonged
asymptomatic carriage. Because small children are frequently treated
with repeated courses of antibiotics, serotypes 6, 14, 19, and 23,
which commonly colonize this age group, also commonly develop drug
resistance.2
3
A second significant virulence factor is the ability to adhere to
mucosal linings. If mucociliary clearance is impaired, colonization is
followed by rapid replication and clinical infection. Although not
capable of producing significant systemically active toxins, the
pneumococcus vigorously activates inflammatory mediators, which are
then responsible for the bulk of systemic symptoms and local tissue
damage.4
The organism can also invade to spread
hematogenously to distant sites, including bone, joint, and CNS. Local
inflammation causes further impairment in clearance mechanisms and
permits ongoing replication. In the absence of effective antibiotic
therapy, this cycle continues until protective antibody facilitates
immune clearance or until the host is overwhelmed.
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Historical Perspectives on Resistance
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Following World War II, the widespread use of penicillin for
pneumococcal pneumonia reduced the fatality rate of this disease from
approximately 30% to as low as 5% in some studies.5
For
the next 25 years, the widespread successful use of antibiotics
gradually fostered complacency about the significance of bacterial
infections. However, there were early indications that antibiotics
would lose their effectiveness. Optochin, now used only to identify
pneumococci in the laboratory, was one of the first drugs to be used
for pneumococcal infections until it was abandoned because of toxicity.
Yet even before the generalized use of optochin in humans, resistance
had been reported in laboratory animals in 1912.6
This
report was followed by identification of optochin-resistant clinical
isolates.7
History then repeated itself, and laboratory
resistance to penicillin was reported in the year before the
publication of the first successful use of this drug for pneumococcal
pneumonia.8
9
It was not until the mid-1960s that clinical isolates of
penicillin-resistant pneumococci were identified.10
Significant high-level penicillin resistance still was not considered a
major problem until the early 1980s in Europe and the early 1990s in
the United States.11
12
In addition to penicillin
resistance, multidrug-resistant pneumococci are now becoming more
commonplace. More attention has been drawn to the problem of resistance
in recent years with the simultaneous evolution of other resistant
organisms. From the isolation of methicillin-resistant
Staphylococcus aureus in 196113
to
vancomycin-resistant enterococci in the late 1980s,14
and vancomycin-resistant staphylococci more recently,15
we
have clearly been witnessing a progressive and inevitable loss of
antimicrobial effectiveness against important Gram-positive pathogens.
What first appeared to be coincidental evolution of Gram-positive
resistance in different species, now seems to represent to some degree
a coordinated and shared evolution not only in response to ß-lactams,
but, in many cases, multiple classes of antibiotics.
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Mechanisms of Resistance
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Penicillin resistance in pneumococci is achieved through reduced
affinity of penicillin-binding proteins (PBPs) for ß-lactams.
Although alterations in several PBPs have been described, PBP2B appears
to be the most important for expressing the structural changes that
result in resistance and defective autolysis.16
17
Molecular techniques have identified genetic mosaicism among the PBPs
of resistant isolates of pneumococci. This mosaicism suggests that
genes for these proteins were imported from some heterogeneous
"nonpneumococcal" source rather than evolving in an individual
organism.18
The leading suspects for the origin of these
genes are viridans streptococci in the oral flora. Similar gene
transfers have been implicated in the development of vancomycin
resistance among enterococci, and in other resistance models as
well.19
20
21
Isolates with high-level (
2 µg/mL) penicillin resistance are also
more likely to demonstrate resistance to multiple drugs. Most commonly,
these drugs include macrolides, tetracyclines, chloramphenicol,
trimethoprim-sulfamethoxazole (TMP/SMX), and
aminoglycosides.22
The genes encoding these resistance
traits appear similar to those found in strains of Escherichia
coli, Klebsiella spp, Haemophilus spp, Neisseria spp, Helicobacter
spp, and Enterococcus spp. These gene transfers thus appear to occur
across genus levels, and even between Gram-negative and Gram-positive
organisms. These traits are stable and persist in the absence of drug
pressure, with no effect on bacterial fitness.23
Resistant
organisms should not be expected to regain susceptibility over time.
It is hypothesized that different mechanisms are involved in the
acquisition of resistance traits. Intermediate resistance seems to
evolve in a stepwise fashion in smaller geographic regions, and perhaps
in individuals, through a series of genetic events under drug pressure.
Molecular characterization of high-grade and multidrug-resistant
strains points to worldwide clonal expansion of a small number of
isolates.24
25
Infection with these highly resistant
organisms is more likely to follow contact with a carrier than from
independent evolution.
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Epidemiology and Risk Factors for Colonization
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Penicillin resistance in the pneumococcus is seen in two general
categories: intermediately susceptible isolates with minimal inhibitory
concentrations (MICs) between 0.1 and 1 µg/mL, and those with
high-grade resistance having MICs 2 µg/mL. Prevalence of these
two groups varies considerably, not only by geographic region but also
by anatomic site of culture. In our hospital in 1997, intermediate
resistance was seen in 8% of isolates, with high-grade resistance in
only 4%. Overall in the United States, about 28% of organisms are
intermediately susceptible and 16% are highly
resistant.26
High-grade resistance is also commonly
associated with multidrug resistance. In a recent review of 1,476
pneumococcal strains isolated in regional laboratories, macrolide
resistance was found in 30% of the total but in 67% of strains highly
resistant to penicillin.27
Drug-resistant pneumococcal infections are much more common among young
children than adults.27
A number of risk factors have been
identified for carriage of antibiotic-resistant pneumococci. For
children, the most important of these includes attendance in group
daycare, recent hospitalization, and recent ß-lactam use, especially
for prophylaxis.28
29
The period of significant antibiotic
exposure appears to be within the previous month. This is consistent
with results from a Swedish study that examined the length of time
between acquisition and loss of carriage of these
organisms.30
About 65% of carriers were free of resistant
organisms by the end of 1 month. Ninety-four percent spontaneously lost
their resistant strain in 12 weeks. Longer duration of carriage was
associated with age < 1 year, more than six episodes of otitis media,
first episode of otitis media before the age of 1 year, carriage by
another family member, and acquisition in the winter months.
Among adults, recent studies have found a higher rate of recovery of
antibiotic-resistant pneumococci from HIV-infected
patients.31
Alcoholism and age > 65 years also are
associated with an increase in risk.32
Some of the same
risk factors for children apply to adults, particularly with regard to
cohorting and recent antibiotic use. Pallares et al33
demonstrated that recent antibiotic use and hospitalization are
important clues to a potential drug-resistant infection. Interestingly,
resistance is reported less commonly in invasive organisms than in
those from upper airway colonization or infection.27
This
may be explained in part by bias in sampling, as otitis and sinusitis
are usually treated empirically without obtaining a culture until
primary treatment has failed. Middle ear and sinus isolates are thus
more likely to have been exposed to repeated courses of antibiotics.
Noninvasive strains in the upper airway also have prolonged contact
with the viridans streptococci thought to be the reservoir of
resistance genes.34
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Susceptibility Testing
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Because the pneumococcus is a relatively fastidious
organism, susceptibility testing should be interpreted with care.
Growth conditions must be strictly controlled to avoid reporting false
susceptibilities. In addition, the spread of multidrug resistance has
prompted the National Committee for Clinical Laboratory Standards to
recommend susceptibility testing of all blood and CNS isolates not only
for penicillin, but also for cefotaxime/ceftriaxone, meropenem, and
vancomycin.35
Consideration should be given to testing
cephalosporin-resistant CNS strains for chloramphenicol and rifampin
activity. Non-CNS strains should also be tested against erythromycin,
tetracycline, TMP/SMX, and possibly clindamycin and newer
fluoroquinolones.
Interpretation of results should be made in clinical context.
Particular attention should be paid to the site of infection and the
immune competence of the patient. For example, nonmeningeal infections
may in fact be treatable with penicillin despite relatively high MICs.
This may be true of other antibiotic classes as well. Susceptibility
testing is an in vitro phenomenon, and the clinical
relevance of the results of this testing cannot always be evaluable.
Lastly, profoundly immunocompromised patients—such as those who have
advanced HIV infection or neutropenia or are taking prolonged
immunosuppressive therapy—may not respond to treatment with a
bacteriostatic drug, despite clear in vitro susceptibility.
Bacteriocidal drugs such as ß-lactams, fluoroquinolones, and
vancomycin should be preferentially used in such patients.
Disk Diffusion
Oxacillin disk diffusion is adequate initial screening for
penicillin resistance on plated isolates.35
Initial
resistance identified by a zone size of < 20 mm around a 1-µg
oxacillin disk should be confirmed by another method, typically the E
test (see below). Valid zone sizes have also been determined for the
macrolides, clindamycin, vancomycin, levofloxacin, ofloxacin,
sparfloxacin, grepafloxacin, trovafloxacin, TMP/SMX, rifampin,
chloramphenicol, and tetracycline.
Although not validated for pneumococci, clinical isolates with Gram’s
stains consistent with pneumococci (especially cerebrospinal fluid
[CSF]) can be directly plated with oxacillin disks, and examined in 6
to 8 h for early identification of potentially resistant
organisms.
Microdilution
Several commercial microdilution systems have been reported to
have recurrent major interpretive-error and reproducibility problems.
One should be sure the system being used has been validated for
pneumococcal testing.
E Test
A calibrated antibiotic-impregnated strip produces a gradient
through diffusion when applied to an inoculated agar plate. The strip
is calibrated in such a way that bacterial growth intersects the strip
at a point where the corresponding MIC can be read directly. Such
"MICs on a stick" are available for a number of antibiotics. When
the Gram’s stain of a clinical specimen is suspicious for pneumococci,
rapid screening tests similar to those mentioned above for disk
diffusion may also be performed using E test strips directly plated and
read at 6 to 8 h.36
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Treatment
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Treatment options for pneumococcal infections are dependent on the
site of infection and the degree of intrinsic drug resistance.
Consideration is being given to modifying the current MIC cutoffs for
identifying strains with intermediate (0.1 to 1 µg/mL) and high-grade
penicillin resistance ( 2 µg/mL) based on achievable drug levels
at the site of isolation. A reasonable resistant cutoff might be
4 µg/mL for infections that are outside the CNS and can easily be
managed with standard parenteral regimens.37
Pneumonia
Diagnosis and treatment of pneumonia is complicated by the
relative inaccessibility of the infected site for examination and
culture. Definitive microbiologic diagnosis of any infection can only
be established by culture of the organism from a sterile specimen. An
expectorated sputum sample has served as a surrogate for such a
specimen, but with variable results. Up to 30% of patients with
community-acquired pneumonia will have a nonproductive cough, and many
will have undergone some form of antibiotic pretreatment prior to
specimen collection.38
However, if correctly collected and
processed, a Gram-stained sputum is a rapidly available and inexpensive
way to accurately identify patients with pneumococcal
pneumonia.39
In the majority of patients with
community-acquired pneumonia for whom an organism is not immediately
identified, empiric therapy must be employed. Guidelines for choosing
empiric therapy have been developed by the American Thoracic Society
and the Infectious Disease Society of America.40
41
After
blood cultures (and sputum, if available) have been collected, options
for empiric therapy in an ambulatory patient include a newer
fluoroquinolone, a newer macrolide, or doxycycline. For the more
seriously ill, hospitalized patient, these drugs should be combined
with a parenteral ß-lactam.
For intermediately susceptible strains of pneumococcus, penicillin and
its derivatives in standard doses are still effective. In the absence
of immediate hypersensitivity reactions, penicillin can be safely
administered in doses high enough to overcome these intermediate
resistance mutations. For an adult, a single oral dose of 1 g of
amoxicillin achieves a sputum concentration of 0.5 µg/mL, or up to 2
µg/mL with multiple doses.42
Although studies have shown
that infection with drug-resistant organisms does not increase
mortality,43
even if patients are treated with penicillin,
they may require IV therapy for adequate treatment. Pallares et
al43
and Austrian44
have advocated separately
for doses of 14 MU/d for all but the most resistant isolates with
MICs 4 µg/mL. One effective way to maintain penicillin
concentrations well above the MICs of even these highly resistant
organisms is by continuous infusion. A 24-MU continuous infusion
following a 3-MU loading dose maintains a serum concentration of 20
µg/mL, well above the MIC for all reported clinical
isolates.37
This approach is also cheaper than
intermittent administration of the same total daily dose. Alternative
ß-lactam agents are listed in Table 1 . Selection of these agents should be based on MIC data, severity of
illness, and coexisting diagnoses.
Although vancomycin-tolerant strains of pneumococci have been
described,48
no resistant clinical isolates of S
pneumoniae have been reported to date. Vancomycin remains an
effective alternative for highly resistant organisms. Loss of
ubiquitous susceptibility to this drug can only be delayed by its
judicious use, and empiric vancomycin should be discouraged. The newer
fluoroquinolones are another promising class of drugs for resistant
pneumococci. Reported resistance is extremely low (< 1%), although
Wise et al49
have suggested that one of the two mutations
required for resistance may already exist at baseline. With a spectrum
of activity against the major respiratory pathogens, the
fluoroquinolones have become one of the primary therapeutic options for
empiric treatment of community-acquired
pneumonia.41
50
These drugs have the added advantage of
high oral bioavailability, which eliminates the need for IV
administration in an otherwise stable patient. The major disadvantage
of the fluoroquinolones is that their spectrum may in fact be too
broad, thereby promoting the outgrowth of more resistant colonizing
strains. Trovafloxacin, for example, has excellent activity against
pneumococci, but also against Gram-negative organisms (including
Pseudomonas spp) and anaerobes. When this drug is used for a
respiratory infection, normal gut flora are nonetheless exposed to
antibiotic selective pressure. Fluoroquinolone resistance by a
transferable plasmid has been described.51
Highly
resistant E coli, a common gut commensal, has been
isolated.52
53
Resistance among more pathogenic organisms
such as Neisseria gonorrhea, Campylobacter spp, and
Salmonella spp is also becoming more widespread.54
55
56
Campillo and colleagues57
have demonstrated that long-term
norfloxacin administration results in an increased rate of infection by
more resistant organisms. For clear cases of documented pneumococcal
pneumonia, narrower-spectrum agents may thus be more appropriate than
the broader-spectrum fluoroquinolones. Special mention should be made
of ciprofloxacin, which has an indication for lower respiratory
infections caused by S pneumoniae. The in vitro
minimal inhibitory concentration for 90% of isolates
(MIC90) range for this drug is 1 to 4 µg/mL for
S pneumoniae, while the mean peak bronchial concentration
with standard oral dosing is 1.2 to 2.3 µg/mL.58
Superinfection with S pneumoniae during therapy with
ciprofloxacin has been reported.59
For these reasons, both
the Infectious Disease Society of America and the American Thoracic
Society have not included ciprofloxacin in their primary treatment
recommendations for community-acquired pneumonia. Because of toxicities
observed in juvenile animals,60
the fluoroquinolones are
currently not approved for use in children. MICs for these drugs are
listed in Table 2
.
Other drugs that have historically been effective against pneumococci
are listed in Table 3
. In vitro resistance to these medications is widespread and
often coexists with penicillin resistance. Use of these agents for
empiric therapy has been limited as a result. A recent randomized
prospective trial of doxycycline for mild to moderately severe
community-acquired pneumonia found it to be as efficacious as the
control treatments, again raising questions about the clinical
relevance of in vitro resistance.61
In this
study, 87 patients hospitalized for community-acquired pneumonia were
randomized to IV doxycycline or the antibiotic of the admitting
physician’s choosing. These results are encouraging but, because of
the small study size, the study should be repeated on a larger scale.
Macrolide antibiotics have traditionally formed the cornerstone of
empiric therapy for community-acquired pneumonia because of their broad
spectrum of activity against all of the major pathogens. Enthusiasm for
these drugs has diminished in recent years as the result of rapidly
evolving in vitro resistance, which is even more prevalent
among penicillin-resistant isolates.62
It has recently
been demonstrated that the majority of macrolide resistance is on the
basis of an efflux mechanism rather than ribosomal binding site
modification.63
With higher doses of the newer macrolides,
which obtain concentrations in epithelial lining fluid of 
30
µg/mL, it may be possible to overcome this resistance mechanism,
which confers an MIC90 of 4
µg/mL.64
Otitis Media and Sinusitis
The pneumococcus is the most important cause of otitis media and
sinusitis, and is the organism most often associated with treatment
failure.65
Patients with frequent episodes of upper
respiratory pneumococcal infections are therefore at risk for
colonization by a resistant isolate and, potentially, for subsequent
lower respiratory infection. Despite the extremely high frequency with
which resistant organisms are isolated from middle ear fluid,
amoxicillin remains the drug of choice for otitis media. Amoxicillin
retains its usefulness because it is possible to achieve middle ear
fluid drug levels that exceed the MICs of most resistant
isolates.42
66
Although resistance has not altered first
antibiotic selection, it has made an impact on management of otitis
media in other ways. Dutch investigators have shown that for children
> 5 years old, observation for 1 to 3 days limits antibiotic use for
the majority of cases, which spontaneously resolve.67
This
is certainly reasonable for otitis media with
effusion.68
69
With an inflamed middle ear and systemic
signs of illness, as is the case with acute otitis media, therapy is
generally recommended. For the young child, the acutely ill, and those
who fail observation, consideration should be given to use of higher
doses of amoxicillin with less frequent dosing. Middle ear
concentrations of amoxicillin that exceed the MIC of resistant
pneumococci can be achieved by administering 60 to 80 mg/kg/d
bid.68
This bid dosing schedule may also improve
compliance and prevent the evolution of resistance through intermittent
exposure of the bacteria to subtherapeutic drug levels when doses are
missed.
Treatment failures may be treated with amoxicillin/clavulanate to
improve the Gram-negative activity while maintaining pneumococcal
coverage. In the current formulation, the 60- to 80-mg/kg dose may be
achieved by administering 40 mg/kg of amoxicillin in addition to a
40-mg/kg dose of amoxicillin/clavulanate in two divided doses. A 14:1
amoxicillin/clavulanate formulation is under review for use in otitis
media to eliminate the need for these two separate
administrations.70
A single parenteral dose of ceftriaxone
is another alternative, although this approach has been associated with
treatment failures and may need to be followed by an oral course in
difficult cases.71
Others have used ceftriaxone daily for
3 days.72
A recent trial randomized children to 10 days of
amoxicillin/clavulanate vs a single dose of ceftriaxone with similar
rates of success.73
For chronic and/or recurrent cases,
consideration should be given to surgical evaluation for determination
of the microbiologic causes, as well as for potential tympanostomy tube
placement.
The microbiology and pathogenesis of sinusitis is nearly identical to
that of otitis media. For this reason, the principles of antibiotic
therapy for sinusitis are nearly the same. As with otitis media, many
cases of sinusitis spontaneously resolve. Many experts recommend
withholding therapy for sinusitis until symptoms have persisted or
worsened over 7 to 10 days. In addition to antimicrobial therapy,
adjunctive measures to facilitate drainage are also recommended,
including nasal steroids, decongestants, and nasal saline solution
lavages.
Meningitis
Meningitis caused by drug-resistant pneumococci can be one of the
most serious and challenging clinical problems in infectious diseases
practice. Pneumococcal meningitis frequently complicates bacteremic
pneumonia and should be considered when such patients present with
evidence of CNS dysfunction. The CNS is an immunologically privileged
site with significant barriers to drug penetration, diminished
complement levels, and impaired bacterial killing. Standard therapies
for susceptible pneumococci may not achieve drug levels sufficient to
kill highly resistant organisms. Currently, ceftriaxone and cefotaxime
remain the drugs of choice for pneumococcal meningitis, although
additional therapies should be considered for highly resistant
isolates. It has been suggested that one of the few circumstances where
empiric use of vancomycin is warranted is for the treatment of
meningitis caused by Gram-positive cocci pending identification and
susceptibility testing. Vancomycin penetration into the CSF is limited
even with inflamed meninges, however, and vancomycin may be unreliable
as a single agent. Steroids reduce this permissive inflammation and may
limit drug penetration still further; steroids should be used with
caution when vancomycin is the cornerstone of therapy.74
Higher doses of vancomycin should be used initially and then adjusted
downward to maintain a serum level of 40 to 50 µg/mL. Starting
dosages of 60 to 80 mg/kg divided q6h in children, and 2,500 to 3,000
mg divided every 12 h in adults, would be reasonable with normal renal
function. In one report, intrathecal vancomycin, given at a dosage of
20 mg/d to maintain CSF levels of 10 µg/mL and combined with standard
IV therapy, was successful when treatment with cefotaxime had
failed.75
For meningitis, another useful drug is meropenem, a new carbapenem that
penetrates inflamed meninges but lacks the epileptogenic potential of
imipenem. This drug retains the broad-spectrum activity of the class,
with few resistant strains identified. Rifampin has also been used
successfully in combination with vancomycin, ceftriaxone, or
cefotaxime. Animal models of meningitis have demonstrated activity of
rifampin paired with one of these agents, even with
cephalosporin-resistant organisms.76
Combination therapy
with rifampin may be used when options are limited and clinical
response is delayed. Chloramphenicol has historically been used with a
high degree of efficacy for meningitis. Unfortunately, an unacceptable
number of failures have been associated with chloramphenicol use
for penicillin-resistant pneumococcal
meningitis.77
These organisms demonstrate defective
autolysis, and may have minimal bactericidal concentrations (MBCs) that
are unachievable in the CSF. Highly resistant strains may also carry
multidrug resistance genes which include chloramphenicol. This drug
should not be used unless MBCs can be demonstrated to be 4 µg/mL.
Drugs for treatment of resistant pneumococcal meningitis are
listed in Table 4
.
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Investigational Drugs
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After rather slow progress, the last few years have shown a rapid
increase in the number of new antimicrobial agents. In addition to new
formulations of old compounds, completely new classes of drugs with
as-yet poorly defined mechanisms of action have been identified.
As a class, the quinolones have yielded the most numerous and effective
antibiotics in recent years. The recently released
agents—levofloxacin, sparfloxacin, grepafloxacin, and
trovafloxacin—have excellent antipneumococcal activity, even
against penicillin-resistant strains.78
This is in
contrast to previously employed agents such as ciprofloxacin and the
racemic mixture ofloxacin. Building on this improved pneumococcal
activity, newer agents are still in development. Gatifloxacin and
moxifloxacin should be available in the near future.
Despite the promise of the quinolones, resistance to them has been
shown to develop relatively easily among some Gram-positive organisms.
The streptogramin class has shown excellent activity against a wide
range of multidrug-resistant Gram-positive organisms. The agent that
has progressed the farthest in clinical trials is the combination
quinupristin/dalfopristin (Synercid; Rhône Poulenc Rorer, Inc;
Collegeville, PA). This parenteral combination produces a synergistic
interruption of protein synthesis.79
Dalfopristin binds to
the peptidyltransferase site of the 50S ribosomal subunit, producing a
conformational change that increases the binding affinity for
quinupristin at a neighboring site. Each individual component is
bacteriostatic, but the combination is bacteriocidal. Because
dalfopristin utilizes the erythromycin attachment site, there is some
concern that synergy is lost for erythromycin-resistant strains. This
appears to be true for Enterococcus faecium but not for the
pneumococcus. Oral streptogramins that have excellent activity against
resistant pneumococci are also in development.
Ketolides are a newer semisynthetic formulation of macrolides that have
been modified to retain activity against erythromycin- and
clindamycin-resistant pneumococci. One in vitro study of 230
strains of pneumococci, 100 of which were erythromycin resistant, found
the ketolide agent to have activity similar to vancomycin, imipenem,
and sparfloxacin despite erythromycin resistance.80
The
MIC90 for this ketolide was 0.03 µg/mL for
erythromycin-susceptible strains and 0.25 µg/mL for
erythromycin-resistant strains (range, 0.008 to 1.0 µg/mL).
Erythromycin-resistant, clindamycin-susceptible (presumably through an
efflux mechanism) strains also retain susceptibility to ketolides.
Oxazolidinones represent a new class of antimicrobials with a unique
structure and excellent Gram-positive activity. Linezolide is in
advanced clinical trials for use against S aureus, E
faecium, and S pneumoniae. The mechanism of action of
the oxazolidinones is not well understood, but appears to be inhibition
of protein synthesis through prevention of translation at the
initiation phase.81
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Prevention
|
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The 20th century has been marked by a tremendous increase in life
expectancy and quality of life. These advances have come largely
through public health measures and an understanding of the microbiology
of infectious diseases. While most biomedical research in recent times
has focused on treatment, the ever-widening problem of drug resistance
has increased interest in prevention as the primary means of
controlling infectious diseases. The principles of prevention can be
applied to the pneumococcus in three ways: limiting the selective
pressure of antibiotic use, vaccination, and infection control.
Recent studies have highlighted the overwhelming misuse of antibiotics
in the United States.82
83
84
The National Center for Health
Statistics reports that antibiotics were prescribed in 1992 for 70% of
cases of nonstreptococcal pharyngitis, 50% of cases of rhinitis, and
30% of cases of nonspecific upper respiratory infection. Not only for
appropriate therapy, but also for epidemiologic reasons, every effort
should be made to make specific microbiologic diagnoses of bacterial
infections requiring antibiotic treatment. This allows for early
identification of outbreak strains, isolation of patients carrying
highly resistant strains, and prevention of sequelae from untreated or
undertreated resistant infections. Guidelines are available, or are in
development, for the use of antibiotics for specific indications. The
American Academy of Pediatrics has been particularly active in
developing recommendations for the use of antibiotics for upper
respiratory infections in children.85
Where they have been
applied, limitations on antibiotic use have been demonstrated to reduce
the prevalence of resistant organisms.86
In Iceland,
reductions in antibiotic use have been correlated with a decline in the
incidence of pneumococcal resistance.87
The first
resistant strain was identified in 1988, with annual incidence climbing
to 20% in 1993. In 1990, a national effort to reduce antibiotic use
produced an overall use reduction of 10% and a 30% reduction in
TMP/SMX and macrolide use. Since 1993, pneumococcal resistance to
penicillin in Iceland has declined every year, to 13% in 1997. The
converse has been indirectly demonstrated in the United States, where
the counties with the greatest amounts of antibiotic consumption also
have the highest rates of pneumococcal resistance.88
Many
other studies have shown that control of antibiotics in more local
environments, such as an ICU or a hospital, has a strong influence on
resistance patterns.89
90
The weight of evidence points to
antibiotic pressure as the driving force for the amplification of a
small number of resistant clones that have spread worldwide. A key
component of any prevention plan must be substantial reductions in
antibiotic use for conditions in which they are not indicated and
appropriate use of antibiotics for conditions in which they are
indicated.
Clonal spread of resistant organisms has been documented
worldwide.25
Multidrug-resistant Spanish clones have
spread to Iceland, presumably by Icelanders vacationing in
Spain.91
These organisms in most cases have identical
pulse-field gel electrophoresis patterns. Daycare studies clearly show
organisms are easily passed around among children.92
93
Therefore, passive contact permits the spread of these organisms, which
are then amplified under antibiotic pressure. It has been speculated as
well that these organisms may have evolved superior colonizing
abilities.21
When extremely resistant isolates are
identified, individuals at risk for invasive infection should be
protected from colonization. To this end, many hospital infection
control policies require contact isolation for the index patient.
The ultimate tool of modern medicine for combating infectious diseases
may be the vaccine. The modern pneumococcal vaccine was introduced in
1977, and expanded from 14 to 23 valent in 1983 to include between 75
and 90% of all pathogenic strains associated with bacteremia.
Initially criticized as ineffective, the vaccine has now been shown to
have up to 93% efficacy, depending on the age and immune competence of
the host, and is typically considered to be between 80 and 85%
effective.94
Even so, most studies show that only about
30% of those for whom it is indicated actually receive the vaccine,
despite evidence that routine vaccination of suboptimal responders is
cost-effective.95
96
As demonstrated by the tremendous
decline in invasive Haemophilus influenzae type B disease
following routine childhood immunization, similar gains may be
achievable with the development of a protein-conjugate vaccine for the
pneumococcus. Although the currently available vaccine is poorly
immunogenic in children < 2 years old, a protein-conjugate vaccine is
in development and has been shown in early clinical trials to be
effective in this age group. Vaccine recommendations are listed for
adults in Table 5
and for children in Table 6
.
|
Conclusion
|
|---|
Despite great scientific advances in the chemotherapy of
pneumococcal infections, the recent evolution of resistance among all
infectious diseases suggests that prevention may be the only durable
weapon. At present, the primary treatment of pneumococcal pneumonia
continues to be penicillin. Empiric use of other agents such as
macrolides, fluoroquinolones, and doxycycline may still be reasonable
in ambulatory settings. MICs for penicillin continue to rise, however.
Isolates resistant to multiple drugs have spread worldwide and are
amplified locally under antibiotic pressure. An effective vaccine is
available but underutilized. As often as possible, clinicians should
attempt to make specific diagnoses in order to treat narrowly and
effectively and to avoid the use of antibiotics for conditions in which
they are not indicated. Identification of a resistant organism can aid
in tracking local resistance patterns, preventing the further spread of
these organisms, and selecting appropriate empiric therapy.
|
Footnotes
|
|---|
Abbreviations: CSF = cerebrospinal fluid;
MBC = minimal bactericidal concentration; MIC = minimal inhibitory
concentration; MIC90 = minimal inhibitory concentration
for 90% of isolates; PBP = penicillin-binding protein;
TMP/SMX = trimethoprim-sulfamethoxazole
Received for publication March 10, 1999.
Accepted for publication June 11, 1999.
|
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Abstract
Introduction
