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Monotherapy May Be Suboptimal for Severe Bacteremic Pneumococcal Pneumonia
Grant W. Waterer, MBBS, FRACP;
Grant W. Somes, PhD;
Richard G. Wunderink, MD, FCCP
Arch Intern Med. 2001;161:1837-1842.
ABSTRACT
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Background Although monotherapy for pneumococcal pneumonia is standard, a survival
benefit of combination ß-lactam and macrolide therapy has been suggested.
Hypothesis Initial empirical therapy with a combination of effective antibiotic
agents would have a better outcome than a single effective antibiotic agent
in patients with bacteremic pneumococcal pneumonia.
Methods A review of adult bacteremic pneumococcal pneumonia within the Methodist
Healthcare System, Memphis, Tenn, between January 1, 1996, and July 31, 2000.
Empirical therapy was defined as all antibiotic agents received in the first
24 hours after presentation. On the basis of culture results, empirical therapy
was classified as single effective therapy (SET), dual effective therapy (DET),
or more than DET (MET). Acute Physiology and Chronic Health Evaluation II
(APACHE II)–based predicted mortality, and Pneumonia Severity Index
scores were calculated.
Results Of the 225 patients identified, 99 were classified as receiving SET,
102 as receiving DET, and 24 as receiving MET. Compared with the other groups,
patients who received MET had statistically significantly more severe pneumonia
as measured by the Pneumonia Severity Index score (P = .04) and predicted mortality (P = .03). Mortality
within the SET group was significantly higher than within the DET group (P = .02, odds ratio, 3.0 [95% confidence intervals, 1.2-7.6]),
even when the DET and MET groups (P = .04) were combined.
In a logistic regression model including antibiotic therapy and clinical risk
factors for mortality, SET remained an independent predictor of mortality
with a predicted mortality–adjusted odds ratio for death of 6.4 (95%
confidence intervals, 1.9-21.7). All deaths occurred in patients with a Pneumonia
Severity Index score higher than 90, and the predicted mortality–adjusted
odds ratio for death with SET in this subgroup was 5.5 (95% confidence intervals,
1.7-17.5).
Conclusions We found that SET is associated with a significantly greater risk of
death than DET. Therefore, monotherapy may be suboptimal for patients with
severe bacteremic pneumococcal pneumonia who have Pneumonia Severity Index
scores higher than 90.
INTRODUCTION
THE INTRODUCTION of antibiotic agents dramatically reduced mortality
from pneumococcal pneumonia.1-2
However, the mortality rate from bacteremic pneumococcal community-acquired
pneumonia (CAP) has shown little improvement in the past 3 decades, remaining
between 19% and 28% depending on the population and institution studied.3-5
The aging population, increased prevalence of comorbid illnesses, the
human immunodeficiency virus, and increasing microbial resistance have all
probably contributed to maintaining the high mortality rate despite advances
in medical care. However, even allowing that some patients are seen too late
to benefit from antibiotic therapy, the continued high mortality rate, despite
apparently appropriate antibiotic therapy, is a cause for concern.
Since pneumococci are consistently identified as the most common pathogen
in CAP, all current guidelines for empirical therapy include an antipneumococcal
antibiotic.6-7 Increasing pneumococcal
antibiotic resistance has led physicians to shift from penicillin to broader
spectrum ß-lactams, such as third-generation cephalosporins, as first
choice for empirical therapy. The ability to cover penicillin-resistant pneumococci
at the same time as atypical pathogens with the newer quinolones has also
contributed to their rising popularity.
Use of combination antibiotic therapy is not uncommon in the treatment
of CAP. The potential for a drug-resistant isolate is the principal indication
for combination therapy. In addition, increasing recognition of polymicrobial
CAP, particularly combinations of Streptococcus pneumoniae and atypical pathogens such as Legionella
spp and Mycoplasma pneumoniae,8-10
suggests that a significant proportion of patients, even with bacteremic S pneumoniae pneumonia, may have additional pathogens not
covered by ß-lactam monotherapy.
Combination therapy has not generally been recommended when pneumonia
is known to be caused by antibiotic-sensitive S pneumoniae. However, 1999 data suggested that patients with bacteremic pneumococcal
CAP treated with a combination of a ß-lactam and a macrolide may have
a better outcome.4
In our institution, we have observed that physicians usually follow
the published antibiotic guidelines in patients with mild to moderate CAP,
but the use of multiple antibiotics in excess of guidelines increases with
the severity of the pneumonia. This allowed us to test the hypothesis that
the use of a combination of effective antibiotic agents as empirical therapy
is superior to a single effective antibiotic agent in patients with bacterermic
pneumococcal CAP.
SUBJECTS, MATERIALS, AND METHODS
STUDY DESIGN AND SUBJECTS
We performed a retrospective case analysis based on data available in
the subjects' medical records. Subjects were all patients age 18 years or
older admitted to hospitals within the Methodist Le Bonheur Healthcare System,
Memphis, Tenn, with a diagnosis of CAP and pneumococcal bacteremia between
January 1, 1996, and July 31, 2000. Three tertiary, 2 secondary, and 8 rural
community hospitals comprise the Methodist Le Bonheur Healthcare system. Patients
with blood cultures positive for pneumococci were identified from a microbiological
database and the medical records were then reviewed to determine whether they
met the enrollment criteria for inclusion in the study.
INCLUSION CRITERIA
All patients with a diagnosis of CAP and at least 1 positive blood culture
for S pneumoniae taken within 48 hours of presentation
to the hospital were included in the analysis. To be diagnosed with CAP, patients
had to have had an acute illness (<10 days of symptoms), a new chest radiographic
infiltrate confirmed by a radiologist, and clinical signs suggestive of acute
pneumonia including either 1 major criteria of fever (temperature, >37.8°C),
hypothermia (temperature, <36.0°C), cough, or sputum production or
2 minor criteria of dyspnea, pleuritic pain, clinical evidence of lung consolidation,
and a leukocyte count of higher than 10 000 cells/µL or lower than
4500 cells/µL. These criteria are consistent with published guidelines
for diagnosing CAP.11
EXCLUSION CRITERIA
Exclusion criteria included patients with severe immunodeficiency as
defined by the Centers for Disease Control and Prevention criteria12 for patients with acquired immunodeficiency syndrome;
patients receiving chemotherapy in the past 60 days; patients receiving treatment
with corticosteroids equivalent to more than 20 mg/d of prednisolone for longer
than 14 days; patients receiving immunosuppression following organ transplantation;
patients receiving cyclosporine, cyclophosphamide, or azothioprine; and patients
hospitalized within the past 30 days. We also excluded any subject who did
not receive at least 1 dose of antibiotic agents within the first 24 hours
after presentation, and any subject whose pneumococcal isolate was resistant
to the initial antibiotic therapy chosen.
DATA COLLECTION
Demographic data, medical history, clinical features at presentation,
antibiotic treatment, daily vital signs, microbiological culture results,
and outcome were all recorded. Clinical data sufficient to calculate both
the Acute Physiology and Chronic Health Evaluation II (APACHE II) score13 and the Pneumonia Severity Index (PSI) score as defined
by Fine et al14 were collected. The PSI score
was calculated from data available at the time of admission. The APACHE II
scores were calculated from the worst physiological scores during the first
24 hours after presentation. Predicted mortality (PM) was calculated based
on the APACHE II score.13
Empirical antibiotic therapy was defined as any antibiotic therapy administered
within the first 24 hours after presentation to the hospital. Based on the
subsequent culture and sensitivity results, empirical antibiotic therapy was
classified as single effective therapy (SET), dual effective therapy (DET),
or more than DET (MET).
DEFINITIONS OF RESISTANCE
The antibiotic sensitivity of isolates from all hospitals was determined
at a central laboratory. All isolates are classified as antibiotic resistant
according to the 2000 guidelines of the National Committee for Clinical Laboratory
Standards.15 Definitions of resistance for
the main antibiotic agents used were penicillin, minimum inhibitory concentration
(MIC) 2 µg/mL or higher (high-level resistance); cefotaxime sodium and/or
ceftriaxone sodium, 2 µg/mL or higher; erythromycin lactobionate, 1
µg/mL or higher; and levofloxacin, 2 µg/mL or higher. Although
debate exists regarding the applicability of in vitro definitions of antibiotic
resistance, we chose the conservative definitions to favor the null hypothesis,
including classifying all macrolides according to the level of resistance
to erythromycin.
DATA ANALYSIS
Univariate analysis was performed using GraphPad (InStat Version 3.01;
GraphPad Software Inc, San Diego, Calif). Differences in continuous variables
were assessed using a 2-tailed t test after confirming
they were normally distributed. Differences in categorical variables were
calculated using the Fisher exact test. P<.05
was considered statistically significant. Odds ratios (ORs) are expressed
as ORs (95% confidence intervals [CIs]).
To control for potential confounding factors, a multivariate logistic
regression analysis was performed evaluating the possible covariates of antibiotic
therapy, age, sex, underlying chronic disease (history of cardiac disease,
renal disease, chronic obstructive pulmonary disease, liver disease, cerebrovascular
disease, or neoplastic disease), excess alcohol consumption, and APACHE II–based
PM was performed. The calculated ORs and 95% CIs after adjusting for confounding
factors are expressed as an approximation of relative risk.
RESULTS
Two hundred twenty-five subjects met the inclusion criteria for analysis.
A further 7 cases of CAP with pneumococcal bacteremia were identified but
were excluded because the isolate was resistant to the empirical therapy the
patient received. A summary of demographic information, severity indices,
and outcome by empirical antibiotic therapy classification is listed in Table 1. The subjects who received MET
were significantly sicker than the subjects who received SET or DET as measured
by the PSI (P = .04) and APACHE II–based PM
(P = .03). Data in Table 2 demonstrate that there was no statistically significant
difference between the prevalence of chronic disease states between the SET
and DET groups.
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Table 1. Comparison of Severity Indices in Each Empirical Antibiotic
Therapy Group*
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Table 2. Chronic Organ Failure in the SET and DET Groups*
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Table 3 lists the most common
antibiotic agents used in the SET and DET groups. The most common combinations
in the MET group were third-generation cephalosporin–macrolide-other
drugs (10 subjects), quinolone and third-generation cephalosporin and other
drugs (4 subjects), and quinolone–third-generation cephalosporin–macrolide
(3 patients). Levofloxacin was the main quinolone chosen (70.4%), with only
4 subjects treated with ciprofloxacin (1 in the SET group, 2 in the DET group,
and 1 in the MET group; all with no fatalities). Eight subjects who received
more than 1 antibiotic agent as empirical therapy were classified as SET on
the basis of the isolate being resistant to azithromycin (5 subjects), cefotaxime
(2 subjects), or combined ticarcillin–clavulanate potassium (1 subjects).
Twenty-nine subjects (12.9%) died. Figure
1 shows a Kaplan-Meier plot of mortality over time for each antibiotic
therapy group. Mortality with the SET group was significantly higher than
with the DET group (P = .02; OR, 3.0 [95% CI, 1.2-7.6]).
Even when the DET and MET groups are combined, the mortality was still significantly
higher in the SET group (P = .04; OR, 2.3 [95% CI,
1.0-5.2]). Because only a few subjects received MET and the subjects who received
MET were significantly sicker than the other subjects, subsequent analysis
is confined to the SET and DET groups.
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Table 3. Antibiotic Therapy in the SET and DET Groups*
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Survival by antibiotic therapy group. SET indicates single effective
therapy; DET, dual effective therapy; and MET, more than DET. For further
explanation see the "Subjects, Materials, and Methods" section.
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Because subjects who received SET had a lower PM than those who received
DET, we used a logistic regression model to calculate the OR for death of
SET vs DET adjusted for PM, which was 6.4 (95% CI, 1.9-21.7). All deaths occurred
in patients with a PSI score higher than 90 (PSI classes IV and V). In subjects
with PSI class IV or V CAP who were given SET, the PM-adjusted OR for death
was 5.5 (95% CI, 1.7-17.5).
As antibiotic therapy would be expected to have little influence on
early deaths, we reanalyzed SET vs DET groups after excluding all deaths that
occurred within 48 hours of presentation (n = 4, 3 in the SET group and 1
in the DET group). Univariate analysis of this subgroup showed a trend to
better outcome with DET compared with SET (94% survival vs 85%, respectively, P = .06). Multivariate analysis again confirmed that SET
was an independent predictor of worse outcome (P
= .01), with the PM-adjusted OR for death in subjects given SET being 4.9
(95% CI, 1.6-18.3).
Subgroup analysis did not show any significant trends to suggest any
advantage or disadvantage of any specific antibiotic agents or combinations
of antibiotic agents. One hundred seventy-two subjects (76.4%) were given
antibiotic coverage for atypical organisms (ie, Legionella spp, M pneumoniae, or Chlamydia pneumoniae). Seventeen (9.9%) of these 172 patients died,
compared with 12 (22.6%) of the 53 subjects without atypical coverage (P = .02), although culture and serological studies were
not performed to confirm or exclude the presence of these pathogens. Subjects
who did not receive coverage for atypical organisms had a significantly higher
PM (27.3% vs 21.8%, P = .047), which was also reflected
in a trend to higher APACHE II (15.9 vs 14.1, P =
.09) and PSI scores (110.1 vs 98.1, P = .07). In
a multivariate nominal regression model, coverage of atypical organisms was
not a significant predictor of outcome when corrected for PM at presentation
(P = .17).
COMMENT
We have found that patients with bacteremic pneumococcal CAP who receive
at least 2 effective antibiotic agents within the first 24 hours after presentation
to a hospital have a significantly lower mortality than patients who receive
only 1 effective antibiotic agent. In fact, among high-risk patients (PSI
class IV or V), receiving only 1 effective antibiotic agent increases mortality
over 5-fold compared with patients receiving 2 effective antibiotic agents.
Although our findings need to be confirmed by a prospective study, current
approaches to the empirical therapy of severe CAP may need to be reevaluated.
Increasing antibiotic resistance in pneumococci, particularly to penicillin,
has become a problem worldwide,16-17
leading to the increased use of broad-spectrum antibiotic agents, including
the newer fluoroquinolones as empirical therapy for CAP. Controversy exists
over the current in vitro MIC susceptibility guidelines for S pneumoniae, with a widely held view that the cutoff of 2 µg/mL
for penicillin is too low in patients with pneumonia.18
However, in our study, we chose to remove antibiotic resistance as a factor
by excluding all subjects who did not receive at least 1 antibiotic agent
in the first 24 hours to which the pneumococcal isolate was sensitive. Furthermore,
we deliberately chose conservative definitions of antibiotic resistance that
would have favored the SET group.
Many potential mechanisms may explain a benefit of DET over SET. Although
sensitive pneumococci are rapidly killed by antibiotics in normal hosts, a
synergistic combination of antibiotic agents may still be valuable in critically
ill or immunocompromised hosts. The combination of a ß-lactam and an
aminoglycoside has been shown to reduce mortality in patients with bacteremic Klebsiella species pneumonia.19
Synergy has been demonstrated for cefotaxime and vancomycin hydrochloride
against some isolates of pneumococci,20 but
this combination represented only 8% of the DET group. Synergy has been shown
between many quinolones and vancomycin against pneumococci,21-22
although not levofloxacin and vancomycin, the only combination used in our
subjects. Most patients in the DET group received either a macrolide-cephalosporin
or quinolone-cephalosporin combination. To our knowledge, no studies showing
synergistic effects of these combinations have been published. Whether an
additive but nonsynergistic combination could be sufficient to have an influence
on mortality in a critically ill host is unknown.
Although the MICs indicated the pneumococcal isolates were antibiotic
sensitive, there may still be significant differences in the rate of death
of pneumococci after antibiotic exposure, which may, in turn, influence the
outcome. Using time-kill studies, different strains of S pneumoniae have been shown to have different rates of death following
antibiotic exposure in experimental meningitis.23
Similarly, although the MIC value may indicate that the pneumococcal isolate
is susceptible to an antibiotic agent, bacterial death following antibiotic
exposure does not necessarily occur. Up to 20% of pneumococcal isolates within
our community exhibit antibiotic tolerance,24-25
and a completely tolerant bacteria may be missed by disk diffusion testing.
In the event that the infecting pneumococcal strain was penicillin tolerant,
a second antibiotic agent may be clearly beneficial.
Apart from synergy, interaction between antibiotic agents with respect
to the modulation of the immune response to pneumococcal infection may also
be important. Compared with other classes of antibiotic agents, ß-lactam
therapy results in significantly greater endotoxin release and subsequent
cytokine production, including tumor necrosis factor  , in patients
with gram-negative sepsis.26-27
In mice with pneumococcal disease, significantly less tumor necrosis factor
accumulation occurs in macrophages following clindamycin hydrochloride compared
with oxacillin sodium.28 Greater or more rapid
release of bacterial products may cause or exacerbate proinflammatory complications
of sepsis, such as septic shock. Macrolides were the second antibiotic agents
in 46% of the DET regimens, but only 8% of the SET regimens. The potential
anti-inflammatory or immunomodulatory properties of macrolides,29-30
including the reduction of tumor necrosis factor production,30 may also be relevant, particularly in patients with
severe sepsis. Another potential benefit of macrolides is the finding that
subinhibitory concentrations of erythromycin reduce the adherence to and disruption
of respiratory epithelial cells by pneumococci.31
Other antibiotic classes may also have beneficial immunomodulatory properties
in pneumococcal disease,32 further increasing
the possibility that antibiotic-host interactions may be responsible for some
or all of the benefit of DET.
The coexistence of multiple pathogens in patients with CAP seems to
be common8-10 and
could also explain an advantage of DET over SET. Because diagnostic studies
for atypical pathogens were not performed, we cannot exclude coinfection with
an atypical pathogen as a confounding factor. However, multivariate analysis
suggested that coverage of these organisms did not contribute to the apparent
benefit of DET over SET. Dual effective therapy with a quinolone may also
be advantageous if a coinfection of S pneumoniae
with other commonly antibiotic-resistant pathogens, such as Hemophilus influenzae or K pneumoniae existed.
However, equivalence of quinolone and macrolide combinations would suggest
this is not a major determinant.
Another explanation for our findings is that rather than DET being superior,
the SET administered may have been inadequate. Although in vitro techniques
confirmed the appropriateness of antibiotic therapy in subjects given SET,
concern has been expressed over the adequacy of the standard dose (500 mg/d)
of levofloxacin prescribed in the United States,33-34
particularly in patients with severe pneumonia.35
We did not find an excess mortality for patients with levofloxacin-based SET
compared with other SET regimens. It is possible that the newer quinolones
such as gatifloxacin and moxifloxacin, which have lower MICs against pneumococci
and more favorable pharmacodynamic properties, may be more effective SET in
pneumococcal disease,36 but, to our knowledge,
there are no clinical trials to support this.
Because of the retrospective nature of our analysis, care must be taken
not to over interpret the results. Although there are many potential sources
of bias, both the univariate and multivariate analyses strongly suggest that
patients receiving SET had less severe pneumonias than patients receiving
DET. Also, no difference in the prevalence of chronic organ disease between
the groups existed. Although a systematic bias toward DET is unlikely, one
potential confounding factor, which we could not control for, is the time
taken to receive the first dose of effective antibiotic agents, since a delay
in the institution of an antibiotic agent is associated with higher mortality.37 An additional limitation of our study is that a wide
range of antibiotic agents and antibiotic combinations were used, making it
impossible to draw any conclusions about specific antibiotic agents or antibiotic
regimens. It was interesting that the lowest mortality was seen in in subjects
receiving the combination therapy of cephalosporin-macrolide, in keeping with
the findings of Mufson and Stanek.4 The optimal
duration of DET could also not be determined as patients were classified as
receiving MET, DET, or SET based on antibiotic treatment received in the first
24 hours after presentation. Subsequent changes in antibiotic therapy may
be an additional confounding factor, although historical data suggest that
any change in antibiotic therapy would take several days to have any influence
on outcome,2 limiting the potential influence
since 50% of the deaths occurred before day 5.
Trials comparing the combination of a cephalosporin and a macrolide
with a quinolone have not shown any advantage of combination therapy,38-39 but the number of subjects with pneumococcal
bacteremia in each of these studies was small. As the newer fluoroquinolones
cover atypical pathogens as well as S pneumoniae,
until now there has been no justification for any trial investigating the
efficacy of these agents combined with cephalosporins.
Only a prospective, randomized, double-blind trial will resolve whether
DET is truly more effective than SET for bacteremic pneumococcal pneumonia.
However, the strength of the association we have demonstrated provides significant
justification for undertaking such a trial. As SET was adequate therapy in
patients with a PSI score lower than 90, a prospective trial should focus
on patients with PSI class IV or V CAP. Newer diagnostic tools such as pneumococcal
urinary antigen testing,40 and the rapid detection
of pneumococcal DNA in serum by polymerase chain reaction–based techniques,41-42 will make it easier to identify subjects
with CAP who are most likely to have pneumococcal bacteremia.
CONCLUSIONS
After accounting for antibiotic resistance, we have found a substantial
benefit of DET over SET for patients with bacteremic pneumococcal pneumonia.
The finding that subjects receiving a SET, after adjusting for the severity
of pneumonia, were 6.4 times more likely to die of their illness is a strong
argument for a randomized, double-blind, prospective study of combination
therapy vs SET in patients suspected of having bacteremic pneumococcal pneumonia.
AUTHOR INFORMATION
Accepted for publication April 9, 2001.
We thank Elaine Tuomanen, MD, University of Tennessee, for her review
of the manuscript.
Corresponding author: Grant W. Waterer, MBBS, FRACP, Department of
Medicine, University of Western Australia, Royal Perth Hospital, GPO Box X2213,
Perth 6847, Western Australia.
From the Department of Medicine, University of Western Australia, Royal
Perth Hospital (Dr Waterer); Department of Preventative Medicine, University
of Tennessee, Memphis (Dr Somes); and the Methodist Le Bonheur Healthcare
Foundation, Memphis, Tenn (Dr Wunderink).
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