Oral versus intravenous clarithromycin in moderate to severe community-acquired pneumonia: an observational study
Rae et al. Pneumonia
Oral versus intravenous clarithromycin in moderate to severe community-acquired pneumonia: an observational study
Nikolas Rae 0
Aran Singanayagam 1
Stuart Schembri 0
James D. Chalmers 0
0 Scottish Centre for Respiratory Research, University of Dundee , DD1 9SY Dundee , UK
1 Imperial College London , SW7 2AZ London , UK
Objectives: British Thoracic Society guidelines recommend clarithromycin in addition to beta-lactam antibiotics for patients with community-acquired pneumonia and CURB-65 score 2-5. Intravenous therapy is commonly used but there are few data on whether oral therapy is equally effective. Methods: This observational study used propensity matching to compare two groups of patients with moderate to severe community-acquired pneumonia (CURB-65 score 2-5) treated with oral (n = 226) or intravenous (n = 226) clarithromycin on admission. Outcomes were 30-day mortality, intensive care unit admission, time to clinical stability, and length of hospital stay. Results: There was no significant difference in 30-day mortality (16.8% for intravenous [IV] group vs. 14.6% for oral group, hazard ratio for IV group 1.11 95% CI 0.70-1.78), ICU admission (10.6% in both groups) or complications (10.6% for IV group and 9.3% for oral group) between the groups. The time to clinical stability in both cohorts was a median of 5 days (interquartile range 3-7 days, p = 0.3). The median length of hospital stay was 8 days in the IV group (interquartile range 4-14 days) and 7 days in the oral group (interquartile range 4-13 days), p = 0.5. No other differences were observed between oral and IV groups. Conclusion: Where the oral route is not compromised, oral macrolides appear to be equivalent to IV in treating moderate to severe CAP.
Macrolide; Pneumonia; Severity; Combination therapy; Antibiotic
Guidelines for treatment of community-acquired
pneumonia (CAP) recommend adding an intravenous
(IV) macrolide to a β-lactam agent (penicillin,
penicillin/β-lactamase inhibitor combination or second/third
generation cephalosporin) in the treatment of
moderate to severe CAP [1, 2]. There is currently no
evidence that the route of administration of macrolides
alters clinical outcome.
Macrolides are commonly used in the management of
respiratory tract infections, with particular activity
against atypical organisms in addition to Streptococcus
pneumoniae, Haemophilus influenzae and Moraxella
catarrhalis [3, 4]. Oral clarithromycin has a
bioavailability of approximately 55% and excellent pulmonary tissue
penetration, achieving concentrations higher than those
observed in plasma [5, 6]. Peak plasma concentrations
are achieved within 2 h . IV administration is more
expensive and may be associated with a higher rate of
adverse effects, thus administration by the oral route
is preferable wherever possible [7, 8]. Recent
randomized controlled trials have given conflicting data on
the overall value of macrolides in the management of
community-acquired pneumonia [9, 10]. A non-inferiority
trial from Switzerland  comparing β-lactam
monotherapy to β-lactam plus macrolide concluded that β-lactam
monotherapy was not non-inferior in terms of time to
clinical stability. A significant difference suggesting that
macrolides improve rate of clinical recovery was
demonstrated, driven by a higher effectiveness in a small group
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of patients with atypical pathogens . In contrast, a
cluster randomized controlled trial in The Netherlands 
has recently reported no benefit in terms of mortality for
hospitals randomized to a regime consisting of β-lactam
plus macrolide, compared to β-lactams alone. None of
these studies have addressed whether macrolides should
be administered orally or intravenously. A recent study
 has examined the administration of fluoroquinolones
and concluded that administration of fluroquinolones
orally was at least equivalent to IV administration in CAP
The aim of this study was to ascertain if the route of
administration of macrolides was associated with
outcome in patients with moderate or severe
This study was a secondary analysis of a prospectively
collected database (2005–2009) that has been described
previously. Data collection was approved by the South
East Scotland Research Ethics Committee (reference
numbers S1104/15 and S1103/27).
Inclusion and exclusion criteria
Patients were included in the study if they presented
with new infiltrates on chest radiograph along with signs
and symptoms suggestive of pneumonia . In
addition, patients were eligible for inclusion in the
present analysis if they had a CURB-65 score of between
2 and 5 and received an IV β-lactam with clarithromycin
(either IV or oral) as the initial antibiotic treatment
regimen on admission, as per British Thoracic Society (BTS)
Exclusion criteria were hospital-acquired pneumonia,
active malignancy, immunosuppression, pulmonary
embolism, tuberculosis, and patients in whom active
treatment was not considered appropriate. In addition, for
this analysis patients were excluded if the oral route
was compromised or if they received a non-guideline
concordant antibiotic regime.
The probability that a patient would receive oral or IV
clarithromycin was assessed with multivariable logistic
regression to create a propensity score . The
variables included in the propensity model were all of
those available to clinicians at admission (symptoms,
demographics, co-morbidities, clinical variables,
laboratory results and radiology). Each patient treated
with IV ß-lactam and oral clarithromycin was then
matched to a patient treated with IV ß-lactam and IV
clarithromycin with a similar propensity score, using
greedy matching. This created two cohorts that were
well matched for measured confounders. As a sensitivity
analysis to exclude strong differential effects among
patients that could not be matched, the analysis was also
repeated including the propensity score as a covariate in the
Cox proportional hazards regression .
The group who received initial IV β-lactam with IV
clarithromycin are referred to in the manuscript as the
IV group, and those who initially received IV β-lactam
with oral clarithromycin are referred to as the oral
The primary outcome was 30-day mortality, with
secondary outcomes including length of hospital stay,
intensive care unit (ICU) admission and development of
empyema or complicated parapneumonic effusion.
Statistical analyses were performed using SPSS version
21 (IBM, New York, United States). Propensity matching
was performed using the propensity matching add-on
for SPSS (SPSS essentials for R and R version 2.14.2).
The propensity analysis is described above. Between the
treatment groups, outcomes were assessed after
multivariable adjustment using Cox proportional hazards
regression. The multivariable analysis included age,
gender and CURB-65 score. More extensive models
including all variables in Table 1 were also tested to
reduce unmeasured confounding. A sensitivity analysis
was performed in patients with CURB-65 scores 3–5,
as this group are recommended for IV macrolides in
the BTS guidelines .
There were 1,113 patients who had a CURB-65 score
2–5 and were eligible for inclusion in the study. Of
these, 761 patients received guideline concordant
therapy consisting of a ß-lactam and a macrolide. There
were 118 patients with a compromised oral route that
were excluded (all had IV therapy). The final cohort for
matching consisted of 226 patients in the oral
clarithromycin group and 417 patients treated with IV
clarithromycin. The dose administered was not recorded but
local guidelines recommended 500mg twice daily for
both oral and IV administration.
In the logistic regression analysis, IV therapy was not
independently associated with any of the variables
considered; the strongest relationship was with oral antibiotic
therapy prior to admission (odds ratio for IV therapy,
1.67 95% CI 0.96–2.92) (Table 1).
There were no patients in the oral group that could
not be matched and, therefore, 452 patients were
Table 1 Multivariable analysis of factors associated with
intravenous macrolide treatment
Table 2 Characteristics of the IV and oral clarithromycin groups
after propensity matching
Congestive cardiac failure
Odds ratio (95% CI), p-value
0.79 (0.55–1.13), p = 0.2
1.01 (0.99–1.03), p = 0.1
0.83 (0.51–1.35), p = 0.5
0.94 (0.44–2.00), p = 0.9
1.23 (0.68–2.22), p = 0.5
0.80 (0.52–1.23), p = 0.3
1.06 (0.63–1.80), p = 0.8
1.04 (0.71–1.52), p = 0.8
1.13 (0.90–1.41), p = 0.3
1.07 (0.89–1.29), p = 0.5
1.0 (0.99–1.01), p = 0.4
1.11 (0.71–1.75), p = 0.7
1.01 (0.65–1.56), p = 0.9
0.90 (0.56–1.45), p = 0.7
0.89 (0.56–1.41), p = 0.6
0.90 (0.49–1.66), p = 0.7
0.99 (0.95–1.03), p = 0.5
1.00 (0.99–1.01), p = 0.4
1.01 (0.99–1.02), p = 0.3
1.00 (0.99–1.00), p = 0.8
1.0 (0.49–1.66), p = 0.7
1.14 (0.73–1.79), p = 0.6
Multilobar radiographic changes
COPD chronic obstructive pulmonary disease, ACE inhibitors,
angiotensinconverting-enzyme inhibitors, ARBs, angiotensin receptor blockers
included after propensity matching, with 226 patients in
the IV group propensity matched to 226 patients in the
oral group. There were no significant differences in
demographics, or physiological or laboratory parameters
between the two groups, as shown in Table 2.
Outcomes: propensity matched cohort
There were 38 deaths (16.8%) in the IV group and 33
deaths (14.6%) in the oral group (p = 0.5). There was no
significant difference in 30-day mortality of multivariable
analysis (hazard ratio [HR] for IV group 1.11 95% CI
0.70–1.78). The time to clinical stability was a median of
5 days in both cohorts (interquartile range [IQR] 3–7
days, p = 0.3).
There were 24 patients (10.6%) who were admitted to
the ICU >24 h after admission in both groups (p = 1.0)
with no differences between the groups evident in
multivariable analysis (HR 1.07 95% CI 0.72–1.59). There
were 24 patients (10.6%) who developed empyema or
complicated parapneumonic effusion in the IV group
compared to 21 (9.3%) in the oral group (p = 0.6) with
Data are median IQR except gender, which is presented as n (%)
SBP systolic blood pressure, CRP C-reactive protein, WCC, white cell count,
IV intravenous, IQR interquartile range
no difference between the groups on multivariable
analysis (HR 1.06 95% CI 0.59–1.91). The median length of
hospital stay was 8 days in the IV group (IQR 4–14 days)
and 7 days in the oral group (IQR 4–13 days), p = 0.5.
Figure 1 shows a Kaplan-Meier curve of 30-day
mortality for the two groups.
In the analysis limited to patients with CURB-65 scores
3–5 (n = 272), the hazard ratio for mortality was 1.16
(0.67–2.03) and for ICU admission was 1.14 (0.73–1.78).
Outcomes: sensitivity analysis
To exclude strong confounding effects from patients
excluded from the propensity analysis, we performed a
Cox proportional hazard regression including all patients
Fig. 1 Kaplan-Meier plot of 30-day mortality between patients
receiving oral or intravenous clarithromycin for moderate to
severe community-acquired pneumonia
(n = 643) considered for inclusion in the propensity
analysis. In this analysis, the hazard ratios were similar to
the primary analysis: 30-day mortality HR for IV therapy
was 1.14 (95% CI 0.74–1.76); 30-day mortality HR for
ICU admission was 1.16 (95% CI 0.83–1.62) and 30-day
mortality HR for complicated pneumonia was 1.18 (95%
0.71–1.98), compared to oral therapy.
The addition of an IV macrolide to a β-lactam agent in
the treatment of moderate or severe CAP is
recommended in national and international guidelines [1, 2].
This study indicates that in patients with moderate or
severe CAP where the oral route is not compromised,
treatment with oral clarithromycin is as effective as IV
clarithromycin when combined with an IV β-lactam.
Oral therapy has several theoretical advantages,
including reducing costs and risk of complications of IV
administration of drugs .
Macrolides are primarily added to provide cover for
atypical pathogens. Atypical pathogens are not
associated with bacteraemia, and bacteraemia is the only
circumstance where prompt IV antibiotic therapy is shown
to give a mortality benefit . Clarithromycin has a
high bioavailability and achieves a peak serum
concentration 2 h following oral administration . The highly
lipophilic nature of macrolides result in excellent tissue
penetration irrespective of route of administration, with
clarithromycin achieving concentrations up to 20 times
greater in pulmonary epithelial tissues than in serum.
Since IV clarithromycin is typically administered over 1
h, the difference in time to reach peak serum
concentrations is highly unlikely to be clinically relevant.
In the UK, IV clarithromycin is at least 10 times more
expensive than oral clarithromycin . This cost does
not include the time required for preparation of IV
medications or consumables used for IV administration of
drugs. CAP is common and even relatively small
increases in the use of oral clarithromycin would result in
significant cost savings.
There has been an ongoing debate about the relative
value of macrolides in the management of CAP [9, 10].
Although some observational studies suggest a mortality
benefit with macrolide containing regimes, a
metaanalysis of observational studies could not conclude a
definite benefit associated with macrolides in CAP 
and a Cochrane review of randomized controlled trials
(primarily of fluroquinolones) have failed to demonstrate
a benefit for giving empirical atypical coverage in CAP
. Macrolides are now known to be associated with
significant adverse effects including the induction of
antibiotic resistance and Clostridium difficile [20–23].
Macrolides have been linked with cardiovascular events,
although this association is controversial [24, 25]. While
attention has focused on the potential for macrolides to
prolong the QT interval or destabilize atherosclerotic
plaques, a more simple explanation for some of the
reported events is the large volume IV infusions required
to administer. The question of the clinical value of
macrolides will not be resolved without definitive
randomized controlled trials. Two randomized trials have
recently evaluated this question but have given
somewhat conflicting results. Garin et al  could not
demonstrate non-inferiority of ß-lactam alone compared to
combination therapy with a primary outcome of time to
clinical stability. This is not the same as saying that
macrolide therapy speeds up clinical recovery, but this
was certainly the case for a subgroup of patients with
atypical infection in this study . Larger studies would
be needed to evaluate if macrolide indeed result in more
rapid clinical response. Postma et al  reported a
cluster randomized trial in The Netherlands where hospitals
were randomized to a strategy consisting of ß-lactam
plus macrolide, ß-lactam alone or fluoroquinolone. The
study found that hospitals had similar mortality rates
regardless of the strategy used, with no mortality benefit
for macrolides demonstrated . Limitations of the
study included the cluster design that allowed significant
deviations from the assigned antibiotic regime and a
population of patients with predominantly mild disease.
Therefore, while awaiting a definitive answer to the
question of which patients benefit from macrolide
therapy, it is possible to minimise the harm associated with
macrolides by following guideline recommendations for
these agents, using the shortest duration necessary and,
as this study shows, some harms and costs may be
minimized by using oral therapy in preference to IV
Limitations of this study must be acknowledged. This
is an observational study, and although the oral and IV
groups were well matched after excluding patients too
severely ill to take oral medications, unmeasured
confounding may remain. A randomized controlled trial
would be required for confirmation. This study is the
largest to address this question, but would be
underpowered to detect small differences in outcome between the
groups. Sample size was determined based on the
available data. Nevertheless, it must be noted that none of
the hazard ratios suggested a harmful effect of oral
This observational study suggests that route of
administration of clarithromycin in patients with moderate or
severe CAP is not associated with a difference in clinical
outcome, in patients able to take oral therapy. This
would justify a definitive randomized controlled trial.
CAP: Community-acquired pneumonia; CRP: C-reactive protein;
CURB65: Confusion, urea, respiratory rate, blood pressure, age > 65; HR: Hazard
ratio; ICU: Intensive care unit; IQR: Interquartile range; IV: Intravenous;
SBP: Systolic blood pressure; WCC: White blood cell count
Availability of data and materials
Please contact the authors for data requests.
The study was conceived by JDC, NR, AS and SS. Data collection was
performed by JDC and AS, with additional contributions from NR and SS.
Statistical analysis was performed by NR and JDC. NR and JDC wrote the
manuscript which was revised by AS and SS. All authors read and approved
the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
Data collection was approved by the South East Scotland Research Ethics
Committee (reference numbers S1104/15 and S1103/27). Requirement for
informed consent was waived due to the observational nature of the study.
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