EDITORIAL
Empiric antibiotics for community-acquired pneumonia:
A macrolide and a beta-lactam please!
Key words: outcomes, resistance, respiratory infections.
Antibiotic selection for patients with community-
acquired pneumonia (CAP) remains empiric because
microbiological diagnostic technology is yet to deliver
anything that is accurate and fast enough to be useful
to clinicians having to make the decision. While there
are many arguments around different aspects of what
the best empiric regime is, probably the largest contro-
versy is whether a macrolide antibiotic should be an
obligatory component. Broadly speaking, there are
three camps based on those who believe that
(i) macrolides are associated with better outcomes,
(ii) there is a benefit of macrolides but that it has an
antibiotic effect that can be obtained by using a tetracy-
cline or fluoroquinolone instead; and (iii) all the data
are highly suspect and there is no benefit.
In this issue of Respirology, Okumura et al.1 add to
the already extensive body of literature suggesting that
optimal empiric therapy for CAP is a macrolide and a
beta-lactam. Although the data presented is a post-hoc
analysis of a prospective observational study, the mor-
tality benefits Okumura et al. identified from adding a
macrolide to beta-lactam monotherapy in patients not
at risk of drug-resistant pathogens (like Pseudomonas
or methicillin-resistant Staphylococcus aureus) was
striking—13.8% versus 1.8% (P < 0.001). Interestingly,
given that one of the putative mechanisms by which
macrolides may have a positive effect is as an anti-
inflammatory drug, the mortality benefit was seen
regardless of whether C-reactive protein was less than
or more than 15 mg/dL.
The very large number of studies showing a mortality
benefit of adding a macrolide to a beta-lactam com-
pared to monotherapy has been extensively reviewed.2,3
Several recent studies, however, are worthy of more
comments. Postma et al.4 conducted a ‘pragmatic’ ran-
domized controlled trial of monotherapy versus combi-
nation therapy in patients with suspected CAP not
severe enough to need intensive care and concluded
that monotherapy was not inferior. This study, how-
ever, has many problems including 25% of patients not
having any radiological confirmation of pneumonia,
nearly 40% of the ‘monotherapy’ patients actually
receiving combination therapy with a macrolide and
significant differences in the choice of antibiotic within
classes (e.g. in the monotherapy arm the additional
macrolide was rarely erythromycin whereas in the
combination therapy arm erythromycin was the most
common; benzyl penicillin was rarely used in the
monotherapy arm but was commonly used in the com-
bination therapy group). Briefly, the study by Postma
et al.5 tells us nothing about how to treat CAP.
© 2017 Asian Pacific Society of Respirology
A second randomized trial by Garin et al.6 took the
approach of using a non-inferiority design, typically
used to get licensing approval for antibiotics, where
they attempted to show that monotherapy was not
inferior to combination therapy. The results of the
study by Garin et al. did not satisfy the criteria for con-
cluding that monotherapy was not inferior to combina-
tion therapy. To put this result in perspective, if
monotherapy was put up as a new therapy against a
standard of combination therapy it would almost cer-
tainly not get approval from regulatory agencies.
Probably, the best example of the improvement in
outcomes from macrolide combination therapy is the
study by Gattarello et al.7 who compared the outcome
of severe CAP in two different large cohort studies from
2001 to 2002 and from 2008 to 2013. Between these
two time periods, the mortality rate from CAP requiring
intensive care unit care dropped 18%, with a 33% drop
in those with septic shock and a 27% drop in those
requiring mechanical ventilation. The two factors that
were identified to explain this significant improvement
in mortality were (i) giving the first dose of antibiotics
within 3 h (odds ratio (OR) 0.36), and (ii) using a
macrolide as part of the empiric regime (OR 0.19).
The final studies to note are two recently published
analyses around the timing of macrolides relative to
the beta-lactam. Peyrani et al.8 analysed a multicenter
prospective cohort study of CAP and found a reduced
time to clinical stability and a reduced length of stay
with a non-significant trend to lower mortality if the
macrolide was given first. Metersky et al.9 analysed a
large electronic health record database from 71 hospi-
tals. While they did not find any statistically significant
differences based on the order of antibiotic administra-
tion, there was a strong trend to lower mortality or hos-
pice discharge if the macrolide was given at least 1 h
prior to the cephalosporin (6.4% vs 9.3%, P = 0.06).
Although neither study can be considered as an con-
clusive evidence, a benefit from giving the macrolide
prior to the beta-lactam would be consistent with
hypotheses that macrolides have their benefit through
either an anti-inflammatory effect and/or an anti-toxin
effect. It is worth noting that macrolides shut down
pnemolysin toxin production even in macrolide-
resistant pneumococci within 20 min of exposure.10
In summary, those that continue to believe that the
data are flawed and do not wish to give a macrolide
are unlikely to be swayed by the study by Okumura
et al.1 While it is possible that tetracyclines have similar
anti-inflammatory and anti-toxin functions to macro-
lides, the lack of any significant studies to show a com-
parative clinical benefit signifies that they cannot be
recommended as empiric therapy in the place of a
Respirology (2018) 23, 450–451
doi: 10.1111/resp.13248
Editorial
macrolide. As for me, I find the data overwhelmingly in
favour of using combination therapy and if I ever get
CAP, I would like a macrolide followed a short time
later by a third generation cephalosporin please, pref-
erably getting both within 2 h of presenting.
Grant Waterer, MBBS, PhD
School of Medicine, University of Western Australia,
Perth, WA, Australia
REFERENCES
1 Okumura J, Shindo Y, Takahashi K, Sano M, Suginoy, Yagi T,
Taniguchi H, Saka H, Matsui S, Hasegawa Y; on behalf of the Cen-
tral Japan Lung Study Group. Mortality in patients with
community-onset pneumonia at low risk of drug-resistant patho-
gens: impact of B-lactam plus macrolide combination therapy.
Respirology 2017; 23: 526–34.
2 Waterer G, Bennett L. Improving outcomes from community-
acquired pneumonia. Curr. Opin. Pulm. Med. 2015; 21: 219–25.
3 Sligl WI, Asadi L, Eurich DT, Tjosvold L, Marrie TJ, Majumdar SR.
Macrolides and mortality in critically ill patients with community-
acquired pneumonia: a systematic review and meta-analysis. Crit.
Care Med. 2014; 42: 420–32.
4 Postma DF, van Werkhoven CH, van Elden LJ, Thijsen SF,
Hoepelman AI, Kluytmans JA, Boersma WG, Compaijen CJ, van
der Wall E, Prins JM et al.; CAP-START Study Group. Antibiotic
treatment strategies for community-acquired pneumonia in adults.
N. Engl. J. Med. 2015; 372: 1312–23.
Respirology (2018) 23, 450–451
451
5 Rozenbaum MH, Mangen MJ, Huijts SM, van der Werf TS,
Postma MJ. Incidence, direct costs and duration of hospitalization
of patients hospitalized with community acquired pneumonia: a
nationwide retrospective claims database analysis. Vaccine 2015;
33: 3193–9.
6 Garin N, Genne D, Carballo S, Chuard C, Eich G, Hugli O,
Lamy O, Nendaz M, Petignat PA, Perneger T et al. Beta-lactam
monotherapy vs beta-lactam-macrolide combination treatment in
moderately severe community-acquired pneumonia: a randomized
noninferiority trial. JAMA Intern. Med. 2014; 174: 1894–901.
7 Gattarello S, Borgatta B, Sole-Violan J, Valles J, Vidaur L,
Zaragoza R, Torres A, Rello J. Decrease in mortality in severe
community-acquired pneumococcal pneumonia: impact of
improving antibiotic strategies (2000-2013). Chest 2014; 146: 22–31.
8 Peyrani P, Wiemken TL, Metersky ML, Arnold FW, Mattingly WA,
Feldman C, Cavallazzi R, Fernandez-Botran R, Bordon J,
Ramirez JA. The order of administration of macrolides and beta-
lactams may impact the outcomes of hospitalized patients with
community-acquired pneumonia: results from the community-
acquired pneumonia organization. Infect. Dis. (Lond) 2018; 50:
13–20.
9 Metersky ML, Priya A, Mortensen EM, Lindenauer PK. Association
between the order of macrolide and cephalosporin treatment
and outcomes of pneumonia. Open. Forum Infect. Dis. 2017; 4:
ofx141.
10 Anderson R, Steel HC, Cockeran R, von Gottberg A, de Gouveia L,
Klugman KP, Mitchell TJ, Feldman C. Comparison of the effects of
macrolides, amoxicillin, ceftriaxone, doxycycline, tobramycin and
fluoroquinolones, on the production of pneumolysin by Streptococ-
cus pneumoniae in vitro. J. Antimicrob. Chemother. 2007; 60:
1155–8.
© 2017 Asian Pacific Society of Respirology