ARTICLE IN PRESS

International Journal of Antimicrobial Agents ■■ (2018) ■■–■■

Contents lists available at ScienceDirect

International Journal of Antimicrobial Agents

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / i j a n t i m i c a g

Is gentamicin safe and effective for severe community-acquired

pneumonia? An 8-year retrospective cohort study
Christopher J. Brereton a,b, Daniel Lennon a, Sarah Browning a, Emily Dunn a,
John K. Ferguson a,b,c, Joshua S. Davis a,b,d,*
a Division of Medicine, John Hunter Hospital, Newcastle, NSW 2305, Australia
b School of Medicine and Public Health, University of Newcastle, Newcastle, NSW 2308, Australia
c
Pathology North, New Lambton Heights, Newcastle, NSW 2305, Australia
d Global and Tropical Health Division, Menzies School of Health Research, Darwin, NT 0811, Australia

A R T I C L E I N F O A B S T R A C T

Article history: Gram-negative bacilli are the causative organisms in a significant proportion of patients with severe
Received 22 October 2017 community-acquired pneumonia (CAP) admitted to the intensive care unit (ICU). Clinical guidelines rec-
Accepted 20 January 2018 ommend broad-spectrum antimicrobials for empirical treatment despite alarming global trends in
Editor: R.A. Seaton
antimicrobial resistance. In this study, we aimed to assess the safety and efficacy of gentamicin, an
aminoglycoside with potent bactericidal activity, for empirical Gram-negative coverage of severe CAP in
Keywords:
patients admitted to the ICU. A retrospective cohort study was performed at a university teaching hos-
Gentamicin
pital where the severe CAP guideline recommends penicillin, azithromycin and gentamicin as empirical
Aminoglycoside
Community-acquired pneumonia cover. Ceftriaxone plus azithromycin is used as an alternative. Adults with radiologically-confirmed severe
Bacterial pneumonia CAP were included, comparing those who received gentamicin in the first 72 h of admission with those
Critical care who did not. Participants were identified using ICD-10 codes for bacterial pneumonia and data manu-
Gram-negative ally extracted from electronic medical records. Of 148 patients admitted with severe pneumonia, 117
were given at least one dose of gentamicin whereas the remaining 31 were not. The two groups were
well matched in terms of demographics, co-morbidities and disease severity. There were no significant
differences between the gentamicin and no-gentamicin groups in the incidence of acute kidney injury
[60/117 (51%) vs. 16/31 (52%), respectively], hospital mortality [20/117 (17%) vs. 7/31 (23%)] and sec-
ondary outcomes including relapse and length of hospital stay. In conclusion, gentamicin is safe and has
similar outcomes to alternative Gram-negative antimicrobial regimens for empirical coverage in severe
CAP patients admitted to the ICU.
Crown Copyright © 2018 Published by Elsevier B.V. All rights reserved.

1. Introduction Haemophilus influenzae, Escherichia coli and Klebsiella pneumoniae

With over 3 million attributable deaths globally per year,
community-acquired pneumonia (CAP) is the world’s most fatal com-
municable disease [1]. Antimicrobial therapy for CAP is largely
empirical because a causative organism is typically only identified
in 30–65% of cases using conventional diagnostic methods [2–4] and
is rarely known at presentation. Empirical regimens are designed
to cover Streptococcus pneumoniae and so-called atypical patho-
gens such as Legionella and Mycoplasma spp. Aerobic Gram-negative
bacilli are an important but less common group of causative or-
ganisms, accounting for ca. 10% of cases of CAP and up to 19% in
severe CAP requiring admission to the intensive care unit (ICU) [5–9].
* Corresponding author. Department of Infectious Diseases, John Hunter Hospital,
Lookout Road, New Lambton Heights, Newcastle, NSW 2305, Australia.
E-mail address: Joshua.Davis@menzies.edu.au (J.S. Davis).
are the most common Gram-negative causative organisms [6,7].
Current US and Australian guidelines recommend a third-
generation cephalosporin plus azithromycin as first-line therapy for
severe CAP [10,11]. However, Australian guidelines recommend ben-
zylpenicillin, gentamicin and azithromycin as a suitable alternative
regimen, providing excellent Gram-negative cover while avoiding
the host and ecological effects of third-generation cephalosporins
on antimicrobial resistance and Clostridium difficile infection [5,10,11].
Gentamicin penetrates well into alveolar lining fluid [12] and has
useful activity against nearly all common community-onset Gram-
negative CAP pathogens. Small observational studies [13–15] as well
as a single phase 3 randomised controlled trial (RCT) [16], all pub-
lished over 20 years ago, suggest that aminoglycosides are associated
with good clinical outcomes in CAP, however larger and more recent
studies are lacking.
The potential for nephrotoxicity is a key concern with the use
of empirical gentamicin for CAP, but the risk is minimised if gen-
tamicin is used for ≤48 h [10,17]. Ototoxicity is a significant but rare

https://doi.org/10.1016/j.ijantimicag.2018.01.018
0924-8579/Crown Copyright © 2018 Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Christopher J. Brereton, et al., Is gentamicin safe and effective for severe community-acquired pneumonia? An 8-year retrospective cohort study,
International Journal of Antimicrobial Agents (2018), doi: 10.1016/j.ijantimicag.2018.01.018
 ARTICLE IN PRESS
2 C.J. Brereton et al. / International Journal of Antimicrobial Agents ■■ (2018) ■■–■■
complication and is also usually associated with cumulative dose
exposure [18].
In this study, we aimed to examine the safety and efficacy of gen-
tamicin in adults with CAP admitted to the ICU. We hypothesised
that the proportion of patients with acute kidney injury (AKI) would
be no higher in the group receiving gentamicin compared with the
group not receiving gentamicin, and that those receiving gentami-
cin would have a lower in-hospital mortality and lower chance of
relapse than those not receiving gentamicin.
2. Methods
2.1. Study design and setting
A retrospective observational study of patients admitted to a
single 650-bed teaching hospital in temperate Australia was per-
formed. This hospital’s local antibiotic guideline for severe CAP is
benzylpenicillin, gentamicin (4–6 mg/kg in a single daily dose for
up to three doses) and azithromycin. Ceftriaxone is an alternative
option for those with minor β-lactam allergy or contraindications
to aminoglycosides. The routine microbiological workup at the hos-
pital for severe CAP includes: two sets of blood cultures; sputum
microscopy and culture if there is purulent sputum; microscopy and
culture of endotracheal aspirate if the patient is intubated; urinary
antigen assays for Legionella pneumophila and S. pneumoniae; base-
line and convalescent serology for Mycoplasma, Chlamydophila,
Legionella and Coxiella burnetii; and multiplex PCR on a combined
nose and throat swab for 10 respiratory viruses (including influ-
enza, parainfluenza, respiratory syncytial virus and others;
AusDiagnostics, Beaconsfield, NSW, Australia). Empirical gentami-
cin is continued for ca. 48 h (i.e. two or three doses). At this stage,
clinical progress and microbiology results are reviewed. If a patho-
gen is identified, the patient is switched to directed therapy, but
further aminoglycosides are avoided. If no organism is identified
and the patient is still severely ill and requiring intravenous (i.v.)
therapy, then they are switched to ceftriaxone. If no organism is iden-
tified and the patient is improving, then penicillin plus azithromycin
is continued. Oral step-down is amoxicillin.
2.2. Participants
Following approval from the local Human Research Ethics Com-
mittee, hospital discharge coding was used to identify patients who
had been admitted between January 2008 and December 2015 with
a primary diagnosis of bacterial pneumonia [International Classi-
fication of Diseases (ICD)-10 codes J13–16 and J18].
Patients had to meet all three of the following criteria to be in-
cluded: (i) at least two clinical features of pneumonia among fever
(body temperature >38 °C), cough, purulent sputum, pleuritic chest
pain, and bronchial breathing or crepitations on examination;
(ii) radiological evidence of new alveolar opacity within 48 h of hos-
pital admission on either chest radiography or pulmonary computed
tomography (CT) scan; and (iii) admitted to the ICU within 72 h of
hospital admission. ICU admission was used as a surrogate for severe
pneumonia.
Exclusion criteria were: (i) an alternative diagnosis was deemed
more likely than CAP (e.g. pulmonary embolism, acute pulmonary
oedema); (ii) death or hospital discharge within 24 h of presenta-
tion; (iii) a clinically recorded diagnosis of aspiration pneumonia;
and (iv) medical records unavailable or incomplete.
2.3. Definitions
Patients were included in the ‘gentamicin’ cohort if they re-
ceived one or more doses of i.v. gentamicin within the first 72 h of
hospital admission.
Please cite this article in press as: Christopher J. Brereton, et al., Is gentamicin safe and effective for severe community-acquired pneumonia? An 8-year retrospective cohort study,
International Journal of Antimicrobial Agents (2018), doi: 10.1016/j.ijantimicag.2018.01.018
For each patient, we selected what we judged to be the single
most important causative organism. To be considered a causative
organism in this study, the following criteria had to be met: (i) the
same organism grown both from blood and sputum, excluding or-
ganisms likely to be skin contaminants; or (ii) an organism grown
from sputum or endotracheal aspirate only if the growth was pure
and moderate or heavy and the sputum was purulent; or (iii) a pos-
itive urinary antigen, serological test or viral PCR was considered
significant if it fitted the clinical presentation and there was no other
likely pathogen identified.
Antibiotics with Gram-negative activity, apart from gentami-
cin, were defined as any antibiotic with clinically relevant activity
against common community-acquired Gram-negative pathogens.
This included ceftriaxone, cefepime, ceftazidime, piperacillin/
tazobactam, ticarcillin/clavulanic acid, ciprofloxacin, meropenem and
moxifloxacin.
Renal function was analysed using serum creatinine and in-
cluded baseline creatinine (lowest of the three most recent creatinine
levels within the 3 months prior to hospital admission), creati-
nine on presentation (±24 h), peak creatinine between Days 3 and
14 of admission, and creatinine on discharge (±24 h). AKI was defined
as a 1.5-fold increase in the serum creatinine from baseline (stage
1 or greater of the modified RIFLE criteria) [19]. Creatinine on pre-
sentation to hospital was used if no baseline creatinine was available.
The primary efficacy outcome was in-hospital mortality. The key
secondary outcome was relapse, defined as at least one of: re-
admission to hospital within the subsequent 6 weeks attributable
to CAP; or a new diagnosis of lung abscess or parapneumonic ef-
fusion after Day 7 of admission but before hospital discharge.
2.4. Data management and statistical methods
Data were collected by hand review of medical records as well
as hospital pathology and radiology databases using purpose-
built paper case report forms.
Data were compiled using EpiData v.4.2 (EpiData foreningen,
Odense, Denmark) and were analysed using Stata v.12 (StataCorp,
College Station, TX). Continuous variables were summarised as
mean ± standard deviation (S.D.) and were compared by Student’s
t-test if normally distributed, or were summarised by median
[interquartile range (IQR)] and were compared by Mann–Whitney
U-test if non-normally distributed. Categorical variables were com-
pared using Fisher’s exact test. To adjust for disease severity, a logistic
regression model was built with in-hospital mortality as the de-
pendant variable and gentamicin use and Acute Physiology and
Chronic Health Evaluation (APACHE) II score as the independent vari-
ables. To adjust for receipt of other antibiotics active against Gram-
negative bacteria, APACHE II score in the above model was replaced
with a categorical variable coding for receipt of other antibiotics
active against Gram-negative organisms. A P-value of <0.05 was con-
sidered statistically significant.
3. Results
3.1. Participants
A total of 225 patients were identified by discharge coding as
being admitted to the hospital’s ICU between January 2008 and De-
cember 2015 with a primary diagnosis of community-onset bacterial
pneumonia. After application of the eligibility criteria, 148 partici-
pants were included in the study (Fig. 1). The mean ± S.D patient
age was 64.1 ± 17.6 years and 63% of patients were male. It was a
severely ill cohort, with a median APACHE II score of 21 (IQR 16–
27) and with 43% of patients having septic shock (Table 1).
The majority of the cohort (n = 117) received at least one dose
of gentamicin in the first 72 h of hospital admission, with 31 patients
 ARTICLE IN PRESS
C.J. Brereton et al. / International Journal of Antimicrobial Agents ■■ (2018) ■■–■■ 3

receiving no gentamicin in this time period. These two groups were

well matched in terms of demographics, co-morbidities and disease
severity. Thirty patients (20%) received more than one dose of gen-
tamicin (median number of doses = 1, range 0–5). A causative
organism was identified in 67 patients (45%) (Table 1), with S.
pneumoniae being the most prevalent (27/67; 40%), followed by
H. influenzae (16/67; 24%) and Staphylococcus aureus [9/67 (13%);
methicillin-resistant S. aureus (MRSA) accounted for 2 of the 9 cases].
A Gram-negative pathogen was the causative organism in 18 pa-
tients (27% of the 67 patients with a causative organism identified
and 12% of the overall cohort), with H. influenzae accounting for 16
cases and E. coli the remaining 2 cases. Counterintuitively, the group
that did not receive gentamicin were more likely to have a Gram-
negative causative organism subsequently identified than those in
the gentamicin group (26% vs. 9%; P = 0.01).

3.2. Safety outcomes

Fig. 1. Flow chart of patients included in and excluded from the study (reasons were Seventy-six patients (51%) experienced AKI, but this did not differ
not mutually exclusive). ICU, intensive care unit; CAP, community-acquired pneumonia. between the gentamicin group (60/117; 51%) and the no-gentamicin
group (16/31; 52%) (Table 2). There was no dose–response rela-
tionship between the number of doses of gentamicin received in
Table 1 the first 7 days of hospitalisation and the proportion experiencing
Baseline characteristics according to receipt of gentamicin in the first 72 h of hos- AKI (no doses, 52%; one dose, 46/87 (52.9%), two doses, 5/12 (41.7%),
pital admission. three doses, 5/9 (55.6%), four doses, 3/6 (50.0%), and five doses, 1/3
No Received P-value (33.3%)]. Furthermore, the peak serum creatinine and the propor-
gentamicin gentamicin tion of patients requiring renal replacement therapy did not differ
(n = 31) (n = 117) according to receipt of gentamicin (Table 2).
Demographics
Male sex [n (%)] 16 (52) 77 (66) NS
Age (years) (mean ± S.D.) 61 ± 19 65 ± 17 NS 3.3. Efficacy outcomes
Co-morbidities [n (%)]
Hazardous alcohol use 4 (13) 15 (13) NS There was no significant difference in in-hospital mortality
Smoker 3 (10) 29 (25) NS between those who received gentamicin (20/117; 17%) and those
Chronic lung disease 13 (42) 47 (40) NS
who did not (7/31; 23%) (Table 3). There was also no significant dif-
Immunosuppression 3 (10) 13 (11) NS
Antibiotics in prior 30 days 4 (13) 13 (11) NS ference in any of the secondary efficacy outcomes, including the
Disease severity proportion experiencing relapse and the length of ICU and hospi-
CORB score (mean ± S.D.) 2.3 ± 0.9 2.3 ± 0.9 NS tal stay (Table 3).
APACHE score [median (IQR)] 20 (18–27) 21 (15–27) NS
There was a small but non-significant difference in the propor-
Septic shock [n (%)] 14 (45) 50 (43) NS
Microbiology [n (%)] tion of patients who received concomitant antibiotics active against
Causative organism identified 16 (52) 51 (44) NS Gram-negative pathogens in the gentamicin (56%) and no-gentamicin
Gram-negative causative organism 8 (26) 10 (9) 0.01 (65%) groups. Adjusting for this difference did not affect the effi-
NS, not significant; S.D., standard deviation; CORB, Confusion, Oxygen saturation, cacy outcomes: the raw odds ratio for hospital mortality was 0.71
Respiratory rate, Blood pressure; APACHE, Acute Physiology and Chronic Health Eval- in the gentamicin group compared with the no-gentamicin group,
uation; IQR, interquartile range. and this only changed to 0.74 (with overlapping confidence

Table 2
Safety outcomes according to receipt of gentamicin.

No gentamicin (n = 31) Received gentamicin (n = 117) P-value

AKI in first 7 days [n (%)] 16 (52) 60 (51) 0.90

Peak creatinine (μM/L) [median (IQR)] 143 (71–258) 138 (83–228) NS
New need for RRT [n (%)] 3 (10) 12 (10) NS
Need for RRT persisting at 30 days [n (%)] 2 (6) 2 (2) NS

AKI, acute kidney injury; IQR, interquartile range; NS, not significant; RRT, renal replacement therapy.

Table 3
Outcome according to receipt of gentamicin in the first 72 h of hospital admission.

No gentamicin (n = 31) Received gentamicin (n = 117) P-value

In-hospital mortality 7 (23) 20 (17) NS

Relapse a 4 (13) 19 (16) NS
Length of ICU stay (days) [median (IQR)] 4 (1–6) 3 (1–6) NS
Length of hospital stay (days) [median (IQR)] 9 (6–17) 11 (7–16) NS
Received other Gram-negative cover besides gentamicin [n (%)] 20 (65) 65 (56) NS

NS, not significant; ICU, intensive care unit; IQR, interquartile range.
a Re-admission for pneumonia within 42 days OR new empyema or abscess after Day 7 but before hospital discharge.

Please cite this article in press as: Christopher J. Brereton, et al., Is gentamicin safe and effective for severe community-acquired pneumonia? An 8-year retrospective cohort study,
International Journal of Antimicrobial Agents (2018), doi: 10.1016/j.ijantimicag.2018.01.018
 ARTICLE IN PRESS
4 C.J. Brereton et al. / International Journal of Antimicrobial Agents ■■ (2018) ■■–■■
intervals) after adjustment. Similarly for relapse, the raw odds ratio
was 1.31 in the gentamicin group compared with the no-gentamicin
group, declining to 1.29 after adjustment for APACHE II score and
receipt of other Gram-negative cover. We also adjusted for disease
severity using APACHE II score (a powerful predictor of risk of death)
and found no significant effect on the primary efficacy estimates.
4. Discussion
4.1. Main findings
In this single-centre observational study, use of gentamicin as
part of the empirical treatment regimen in patients with severe CAP
had no significant effect on the incidence of AKI and was associ-
ated with a non-significantly lower chance of in-hospital mortality.
These findings persisted even when adjusting for potential differ-
ences in disease severity and concomitant treatments in the two
groups.
4.2. Comparison with previous literature
In 1991, Collins and Gerding concluded that there was ‘remark-
ably little definitive clinical data in the literature’ to determine the
role of gentamicin either as monotherapy or combination therapy
with a β-lactam in Gram-negative pneumonia [14]. However, there
are strong arguments that once-daily gentamicin dosing protocols
can optimise efficacy while minimising toxicity in these patient
cohorts [15]. We believe this study is the first to compare genta-
micin with other Gram-negative antimicrobials in severe pneumonia
and is intended to re-evaluate the role of aminoglycosides at a time
when they are becoming increasingly sidelined.
This cohort is broadly representative of patients admitted to Aus-
tralian hospitals with severe CAP and is also likely to be applicable
in non-tropical areas globally. Both the proportion with an identi-
fied causative organism and the identified causative organisms in
this cohort are similar to those of other Australian studies [20–22].
Tropical regions have a higher proportion of Gram-negative
pathogens such as Burkholderia pseudomallei (which is inherently
resistant to gentamicin) and Acinetobacter baumannii [23,24] and
hence these results would need to be reproduced in such areas.
However, it is notable that addition of gentamicin to the empirical
CAP treatment regimen in Australia’s Northern Territory was asso-
ciated with a dramatic drop in mortality from severe CAP [25].
4.3. Implications of the findings
The fact that approximately one-half of all of the severe CAP pa-
tients developed AKI was unexpected, but on reflection is explicable
by the illness severity of the cohort: all were admitted to the ICU
and nearly one-half had septic shock. This high incidence of AKI may
in part explain the common misconception that short-course gen-
tamicin is nephrotoxic, a belief that is reinforced every time a patient
who has received one or two doses of gentamicin develops AKI. Such
anchoring bias provides a strong rationale to conduct systematic data
analyses such as the present study.
These data suggest that gentamicin is safe to use for one to three
doses as part of an empirical CAP regimen and that its efficacy is
at least as good as that of other options such as ceftriaxone. This
alone is unlikely to convince clinicians to replace ceftriaxone with
penicillin plus gentamicin in empirical CAP regimens. However, the
antimicrobial stewardship benefits of such a change do provide
strong support for it. The strongest antibiotic association with
hospital-acquired C. difficile infection continues to be third-generation
cephalosporin use [26]. Furthermore, the reliance on carbapenem
class antibiotics in extended-spectrum β-lactamase (ESBL)-producing
Enterobacteriaceae is resulting in more alarming resistance trends
Please cite this article in press as: Christopher J. Brereton, et al., Is gentamicin safe and effective for severe community-acquired pneumonia? An 8-year retrospective cohort study,
International Journal of Antimicrobial Agents (2018), doi: 10.1016/j.ijantimicag.2018.01.018
[27]. Penicillin and gentamicin are associated with much lower risks
of such outcomes [27].
4.4. Strengths and limitations
This is the first published study in over 20 years to address this
question, and we did so using clear pre-specified definitions and
outcome measures at a single centre with a relatively heteroge-
neous patient group. However, observational studies are always
subject to bias from unmeasured confounders and this can only be
fully overcome by conducting RCTs. The high background inci-
dence of AKI in this cohort could have masked a low risk of
gentamicin nephrotoxicity [28]. However, since Gram-negative cov-
erage is only recommended in severe CAP (as opposed to more mild
presentations), the results are relevant to the real-world use of gen-
tamicin in CAP. Finally, we were unable to report ototoxicity in this
study since this is not routinely measured.
4.5. Future directions
The ideal study to address this question would be a RCT where
patients presenting with severe CAP are allocated to either peni-
cillin, gentamicin and azithromycin or to ceftriaxone plus
azithromycin. However, this study design is impractical and un-
likely to ever be conducted. To adequately address the safety and
efficacy of gentamicin, patients in such a study would need to be
screened, consented and randomised within hours of presenting to
the hospital, and ideally before they receive any antibiotic treat-
ment. Since gentamicin is given for empirical cover for 24–48 h only,
even a single dose of either gentamicin or ceftriaxone prior to
randomisation may obfuscate any potential differences between the
two study arms. A larger, prospective observational study would be
the next best thing to augment the data from the present study.
However, in the Australian setting at least, this is unlikely to occur
since the majority of large hospitals in Australia (as well as Aus-
tralia’s national antibiotic guideline [10]) use empirical ceftriaxone
rather than penicillin plus gentamicin.
5. Conclusion
This study suggests that gentamicin may be at least as safe and
effective as alternate Gram-negative cover in the initial empirical
treatment of adults with severe CAP. In the context of worsening
global antimicrobial resistance, further studies are urgently needed
to address this need.
Acknowledgments
JSD received salary support from Australia’s National Health and
Medical Research Council [Career Development Fellowship
#1083105].
Funding: None.
Competing interests: None declared.
Ethical approval: This study was approved by the Hunter New
England Human Research Ethics Committee (NSW, Australia) [NSW
HREC no. LNR/16/HNE/201].
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