Amikacin to achieve clinical cure in adults with gram negative infections. Are therapeutic
levels associated with effectiveness and adverse effects?
Jenkins A, Thomson A, Brown B, Semple Y, Sluman C, MacGowan A, Lovering A and Wiffen P. on
behalf of the BSAC Working Party on Therapeutic Drug Monitoring.
Background
Five aminoglycosides are listed in the British National Formulary for clinical use in the UK: amikacin,
gentamicin, neomycin (only topical), streptomycin (mainly for tuberculosis) and tobramycin.1 All
systemically administered aminoglycosides have a narrow therapeutic window and there is wide
variability in the relationship between the dose and the measured plasma level. Not all of this
variability can be explained by clinical factors, such as renal function and the physiological changes
that occur in sepsis. Consequently, over the last forty years, therapeutic drug monitoring (TDM) has
been an integral part of the management of patients during treatment with an aminoglycoside.
TDM has helped to reduce the incidence of adverse events seen with this class of antibacterial, and
in the UK most patients receiving more than a few days of therapy with such agents will have their
plasma level monitored by TDM.
Although historically there has been a consensus on the general objectives of TDM for
aminoglycosides, at present there are almost no evidence-based guidelines, and in a number of
areas there is wide international variation and controversy. Since the mid-1990s, there has been a
general trend towards the use of once daily administration for aminoglycosides and much of the
usage in the UK is on this basis.
One of the frequently monitored aminoglycosides for which there is a pressing need for clear
guidance is amikacin. From an extensive search, there is only one systematic review which
compares once daily dosing with multiple daily dose administration.2 Despite the lack of high
quality evidence to support dosage recommendations, there are several recent national guidelines
that include specific amikacin TDM regimens. This review will cover the scientific basis for both the
dosing and TDM of amikacin and compare this with current practice within the UK.
Objectives
To identify for amikacin the therapeutic regimens and drug concentrations that are consistent with
a good therapeutic outcome and to determine the drug exposures that are related to the adverse
events of nephrotoxicity and ototoxicity.
Methods
This literature review considered TDM and dose adjustment for amikacin as a single agent.
Comparators could be single or combination agents or different treatment durations or regimens.
The inclusion criteria comprised adults with Gram-negative infections treated with amikacin and
aged 18 and above. Renal impairment was defined as an eGFR of <60 ml/min. Data from patients
with cystic fibrosis, pregnancy, burns or mycobacterial infections were excluded.
Included studies in this literature review were randomised control trials (RCT), controlled clinical
trials (CCTs), interrupted time series with at least three data points before and after implementation
of the intervention (ITS) and controlled before and after studies (CBA). Full journal publication was
also required. The primary and secondary outcomes considered in the review are listed in Table 1.
Table 1: Primary and secondary outcomes of the literature review on amikacin TDM
Primary Outcomes
Secondary Outcomes





Therapeutic cure defined as reduction of fever,
improvement in clinical signs, or reduction in
inflammatory response.
Adverse events defined as toxicity seen as
nephrotoxicity and ototoxicity (auditory or
vestibular). Nephrotoxicity to be defined as mild,
medium or severe using the RIFLE criteria
TDM results as blood levels reported for cure
TDM results for nephrotoxicity measured by
serum creatinine and/or eGFR
Ototoxicity as a report





Serious adverse events or death due to all causes
28 day mortality
Other adverse events as reported in the included
studies
Length of hospital stay
Change in antimicrobial therapy to an alternative
agent
Searches were conducted in Medline, EMBASE and the Cochrane Central Register of Controlled
Trials (CENTRAL), published in The Cochrane Library. The following search strategy was used by
searching in title, abstract and keywords: Amikacin AND (pharmacokinetic* OR pharmacodynamic*
OR efficacy OR resistance OR nephrotoxicity OR ototoxicity OR TDM OR therapeutic drug*
monitoring OR (Antimicrobial-assay*)).
Reference lists of included studies were scanned to identify any further studies that had not been
identified by electronic searching.
Studies meeting the inclusion criteria were identified by two authors (AJ, PW) independently and
any discrepancies were resolved by discussion with other authors. Studies which were excluded
after an initial sorting were recorded with a brief description of the reason for exclusion. Studies
were restricted to those in the English language. A data extraction form was developed to facilitate
the collection of data from each of the included studies.
Two authors independently assessed the risk of bias for each study and the Cochrane Risk of bias
tool for randomised controlled trials was adapted for this review.3 Each study was assessed for
selection, detection and attrition biases and also possible biases confounded by small size and
sponsorship. Additional information can be found in the supplementary information to this article.
Results
The literature search was initially run in 2013 and updated in June 2015 when no new included
studies were identified. A PRISMA flow chart is presented in Figure 1.
We identified 17 included studies (22 reports) comprising 1677 participants. The date of publication
ranged from 1977 to 2011. In most cases, the duration of study was based on clinical cure or an
observable lack of effect. Amikacin doses ranged from 11-15 mg/kg/day with thirteen studies using
15 mg/kg/day. Further details on the comparators used can be found in table 2.
Table 2: Comparators used in included studies
Doses Used
No. Studies
Studies
Amikacin
11-15 mg/kg/day
6
Dillon 1989 4
Galvez 2011 5
Giamarellou 1991 2
Ibrahim 1990 6
Kiel 2008 7
Maller 1993 8
Gentamicin
1-2 mg/kg
three times
daily
4
Gilbert 1977 9
Holm 1983 10
Lerner 1986 11
Smith 1977 12
Netilmicin
6-7.5 mg/kg/day
Tobramycin
4.5-5.1
mg/kg/day
Cefotaxime
1 g four times
daily
4
Barza 1980 13
Bock 1980 14
Maigaard 1978 15
Noone 1989 16
2
DeMaria 1989 17
Gattell 1983 `18
1
Chen 2005 19
Figure 1
Study Selection flow diagram.
Amikacin as comparator
Although six studies considered amikacin as a comparator, the data in the Kiel paper were not
evaluable due to lack of clarity of the study population, short follow-up time (1.3 days) and a dropout rate of 55%.7 The remaining five studies presented data on 614 randomised patients. Three of
these studies, by Giamarellou, Ibrahim and Maller ) investigated daily doses of 14-14.5 mg/kg and
compared administration in either one or two divided doses.2,6,8
The fourth study, by Dillon, compared the outcomes of 82 patients given standard doses of 7.5
mg/kg twice a day against patients whose dose was modified according to plasma levels.4 The study
found that the difference in clinical cure is 'not significant between standard therapy and
(pharmacokinetic dosing)’ with nephrotoxicity rates quoted at 3/41 and 1/41 for the 'standard dose'
and PK dose respectively.
Finally Galvez presented a pharmacokinetic study in 106 patients of plasma levels measured
following administration of different doses of amikacin. No data on clinical cure or toxicities are
presented except that on nephrotoxicity.5 The paper states 'there is no evidence of renal function
impairment at day 28 (in either study arm)'.
The results of the ‘amikacin as a comparator’ studies with respect to clinical cure and toxicity are
summarised in Table 3.
Table 3: Summary data for studies for clinical cure and toxicity
Clinical Cure
Nephrotoxicity
Auditory Toxicity
Studies Comparing Amikacin Once Daily versus Amikacin Twice Daily
Amikacin: once
141/151 (93.4)
11/212 (5.2)
3/164 (1.8)
daily
Amikacin: twice
132/149 (88.6)
13/199 (6.5)
5/202 (2.5)
daily
1/152 (0.7)
Maller 1993 8
Studies Comparing Amikacin versus Gentamicin
Amikacin
87/110 (79.0)
10/175 (5.7)
Gentamicin
74/96 (77.1)
26/177(14.7)
10/139 (7.2)
10/130 (7.7)
7/121 (5.8)
4/109 (3.7)
Gilbert 1977 9
Holm 1983 10
Lerner 1986 11
Smith 1977 12
Gilbert 1977 9
Holm 1983 10
Lerner 1986 11
Smith 1977 12
Gilbert 1977 9
Holm 1983 10
Lerner 1986 11
Smith 1977 12
17/118 (14.4)
13/128 (10.2)
3/45 (6.7)
1/49 (2.0)
Barza 1980 13
Bock 1980 14
Maigaard 1978 15
Noone 1989 16
Barza 1980 13
Bock 1980 14
Study Comparing Amikacin versus Tobramycin
Amikacin
n/a
7/54 (13.0)
Tobramycin
n/a
4/49 (8.2)
n/a
Gattell 1983 18
Included Studies
2/17 (11.8)
2/19 (10.5)
n/a
n/a
Gattell 1983 18
n/a
Study Comparing Amikacin versus Cefotaxime
Amikacin
11/18 (61.1)
1/18 (5.6)
Cefotaxime
15/19 (78.9)
1/19 (5.3)
Chen 2005 19
Chen 2005 19
Included Studies
n/a
n/a
n/a
n/a
n/a
n/a
Included Studies
10
Holm 1983
Smith 1977 12
Giamarellou 1991 2
Ibrahim 1990 6
Maller 1993 8
1/164 (0.6)
Giamarellou 1991 2
Ibrahim 1990 6
Maller 1993 8
Included Studies
Giamarellou 1991 2
Ibrahim 1990 6
Maller 1993 8
Vestibular Toxicity
Studies Comparing Amikacin versus Netilmicin
Amikacin
88/113 (77.9)
14/157 (8.9)
Netilmicin
85/120 (70.8)
15/162 (9.3)
Included Studies
14
Bock 1980
Noone 1989 16
Barza 1980 13
Bock 1980 14
Maigaard 1978 15
Noone 1989 16
Key: data are presented as number/total number (percentage)
Only the Maller paper presented data on 28 day mortality with 15/316 patients dying during the
study period.8 Two of the studies included data on length of hospital stay and one study discussed
duration of therapy. No significant difference in the length of hospital stay between standard
therapy and pharmacokinetically-based therapy was reported by Dillon.4 Similarly, Tulkens, who
reported results from the study by Ibrahim, found no difference in the duration of treatment of
patients with pelvic inflammatory disease given 15 mg/kg/day in one or two divided doses.6 Data
were not presented on the numbers of patients requiring a change of antimicrobial therapy or on
TDM results relating to cure or nephrotoxicity.
Table 4: Summary data for studies for secondary outcomes
28 day Mortality
Length of Hospital
Stay
Duration of
Therapy
Change to
Alternative
Therapy
Studies Comparing Amikacin Once Daily versus Amikacin Twice Daily
Amikacin: once
8/152 (5.3)
‘No significant
7 days 6
daily
difference’
5.4 days 8
Amikacin: twice
7/164 (4.3)
7 days 6
daily
5.4 days 8
8
4
Maller 1993
Dillon 1989
Ibrahim 1990 6
Included Studies
Maller 1993 8
Studies Comparing Amikacin versus Gentamicin
Amikacin
13/39 (33.3)
Gentamicin
6/32 (18.8)
Smith 1977 12
Included Studies
Studies Comparing Amikacin versus Netilmicin
9/35 (25.7)
Amikacin
Netilmicin
Included Studies
6/36 (16.7)
Bock 1980 14
‘No significant
difference’
Lerner 1986 11
Smith 1977 12
11.5 days 14
10.4 days 16
11.7 days 14
8.5 days 16
Bock 1980 14
Noone 1989 16
0/35
1/36
Bock 1980 14
Study Comparing Amikacin versus Tobramycin
Amikacin
4/54 (7.4)
8.5 days
Tobramycin
2/59 (3.4)
8.3 days
Included Studies
Gattell 1983 18
Gattell 1983 18
Study Comparing Amikacin versus Cefotaxime
Amikacin
4/19 (21.1)
13 days
Cefotaxime
4/18 (22.2)
12 days
19
Included Studies
Chen 2005
Chen 2005 19
Key: data are presented as number/total number (percentage)
Gentamicin as comparator
Four studies with a total of 342 patients were identified in which gentamicin was used as the
comparator. Two of the studies (by Holm and Lerner) included 146 patients with infections 'likely to
require an aminoglycoside' and a third, Smith 1977, studied 71 patients with Gram negative sepsis.
The final study by Gilbert followed 30 patients with urinary tract infections (UTI).10,11,12
Gilbert only reported data on bacteriological response rather than clinical cure therefore data from
this study were only included in the toxicity calculations and not the 'cure' calculations.9
Lerner did not present any cure data and therefore cannot be included in this analysis.11 The results
of the gentamicin comparator studies are summarised in Table 3.
Twenty eight day mortality was only reported by Smith with 13/39 and 6/32 dying whilst receiving
amikacin and gentamicin therapy respectively.12 Although none of these papers consider length of
hospital stay, both Lerner and Smith present data indicating that there was no significant difference
between the durations of therapy with amikacin or gentamicin.11,12 Data on the numbers of patients
requiring a change of antimicrobial therapy or TDM results relating to cure or nephrotoxicity are not
presented.
Netilmicin as comparator
Four studies, including 229 patients, were found which included netilmicin as a comparator (Barza
1980, Bock 1980, Maigaard 1978 and Noone 1989).13,14,15,16 Two of these studies (Barza 1980 and
Bock 1980) recruited a total of 161 patients with 'serious infections'; Noone 1989 included patients
with Gram negative sepsis whilst Maigaard studied patients with complicated UTIs.13,14,15,16
Summary data for the four studies is presented in tables 3 and 4.
Data from two studies were not evaluable for clinical cure; Barza combined outcome data for the
two aminoglycosides whilst Maigaard reported on bacteriological cure in patients with UTIs.13,15
Vestibular toxicity outcomes were not reported in the Maigaard and Noone studies.15,16
Twenty-eight day mortality was reported only by Bock.14 The Barza paper reported one death
during the study however it is not made clear which study arm this occurred in.14 Length of hospital
stay was not reported in any of the studies. Papers by Bock and Noone reported mean duration of
therapy (table 4).14,16 Both papers suggest that their observed differences may simply reflect
differences in the type of infections between the two study arms.
Only the study by Bock mentions a patient who required an alternative antibiotic due to treatment
failure with netilmicin.14 None of these papers presented specific data on TDM results related to
cure or nephrotoxicity, however, the Bock paper does mention that the 'TDM results are not related
to nephrotoxicity'.14
Tobramycin as comparator
Two of the included studies had tobramycin as a comparator (DeMaria and Gatell) but the data
presented by DeMaria were not evaluable since the authors combined the results of the tobramycin
and amikacin arms.17,18 Gatell presented data on 157 patients with a suspected sepsis, urinary or
biliary tract infection or pneumonia.18 Clinical cure and toxicity data are presented in table 3. Two
patients in each of the amikacin and tobramycin groups died during the study.
Secondary outcome data is presented in table 4. No data were reported for length of hospital stay,
change of antimicrobial therapy or TDM results for cure or nephrotoxicity.
Cefotaxime as comparator
Chen reported results from 37 cirrhotic patients with spontaneous bacterial peritonitis (table 3).19
Deaths occurred in 5/18 patients treated with amikacin and 4/19 patients treated with cefotaxime.
Secondary outcome data are presented in table 4. No data are reported on changes in antimicrobial
therapy or relationships between TDM and either cure or nephrotoxicity.
Excluded Studies
Twenty eight studies were excluded. Reasons for exclusion can be found in “Characteristics of
excluded studies” in the supplementary information to this paper.
Risk of bias (Figure S2)
Allocation (selection bias): Only Kiel study used a quasi-random method.7 The remaining studies did
not describe the method of randomisation. Galvez described the method of allocation concealment,
the Kiel study could not be concealed and the remainder did not describe any allocation
concealment. 5,7
Blinding (performance bias and detection bias): Thirteen of the 17 studies did not have any form of
blinding. Chen 2005 does not state whether there was blinding of treatment given to patients or
clinicians. Three studies were blinded however Lerner states that the study was blinded but gives
no further details. In Gatell the assessor was blinded whilst in Smith neither the assessor nor the
patients knew which drug had been given.12,18
Incomplete outcome data (attrition bias): In eleven studies there was no evidence that the reporting
of outcome data was incomplete.
Size: Two studies by Maller and Noone were considered to be at low risk of bias with greater than
200 participants.8,16 Studies by Chen, Gilbert, Ibrahim and Kiel were considered to be at high risk
with less than 50 participants.6,7,9,19 The remainder were unclear with participation of between 50
and 199.
Other biases: Studies by Bock, Giamarellou, Ibrahim and Maller were supported by pharmaceutical
industry funding. 2,6,8,14
Effects of interventions
Of the 15 evaluable papers three reported data solely on non-bacteraemic patients suffering from
either pelvic inflammatory disease (Giamarellou), urinary tract infections (Ibrahim) or ‘infections at
various local sites’ (Maigaard). 2,6,15
Ten papers reported on clinical cure however the data from two of the papers are not evaluable due
to pooling of results (Barza and Dillon).2,4,6,8,10,12,13,14,16,19 Table 5 shows the calculated rates of
clinical cure and toxicities in the included and evaluable studies for amikacin.
Table 5: Rates of Clinical Cure and Toxicities in Patients Receiving Amikacin across the Included and
Evaluable Studies
Cure or Toxicity Rate
No. Studies Presenting Data Incidence (%)
Clinical Cure
8
449/543 (82.7)
Nephrotoxicity
15
60/1024 (5.9)
Auditory Toxicity
12
49/690 (7.1)
Vestibular Toxicity
8
9/448 (2.0)
Amikacin concentrations
Serum levels of amikacin were monitored in all 15 of the papers with evaluable data. In eleven
papers therapeutic drug monitoring was undertaken, that is amikacin doses were modified in
response to serum concentration measurements in order to achieve levels within a pre-defined
range.2,4, 8,10, 11, 12,13, 14,16, 18, 19 The Dillon paper presents data from a study where patients were
divided into two arms.4 In the first arm doses were modified in response to serum amikacin levels
and in the second arm doses remained unchanged. In four papers, levels were measured but no
action was taken as a result.5,6,9,15
Nine of the evaluable 15 papers present data from 1,045 participants on target plasma amikacin
levels, rate of clinical cure and toxicity.2,6, 8,10, 12, 14, 15,16,19 Data presented however does not confirm
whether these target levels were achieved and if so for how long. In two of the papers levels were
only measured and doses were not amended in response to these levels.6,15
Table 6: Dosage regimens, efficacy and toxicity measures from studies that include target amikacin
concentrations
Author
Bock 1980 4
Chen 2005 19
Giamarellou 1991
2
Holm 1983 10
Dose
7.5 mg/kg bd
then tailored
500 mg daily then
tailored
7.5 mg/kg bd or
15 mg/kg od then
tailored
7.5 mg/kg bd
then tailored
Clinical Cure
Nephrotoxicity
Ototoxicity
14/33 (42.4)
8/29 (27.6)
7/29 (24.1)
11/18 (61.1)
3/18 (16.7)
NR
Trough <30
52/60 (86.7)
4/60 (6.7)
2/60 (3.3)
Trough <5
Peak >40
97/111 (87.4)
3/49(6.1)
3/38 (7.9)
Ibrahim 1990 6
14 mg/kg daily or
7 mg/kg bd not
tailored
40/40 (100)
0/20 (0)
10/20 (50.0)
Maigaard 1978 15
7.5 mg/kg bd not
tailored
16/28 (57.1)
0/28 (0)
0/28 (0)
181/200 (90.5)
20/311 (6.4)
5/316 (1.6)
74/82 (90.2)
4/96 (4.2)
7/53 (13.2)
20/39 (51.3)
9/62 (14.5)
2/34 (5.9)
Maller 1993 8
Noone 1989 16
Smith 1977 12
15 mg/kg daily
then tailored
7.5 mg/kg bd
then tailored
8 mg/kg initially
then tailored
Target Serum
Concentration
(mg/L)
Trough <5
Peak 15-25
Trough <10
Peak <35
Levels measured but
no TDM
Pre-dose (4.4-5.1)
Post dose (29.032.6)
Levels measured but
no TDM
Peak od (49-7-53.1)
Peak bd (23.5-25.3)
Trough od <5
Trough bd <10
Trough <10
Peak 20-30
Peak 20-40
Key: od, once daily dosing, bd twice daily dosing. Data are presented as number/total number
(percentage)
Discussion
This systematic review found little published evidence to support dosage regimens and TDM targets
for amikacin therapy. Although several studies were identified that met the inclusion criteria, they
were typically designed to compare different aminoglycosides, rather than to examine the impact of
dosing regimens and TDM on outcomes and toxicities. Even those studies which compared once and
twice daily amikacin dosage regimens provided little information on the value of TDM.
The review aimed to focus on proven gram negative bacteraemia however most studies included
patients with a variety of infections and a mixture of suspected and proven bacteraemias. Clinical
cure rates were generally high and amikacin was found to be at least equivalent to that of other
aminoglycosides, depending on organism sensitivity. However, caution needs to be applied when
comparing data on the treatment of urinary tract infections with those on other infections, due to
potential differences in clinical response to plasma concentrations for antibiotics that are renally
excreted, leading to high concentrations in urine.
Another clear finding was that amikacin is associated with nephrotoxicity and ototoxicity,
particularly auditory toxicity. Interestingly, the reported incidence of auditory and vestibular
toxicities was at least comparable to, if not higher than, the reported incidence of nephrotoxicity in
many studies. However, no conclusions can be drawn about the toxicity of amikacin relative to
other aminoglycosides since that was outside the scope of this review and relevant data are
therefore likely to be missing. Furthermore, wide variations in individual study characteristics
regarding the definition of nephrotoxicity, assessment of ototoxicity, duration of therapy,
concurrent medication and overall aminoglycoside exposure confound the interpretation of
incidence rates for toxicities.
This review originally planned to examine patients >75 years old or with an estimated creatinine
clearance <60 mL/min as a separate group. However, none of the included studies characterised
these patients separately and exclusion criteria varied widely, ranging from creatinine
concentrations >180 micromol/L to patients receiving dialysis.
Most studies did not include any commentary on dosing in patients with altered pharmacokinetics
or body habitus. Only one study specified the use of LBW for dosing purposes.14 One study
examined patients with liver cirrhosis, which is likely to have additional effects on drug handling.19
Most of the included studies were published before once daily dosing of aminoglycosides became
routine clinical practice, therefore most target ranges relate to doses of 7.5 mg/kg every 8-12 hours.
Target peak concentrations ranged from 10 – 40 mg/L 1 hour after an IM injection or 20 to 30
minutes after a 20 or 30 minute IV infusion; most target trough concentrations were either <10
mg/L or <5 mg/L, with the exception of one study which used a value of <30 mg/L.19 Although
concentrations were measured using a range of different assay techniques, measured peak
concentrations with twice daily dosing averaged around 28 mg/L and troughs around 5 mg/L.
Target plasma concentrations for once daily dosing were identified in two studies.2,8 Both aimed for
trough concentrations of <5 mg/L, whilst Giamarellou also examined the incidence of peaks >40
mg/L.2 Measured peak and trough concentrations with once daily dosing averaged 40-45 mg/L and
1-2 mg/L, respectively.
Although mean values were reasonably consistent with the proposed target ranges for once and
twice daily dosage regimens, individual measured concentrations were very variable, ranging from
12 to 127 mg/L for peak concentrations and 1 – 74 mg/L for trough concentrations. It is likely that
this variability in reported concentrations reflected the use of fixed dose regimens in patients whose
renal function covered a wide range. Only one study provided specific dose adjustments for renal
impairment.8 However, in contrast with current practice for gentamicin dosing, they modified the
dose rather than the dosage interval. In this study, seven of the nine patients on once daily dosing
and nine of the eleven patients on twice daily dosing with reported nephrotoxicity had measured
trough concentrations > 5 mg/L.8
Conclusions
In conclusion, this systematic review has demonstrated that there are insufficient data to support
evidence-based guidelines for amikacin dosing and TDM. Only two of the seventeen included papers
had more than 200 participants whilst four papers had less than 50. With most papers presenting
data on small groups of participants, the potential for bias is high. Furthermore, studies frequently
did not describe how randomisation was achieved and were often not double blind. At present, the
use of alternative approaches, such as expert opinion and a review of current practice in the UK, will
be required to develop guidelines to maximise therapeutic outcomes and minimise toxicity with
amikacin.
Further research would enable evidence based guidelines to be developed in the future. Such
studies need to report individual patient data to enable intra and inter-patient variations in doseresponse and dose-toxicity relationships to be viewed and evaluated through pharmacokinetic/
pharmacodynamic modelling. Furthermore, a standard approach to TDM studies is required, which
specifies participants, indications, dosage regimen, target levels, outcomes in terms of clinical cure
and relevant adverse effects.
Acknowledgements
BSAC funding
Contributions of authors
AJ undertook the data extraction, wrote the initial draft of the review, and produced the tables. PW
wrote the protocol with NB and this was approved by a clinical guideline group. He was involved
with the data extraction and writing the review. AT wrote the discussion with the support of YS and
CS. All authors agreed the final draft.
Declarations of Conflicts of Interest
AJ, AL, AM, AT, CS, NB, PW and YS have no conflicts related to this literature review.
Differences between protocol and review
In the protocol a lower age range of 18 years was specified, however three studies included
participants of 16 or 17 years old.6,9,10 We also included all infections rather than simply
'bacteraemia'
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