Jenkins A, Thomson A, Semple Y, Brown NM, Sluman C, Lovering A, Macgowan AP, Wiffen P

Supplementary Data

Literature Review Protocol

Title:Amikacin as a sole agentto achieve clinical cure in adults with gram negative blood stream infections. Are therapeutic levels associated with effectiveness and adverse effects?

Jenkins A, Thomson A, Semple Y, Brown NM, Sluman C, Lovering A, MacGowan AP, Wiffen P.

1. Background

1.1 Description of the problem

For over forty years, therapeutic drug monitoring (TDM) has been an integral part of the management of patients receiving aminoglycoside antibacterials. The use of 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 treatment controlled by TDM.

Although historically there has been a consensus on the general objectives of TDM for aminoglycosides, this does not include all indications for these agents and in practice there is a degree of variability in approach to TDM. At present, despite the widespread use of TDM, 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. Currently most adult patients receive 5-7 mg/kg per day of gentamicin, with TDM objectives based around maintaining a pre dose concentration below 1 mg/L. The means by which this is achieved may vary between centres, with approaches based on timed samples with nomograms or baysian pharmacokinetics or just pre dose samples the most commonly used approaches.

1.2 Description of the intervention

The aminoglycoside class of antibiotics consists of a number of different drugs. Five aminoglycosides amikacin,gentamicin,neomycin (only topical), streptomycin (mainly for tuberculosis) and tobramycin are listed in the British National Formulary for clinical use in the UK. There is a significant variability in the relationship between the dose administered and the plasma level that can be measured in blood, due to factors like renal function and physiological changes that occur in sepsis.As these agents have a narrow therapeutic window, therapeutic drug monitoring(TDM) is considered necessary to ensure the correct dose is used.

1.3 Why it is important to do this review

This review will cover two frequently monitored agents for which there is a pressing need for clear guidance. In particular to review the scientific basis for both the dosing and TDM of amikacin and gentamicin and compare this with current practice within the UK. From this, a working party will draw up evidence-based guidelines on the use and control of these agents and provide recommendations that may be adopted into antibiotic policies within individual hospitals. From an extensive search there is only one systematic review of amikacin comparing once daily with multiple dose administration. No systematic reviews of gentamicin were identified and yet there are several recent national guidelines that include specific TDM regimens without any apparent high quality evidence to support these recommendations.

1. Objectives

For the two aminoglycosides, to identify therapeutic regimes 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.

1. Methods

3.1 Criteria for considering studies for this review

3.1.1. Types of studies

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), controlled before and after studies (CBA). Full journal publication is also required.

3.1.2. Types of participants

Adults with proven gram-negative bacteraemia treated with one of two aminoglycosides (amikacin or gentamicin), aged 18 and above. Participants who are over 75 years, or who have renal impairment will be included but analysed as a sub group. Renal impairment will be defined as an eGFR of <60ml/min.

The following participants will be excluded:), cystic fibrosis, pregnancy, burns or mycobacterial infections.

3.1.3 Types of interventions

Therapeutic drug monitoring (TDM) and dose adjustment for aminoglycoside drugs- gentamicin and amikacin as a single agents. (This will mean two reviews- one for each drug.)

Comparators- single or combination of agents or different durations of treatment. (Combination therapy arms will not be analysed but may have useful data from a single agent arm comparator)

3.1.4 Types of outcome measures

3.1.4.1 Primary 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. 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

3.1.4.2 Secondary outcomes

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.

3.2 Search methods for identification of studies

3.2.1 Electronic searches

Searches will be conducted in Medline, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL), published inThe Cochrane Library

The following search strategy will be used by searching in title, abstract and keywords

#1. / Aminoglycoside* (or: gentamicin, amikacin).
#2. / Pharmacokinetic*
#3. / Pharmacodynamic*
#4. / Efficacy
#5. / Resistance
#6. / Nephrotoxicity
#7. / Ototoxicity
#8. / TDM
#9. / (Therapeutic drug* monitoring
#10. / (antimicrobial assay*)
#11. / (#2 OR #3 OR #4 OR #5 OR #6 OR 7 OR #9 OR #10 )
#12. / (#1 AND #11)

3.2.2. Searching other resources

Reference lists of included studies will be scanned to seek to identify further studies not identified by electronic searching.

3.3 Data collection and analysis

3.3.1 Selection of studies

Studies meeting the inclusion criteria will be identified by two authors (initials) independently and any discrepancies resolved by discussion with other authors. Studies which are excluded after an initial sorting will be recorded with a brief description of the reason for exclusion. Studies will be restricted to English language only.

3.3.2 Data extraction and management

A data extraction form will be developed to facilitate the collection of data from each included studies. Data extraction will include the following information:

• Lead author and date of publication, dates that the study was conducted
• Participant details including numbers, age, gender mix, condition
• Setting and geographical location
• The dose used, frequency of dose and length of treatment
• Numbers of participants with therapeutic cure
• Numbers of participants with adverse events
• Methods for TDM, including assay and control approaches
• Detection of significant under/over dosing with each aminoglycoside
• Record of dose or exposure (AUC) and outcome
• Record of dose or exposure (AUC) and toxicity
• Dosing and TDM in therapeutic cure
• Dosing and TDM in participants with adverse events of nephrotoxicity and ototoxicity
• Dosing and TDM in renal impairment or altered pharmacokinetics
• Time of TDM
• Time of report of cure and toxicity

3.3.3. Assessment of risk of bias in included studies

Assessment of risk of bias in included studies

Two authors independently assessed risk of bias for each study and the Cochrane Risk of bias tool for randomised controlled trials was adapted for this review.3

1. Random sequence generation (checking for possible selection bias). We assessed the method used to generate the allocation sequence as: low risk of bias (any truly random process, e.g. random number table; computer random number generator); unclear risk of bias (method used to generate sequence not clearly stated). Studies using a non-random process (e.g. odd or even date of birth; hospital or clinic record number) will be excluded.
2. Allocation concealment (checking for possible selection bias). The method used to conceal allocation to interventions prior to assignment determines whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We assessed the methods as: low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes); unclear risk of bias (method not clearly stated). Studies that do not conceal allocation (e.g. open list) were excluded.
3. Blinding of outcome assessment (checking for possible detection bias). We assessed the methods used to blind study participants and outcome assessors from knowledge of which intervention a participant received. We assessed the methods as: low risk of bias (study states that it was blinded and describes the method used to achieve blinding, e.g. identical tablets; matched in appearance and smell); unclear risk of bias (study states that it was blinded but does not provide an adequate description of how it was achieved). Studies that were not double-blind were excluded.
4. Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data). We assessed the methods used to deal with incomplete data as: low risk (< 10% of participants did not complete the study and/or used ‘baseline observation carried forward’ analysis); unclear risk of bias (used 'last observation carried forward' analysis); high risk of bias (used 'completer' analysis).
5. Size (checking for possible biases confounded by small size). Small studies have been shown to overestimate treatment effects, probably because the conduct of small studies is more likely to be less rigorous, allowing critical criteria to be compromised.20,21,22 Small studies with limited data are subject to large chance effects.23 Studies were considered to be at low risk of bias if they had 200 participants or more, at unclear risk if they had 50 to 200 participants, and at high risk if they had fewer than 50 participants.
6. Other bias. We identified studies that were sponsored by the Pharmaceutical industry. Any other biases will be noted.
7. For ITS and CBA studies we will use the revised EPOC risk of bias tool.24 We will score each study for risk of bias as 'Low' if all criteria were scored as 'Done', 'Medium' if one or two criteria were scored as 'Unclear' or 'Not Done', and 'High' if more than two criteria were scored as Unclear' or 'Not Done'.

3.4Reporting of Results

Details of included studies will be recorded in a characteristics of included studies table based on the data extracted. Those studies which were considered but excluded will be listed in an ‘excluded studies’ table together with a brief explanation of the reason for exclusion.

3.5 Measurement of treatment effects

Where data permit, we will calculate numbers needed to treat to benefit (NNTB) as the reciprocal of the absolute risk reduction (ARR). For unwanted effects, the NNT becomes the number needed to treat to harm (NNH) and is calculated in the same manner. We will use dichotomous data to calculate risk ratio (RR) with 95% confidence intervals (CI) using a fixed-effect model unless significant statistical heterogeneity is found (see below).

If data permit, we plan to analyse according to therapeutic cure and separately for adverse events. We will use a fixed-effect model for meta-analysis; a random-effects model will be used if there is significant clinical heterogeneity and it is considered appropriate to combine studies. In addition we will record therapeutic drug concentrations together with overall results for cure and adverse effects. An intention to treat analysis will be conducted if data permit.

A summary of findings table for the main outcomes will be presented.

Where data are not available for analysis a description of the findings will be presented

3.6 Sub group analysis

Participants who are over 75 years, or who have renal impairment will be included but analysed as a sub group.

3.7 Assessment of heterogeneity

We will deal with clinical heterogeneity by combining studies that examine similar conditions. We will assess statistical heterogeneity visually and with the use of the I² statistic.25 When I² is greater than 50%, we will consider possible reasons.

1. Acknowledgements

Vittoria Lutje was commissioned by BSAC to complete the searching for studies

1. Contributions of authors

All authors contributed to the design of the review

PW wrote the first draft of the protocol and all authors agreed the final draft

1. Declarations of interest

NMB has served on an advisory board for Discuva Ltd.

PW.Manages his own business, Oxford Systematic Review Services which received some payment for involvement with this review.

1. Sources of support

This work has been supported by funds approved by the board of the British Society of Antimicrobial Chemotherapy.

Final version September 2014

Characteristics of Included Studies

Barza 198013

Methods / Prospective, randomised study
Participants / 90 participants with serious Gram negative infections.
Ages of participants not documented.
Pre-treatment renal function of participants is not documented and renal impairment is not an exclusion factor.
Interventions / Amikacin 5mg/kg every 8 hours or netilmicin 2.5mg/kg every 8 hours, usually reduced to 2mg/kg every 8 hrs within 2 days.
Actual body weight was used to calculate dose
Outcomes / Efficacy data not clear.
Nephrotoxicity (assessed in 32 amikacin and 37 netilmicin pts). Increase creatinine due to amikacin (4), nephrotoxicity due to netilmicin (3) - one of these considered to be due to antibiotics.
Auditory toxicity (assessed in 15 amikacin and 19 netilmicin pts): amikacin (4) and netilmicin (3).
Vestibular toxicity: (3/16 and 0/15)
Notes / TDM levels: amikacin peak 15-25µg/ml, netilmicin peak 6-9µg/ml.
Timing of peak levels not given.
17/90 bacteraemia patients. Unable to separate these patients.
Duration of therapy not documented.

Bock 1980 14

Methods / Prospective randomised study
Participants / 80 participants with serious Gram negative infections.
Mean ages were for amikacin 58.5years +/- 11.2 years and for netilmicin 64years +/- 12.2 years.
Renal impairment was not an exclusion criteria.
Interventions / Amikacin 7.5mg/kg bd or netilmicin 2-2.5mg/kg then 2mg/kg every 8 hours. Lean body weight was used for dose calculations.
Outcomes / Clinical evaluation (35,36): cure (14,17), improve (12,13), fail (7,4).
Nephrotoxicity (29,34): definite (1,6), possible (2,4), doubtful (8,13).
Ototoxicity (23,29): definite (6,1), possible (0,1)
Np pts had vertigo or tinnitus.
Notes / TDM levels: amikacin trough ≤ 5µg/ml peak 15-25µg/ml. Netilmicin trough ≤2µg/ml peak 4-8µg/ml.
Trough levels were taken 30 minutes pre-dose whilst peak were taken one hour after the infusion.
Mean duration of therapy for amikacin 11.5days+\- 6.88days and for netilmicin 11.1 days +\- 12.2 days.

Chen 2005 19

Methods / Prospective study
Participants / 45 participants with cirrhosis followed by a spontaneous bacterial peritonitis. Mean age for amikacin group 54 years +/- 17 years and for netilmicin 58 years +/- 11 years.
Patients with a serum creatinine greater than 2mg/dl were excluded from the study.
Interventions / Amikacin 500mg daily ( or 8mg/kg if body weight was less than 60 kg) or cefotaxime 1g qds
Outcomes / Clinical outcomes (18,19): cure (15,11), infection related-mortality (0,3).
Nephrotoxicity (18,19): renal impairment (2,2), nephrotoxicity (1,1).
Notes / TDM levels: trough≤30µg/ml. Timing of samples taken for trough levels is not documented.
No bacteraemia patients.
Antibiotics were administered for up to five days.

DeMaria 1989 17

Methods / Randomised, prospective, non-blinded study
Participants / 122 participants with sepsis or serious Gram negative infection. Only 10 participants received amikacin.
Age for participants for the aminoglycoside group 59.5 years +/-19.1years and for aztreonam 56.8 years +/- 22.5 years.
Particpants with a serum creatinine greater than 2mg/dl were excluded.
Interventions / Participants on ITU received amikacin, those elsewhere received tobramycin.
Amikacin 15mg/kg/day or tobramycin 4.5mg/kg/day or aztreonam 1-2g every 8 hours. Dose were calculated using actual body weight.
The mean duration of therapy was 7.7days for the aminoglycosides and 9.4days for aztreonam.
Outcomes / Data for amikacin and tobramycin pooled- no evaluable data.
Notes / TDM levels: amikacin trough 5-10µg/ml peak 20-30µg/ml, tobramycin trough ≤2µg/ml peak 5-10µg/ml.
Samples were taken for trough levels at 30 minutes before the next dose and peak levels were taken one hour post-dose.
Amikacin not analysed separately- no evaluable data.
No bacteraemia patients.

Dillon 1989 4

Methods / Prospective, randomised, open study.
Participants / Not clearly stated.
Mean ages of the PK and standard dose groups were 45.0years (range 18-81) and 49.6 years (range 23-80) respectively.
Patients with a serum creatinine greater than 1.5mg/dl were excluded.
Interventions / Amikacin 7.5mg/kg of ideal body weight bd or amikacin doses amended to retain levels within recommended limits
Outcomes / Differences between groups for cure, duration of stay and duration of therapy were not significant.
Nephrotoxicity: PK group (3), standard group (1).
Notes / TDM levels: trough 4-8mg/l peak 25-30mg/l.
Trough levels were taken immediately pre-dose. Peak levels were extrapolated to given peak concentrations at time zero.
Pts not retain within range in standard group were crossed over to PK group.
11/82 had suspected or documented G-ve bacteraemia.
Mean duration therapy for PK dosing 8.9 days +/- 6.4 days and for standard dosing 7.4 days +/- 4.3 days.

Galvez 20115

Methods / Prospective study
Participants / 120 participants with severe sepsis or septic shock.
Mean ages for the groups were 61.4 +/- 11 years, 60.7 +/- 13.4 years and 54.5 +/- 17.1 years.
Interventions / Amikacin 15mg/kg/day or 25mg/kg/day or 30mg/kg/day. Doses were based on actual body weight. If this was not available ideal body weight was calculated.
Duration of therapy was 5 days for the 25 and 30mg/kg/days groups and 10 days for the 15mg/kg/day group.
Outcomes / Amikacin 15, 25 or 30mg/kg/day. Cmax > 60µg/ml (0%, 39%, 76%). Day 28 CrCl 95.6+/- 47.4, 89.7+/-26.6, 56.4+/-18.4ml/min.
Notes / TDM levels: amikacin peak levels were measured one hour post dose.

Gatell 1983 18

Methods / Prospective randomised study.
Participants / 113 participants with suspected sepsis, urinary or biliary tract infection or pneumonia.
Mean ages were for amikacin 58+/- 23.2 years and for tobramycin 59+/- 20.4 years.
Interventions / 7.5mg/kg every 12-24 hours or tobramycin 1.7mg/kg every 8,12 or 24 hours. Actual body weight was used for dose calculations.
Outcomes / Nephrotoxicity in amikacin and tobramycin groups did not differ by age, sex, initial creatinine levels, duration for therapy, total dose, mean levels, concurrent drugs and causative agents. Increase in Cr was similar between the groups.
Nephrotoxicity (54,59): (13%, 6.8%). Patients with other potential causes of acute renal failure were excluded from nephrotoxicity calculations.
Ototoxicity (17,19): (2%,3%)
Notes / TDM levels: trough ≤10µg/ml peak 40µg/ml. Tobramycin trough ≤2µg/ml peak 10µg/ml. Timings of the samples are not documented.
Pts who developed auditory toxicity were significantly older, with an abnormally high trough level. In logistic regression only age was retained as a significant and independent factor for toxicity.
Includes non-bacteraemic patients.
Duration of therapy for amikacin 9.5+/- 3.9 days and for tobramycin 9.4+/-3.8 days.

Giamarellou 1991 2