Antibiotics were revolutionary when they were first introduced and have come a long way since. However, the prescribing of them is not always as straightforward as we may like. In the podcast, I talk to Joy Nicholls, the Antibiotic Pharmacist at Chester, about starting and swapping antibiotics and particulars of Gentamicin and Vancomycin prescribing.

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When a patient is diagnosed with sepsis, by whatever definition you use (see sepsis post and podcast), the pressure is on to administer antibiotics within the first hour (1). Most likely, this will be a broad-spectrum antibiotic initially with a view to rationalise to a more targeted antimicrobial agent once more information is available. The exact antibiotic you start will depend on the situation you are presented with and your local trust/hospital antibiotic policies.

Stewardship

In recent years, antimicrobial stewardship has increased in importance with increasing numbers of resistant microbes and complications associated with antibiotics. This has lead to the “Start Smart, Then Focus” algorithm from Public Health England (2). Every hospital and trust will have an antibiotic stewardship policy to follow. Below is an example of the algorithm.

Start Smart

Start Smart describes general principles that comprise good practice for the initiation of antibiotics.

Policies

Using local policies for prescribing provides a degree of cognitive offload, especially in stressful situations. The more you use them, the more familiar you will become with knowing from memory which treatment to start. I remember in medical school having the answer “I would prescribe antibiotics in line with local policies…..” drilled into me for any question asked about what treatment to start for infections. The reason why different policies exist is that they have taken into account local pathogen patterns and resistances. If you want a quality improvement project to enhance your CV then developing a mobile app so the policy can be available at your fingertips without the need for a computer would be a good idea to investigate.

Indication and Review/Stop Date

The clinical indication is important. Those following you treating the patient need to know why antibiotics were started. If the indication was “sepsis” and the source has been found, it may provide a prompt for rationalising and focussing treatment. As we discuss later in the podcast, some drugs such as Vancomycin have different target concentration levels depending on the indication and without a documented indication, pharmacy have difficulty knowing which level to target.

The review date may be predetermined in electronic systems. If you use hand written prescription charts, either writing or drawing the review date is a visual prompt to others involved in the treatment of the patient. 48-72 hours would be the usual timescale for review. If you need to enter a stop date then the length of treatment will be determined by the condition you are treating. It is worth bearing in mind that if the scheduled stop date is over a weekend or bank holiday, the patient may need review prior to cessation or the length of treatment extending beyond this date.

Cultures

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Taking cultures is good practice because once the information from these is available it allows us to change, if appropriate, to a targeted therapy based on microbial sensitivities. Remember to request cultures for everything that is indicated. This may include urine, sputum, stool, swabs or any other possible source.

Timing

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The timing of antibiotic treatment is generally accepted to be within the the hour or as soon as feasible. The reasoning for this could be considered alongside the time zero for the condition. In myocardial infarctions, we have a clear time zero with the onset of pain or ECG changes. In strokes, the onset of symptoms is time zero. For trauma, time zero is the moment of impact or injury. In sepsis, when did that cough become pneumonia? When did that pneumonia lead to development of septic shock? In the absence of definitive time zero for sepsis and infections, we have no way of truly knowing whether we encounter patients one hour, one day, one week or sometimes one month since their own personal time zero. Evidence exists both strongly for and contrary to early antibiotics (3-5). The absence of an identifiable time zero, I would argue, is in favour of promoting prompt treatment to mitigate risks of mobility and mortality from late treatment. Certainly, the largest dataset I could find including over 28000 patients showed an increase in mortality for every hour antibiotics were delayed (3).

The timing of antibiotic therapy and who can prescribe it has been made less clear by the recent update to NICE sepsis guidelines (1). A recent and lengthy Facebook debate about these guidelines would leave you with the impression that potentially only ST3/registrar level doctors and above can prescribe these. What the guidelines do say, is that a patient identified with sepsis, especially if in the “high risk” criteria (again, see sepsis podcast and post), should be reviewed as soon as possible by a doctor at the level of ST3/registrar or above but responsibility for initiating antibiotics is with the doctor first identifying the patient with sepsis.

Then Focus

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Then Focus describes the process for review of antibiotics 48-72 hours after commencement. This would usually happen as part of a ward round or review. You need to undertake a comprehensive review of the clinical status of the patient and relevant biochemical, radiological and microbiological results. In essence, a good patient review. Following this review, five options are available to you:

  1. Stop – the patient may be fully recovered or have an alternative diagnosis that is not an infection.
  2. IV to oral switch – a patient who is apyrexial, symptomatically improved with improving infective biochemical markers and, importantly, an appropriate oral step down alternative is available.
  3. Change antibiotic – this may be indicated by stasis in clinical condition, deterioration or relevant microbiological evidence of resistance or sensitivities to particular antimicrobial agents. This decision is one that you may want to be discussing with a microbiologist to be sure you get the decision correct. The change may be an alternative IV agent with a broader or narrower spectrum or it could be addition of an extra agent.
  4. Continue – an improving patient who is not quite improved enough to change to oral or with no oral alternative.
  5. Outpatient Parenteral Antibiotic Therapy (OPAT) – at Chester, we have access to a ‘Hospital @ Home’ service. This consists of a team of doctors and nurses who administer treatments and review the patient clinically on a regular basis. Other hospitals I have worked at have provided services for patients to attend a clinic setting to receive IV antibiotics but reside in the community.

It may not be exactly clear what decision to take. Continuing the antibiotics without changing them is an option. Whilst this option exists, be weary of taking it simply because you are unsure and because it allows you to defer the decision to another person or time. Abstaining from making a decision in this manner can masquerade as making a decision but please try avoid doing so. If you are unsure then ask someone else who can provide advice.

 

 

Gentamicin

Image credit: Wikipedia https://en.m.wikipedia.org/wiki/Gentamicin accessed 23:26 on 15/4/17

Gentamicin is a bacteriocidal aminoglycoside antibiotic that binds irreversibly to the 30s subunit of the bacterial ribosome. The indication list is long. Consult your local policies for if it is recommended for your patient.

Different dosing regimes are used (6). 5mg/kg is the higher dose and would typically be given to patients who are relatively fit normally without any renal conditions or at risk factors for renal damage.

3mg/kg would be used for patients with poor renal function or at risk of renal damage. Both of these use ideal body weight (IBW) to calculate the dose in order to avoid overdosing larger patients. An example online calculator can be found here. Your hospital may use a different formula so do check first.

For endocarditis, a 1mg/kg regime may also be used but this is specific to this indication and may not be the first line treatment in your place fo work.

Monitoring of levels can be confusing and differ between places as well. At Chester, for the 3mg/kg regime the first level is taken one hour after administration of the first dose. A second sample is then taken between 6-18 hours afterwards and the exact time the samples are taken needs recording. Joy mentions taking the second sample “one half life” after administration. In patients with impaired renal function this may be prolonged and variable which is why knowing the exact timings of blood samples is important. Pharmacy will use a pharmacokinetics calculator in order to provide an indvidualised regime for the patient. If your hospital also uses a once daily dosing regime, the next dose will be determined and may be prescribed by the pharmacist. If the patient has cleared their first dose effectively then the next dose may be less than 24 hours after the first.

For patients with good renal function who have received a 5mg/kg dose initially, a trough level is needed. This is taken immediately prior to the next dose being given. You may not need to wait for this level before giving the next dose. So long as this “trough” level is <1mg/L, they can continue on the same dose.

If you are unsure at all about the dosing or monitoring of gentamicin then you can hold the next dose whilst you get advice from a pharmacist to be sure the dose is correct.

Vancomycin

Vanco

Image credit:https://www.aliem.com/2013/01/diminishing-returns-vancomycin-and-mic/ accessed 01:46 on 19/4/17

Vancomycin is a glycopeptide antibiotic that acts by inhibiting proper cell wall synthesis in Gram-positive bacteria. It is not effective against Gram-negative bacteria. It is used intravenously except in Clostridium Difficile infections when it is given orally.

It is initially given IV as a loading dose dependent on actual body weight irrespective of renal function (7). Below is an example used at Chester (solution is either 0.9% sodium chloride or 5% glucose) (8):

in 250ml over 120 min

60-90kg: 1500mg in 500ml over 160 min

90kg: 2000mg in 500ml over 210 min

 The maintenance dose is then based upon the patient’s creatinine clearance. Find a calculator here. The creatinine clearance then dictates whether the patient receives a 12 hourls or 24 hourly dose.

There are two therapeutic trough ranges to be aiming for with vancomycin treatment. The lower level of 10-15mg/L is for routine use. The higher level of 15-20mg/L indications may vary from place to place but as a guide, the indications used in Chester (8) are:

Hospital acquired pneumonia

Endocarditis

Orthopaedic infections (e.g. osteomyelitis, septic arthritis, discitis, prosthetic joint infection, infected metalwork)

Osteomyelitis associated with diabetic foot

Staph. aureus and MRSA bacteraemia

Vascular graft infection

Dialysis related fistula/line infection

MRSA colonised patients treated empirically for severe sepsis/ septic shock, cellulitis, or skin and soft tissue infection

Microbiology Consultant recommendation

If you are uncertain which range to be aiming for then discuss with your friendly pharamcist or microbiologist and they will be able to help you.

Samples for serum vancomycin levels need to be immediately pre-dose but you do not need to hold the dose, just take the levels then give the dose.

For the 15-20mg/L, the levels need taking within 48 hours from commencement of vancomycin treatment. If on 12 hourly regimes, this can be before doses 3 or 4. If on a 24 hourly regime, this would be before dose 3.

Those on the lower target range (10-15mg/L) need their levels checking before doses 3, 4 or 5, depending on convenience of sampling.

The timing is very important relative to dose timing. The sample should be taken prior to the dose being given and may not coincide with the phlebotomist doing their rounds on the ward so you do need to be vigilent as to when is the best time to take levels.

Summary

Following antimicrobial stewardship guidelines can help guide rational treatment of patients with infections and keep us thinking about the antibiotics they are on. Try to make considered decisions when starting and reviewing antibiotics and remember the options available to you at these stages, using local policies for your hospital to help select the appropriate treatment.

Gentamicin and Vancomycin can feel complicated in their prescribing. Speak to a pharmacist if you are stuck and remember when the serum levels need taking in order to properly guide treatment.

References

  1. Sepsis: recognition, diagnosis and early management, NICE guideline [NG51], Published date: July 2016. Last updated July 2016
  2. Start Smart, Then Focus: Antimicorbial Stewardship Toolkit for English Hospitals, Public Health England. First Published: 17 November 2011, Upadated: March 2015 
  3. Ferrer R et al, Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program.  Crit Care Med. 2014;42(8):1749-55
  4. Garnacho-Montero J et al, Adequate antibiotic therapy prior to ICU admission in patients with severe sepsis and septic shock reduces hospital mortality. Crit Care. 2015;27(19):302
  5. de Groot B et al, The association between time to antibiotics and relevant clinical outcomes in emergency department patients with various stages of sepsis: a prospective multi-center study.  Crit Care. 2015;29(19):194
  6. BNF April 2017, Section 5.1.4: Aminoglycosides, accessed via www.medicinescomplete.com April 2017
  7. BNF April 2017, Section 5.1.7: Some other antibacterials, Glycopeptides, accessed via http://www.medicinescomplete.com April 2017
  8. Antibiotic Guidelines for the Countess of Chester Hospital, Countess of Chester Hospital, last modified April 2017, accessed April 2017

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