Antibiotics in the ICU - when, what and how?
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A presentation by Fredrik Sjövall at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine. All available content from SSAI2017: https://scanfoam.org/ssai2017/ Delivered in collaboration between scanFOAM, SSAI & SFAI.
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Antibiotics in the ICU - when, what and how?
- 1. Antibiotics in the ICU When, What & How FREDRIK SJÖVALL | INTENSIVE CARE SKANE UNIVERISTY HOSPITAL MALMÖ, FACULTY OF MEDICINE | LUND UNIVERSITY | 2017
- 3. The therapeutic ladder Adapted from Rello et al. 2006 Optimal therapy Non-bacterial effects Adequate therapy Timing, penetration, PK/PD Appropriate therapy in vitro susceptibility
- 4. How to reach optimal antibiotic therapy Immunomodulatory effects Adequate coverage (what) Adequate timing (when - start) Correct route (how) Correct dose, PK/PD (how - much) Correct administration (how) Optimal antibiotic therapy Adequate penetration (what) Adapted from Rello et al. 2006 Adequate duration (when - stop)
- 5. When? Immunomodulatory effects Adequate coverage (what) Adequate timing (when) Correct route (how) Correct dose, PK/PD (how - much) Correct administration (how) Optimal antibiotic therapy Adequate penetration (what) Adequate duration (when - stop)
- 6. Surviving sepsis database Ferrer et al CCM 2014 Aug;42(8):1749-55 ~ 18.000 patients from the SSC database
- 7. As good evidence as it gets The Impact of Timing of Antibiotics on Outcomes in Severe Sepsis and Septic Shock: A Systematic Review and Meta-Analysis Sarah A. Sterling, MD; W. Ryan Miller, MD; Jason Pryor, MD; Michael A. Puskarich, MD; Alan E. Jones, MD Sterling et al Crit Care Med. 2015 Sep; 43(9): 1907–1915.
- 8. < or >3 hours from triage < or > 1 hour from septic shock Sterling et al Crit Care Med. 2015 Sep; 43(9): 1907–1915.
- 9. How - much Immunomodulatory effects Adequate coverage (what) Adequate timing (when) Correct route (how) Correct dose, PK/PD (how - much) Correct administration (how) Optimal antibiotic therapy Adequate penetration (what) Adequate duration (when - stop)
- 10. Physiology alterations effecting PK/PD Low plasma concentrations Increased CO Sepsis Organ dysfunction Decreased clearance High plasma concentrations Elevated clearance Adapted from Roberts et al. 2014 Volume resucitation Capillary leak Altered protein binding Increased Vd
- 11. Effect of different administration regimens on meropenem concentration 2000 - 3000 mg4000 - 6000 mg 2000 mg Sjövall et al in press JAC Lowest required dose to reach 2mg/L
- 12. Empirical or targeted treatment of A. baumanii Sjövall et al in press JAC CrCL = 200 CrCL ≤ 100
- 13. What does this mean? • If in doubt of MDRs and renal clearance • If nice resistance pattern and patients renal function starts to decline
- 14. Augmented renal clearance ~65% of patients manifesting ARC on at least one occasion in the first seven study days. Udy et al Crit Care Med 2014; 42: 520-527
- 15. Who are they? Udy et al Crit Care Med 2014; 42: 520-527 Younger males with a normal creatinine
- 16. Obesity • Increased Volume of distribution • Little effect on PK/PD parameters except: ? Alobaid AS, et al. Antimicrob Agents Chemother 60:4577–4584
- 17. Loading dose The loading does is not effected by renal function!
- 18. Does it help? Leander et al Läkartidningen 2150;112
- 19. Continuous versus Intermittent b-Lactam Infusion in Severe Sepsis A Meta-analysis of Individual Patient Data from Randomized Trials Roberts et al Am J Respir Crit Care Med Vol 194, Iss 6, pp 681–69
- 20. BLING III • Meropenem or Piperacellin/Tazobactam • Intermittent or continous infusion • A sample size of 7,000 (3,500 in each group) is required to achieve 90% power to detect an absolute risk reduction of 3.5% (i.e. a 12.7% relative risk reduction) in 90-day mortality in the intervention group from baseline mortality of 27.5%, with a significance level (alpha) of 0.05.
- 21. Therapeutic Drug Monitoring (TDM) • How many of you perform therapeutic drug monitoring of β- laktams? • Do we need a RCT?
- 22. Conclusions • Start antibiotics early. We will likely never have any definitive evidence • Start with a loading dose. • If in doubt on MDR and/or high renalclearance. Aim for a higher than normal dose • If you can, monitor what you are doing and adjust according to that • Reevaluate and STOP antibiotics in time
- 23. Thank you for your attention! World Antibiotic Awareness Week, 13-19 November 2017
- 24. What? Immunomodulatory effects Adequate coverage (what) Adequate timing (when) Correct route (how) Correct dose, PK/PD (how - much) Correct administration (how) Optimal antibiotic therapy Adequate penetration (what) Adequate duration (when - stop)
- 25. Combination or mono antibiotic therapy A previous healthy 39 year old woman is admitted to the intensive care unit for hypotension, anuria and altered mentation despite 3 litres of intravenous lactated ringers infusion. She is febrile and found to have gram negative bacteremia from unknown source. Her lactate is 4.3 mmol/L with a mean arterial pressure of 63 mmHg whilst on norepinephrine and vasopressin infusions. Her urine output is low and she has just been intubated due to respiratory failure.
- 26. Theoretical advantages of combination antibiotic therapy • Broader empirical coverage • Synergistic effect – more effective killing of the causative organism • Decreased risk of developement of resistance
- 27. Theoretical disadvantages of using combination antibiotic therapy • Increased risk of toxicity • Increased exposure to antibiotics – driving resistance • Collateral damage to commensal flora • Increased costs
- 28. Best evidence for septic patients in the ICU Journal of Infection (2017) 74, 331e344
- 29. All-cause mortality at longest follow-up Ten trials, comprising 2267 (86%) patients
- 30. Recommendations from Surviving Sepsis Campaign - 2016 6. We suggest empiric combination therapy (using at least two antibiotics of different antimicrobial classes) aimed at the most likely bacterial pathogen(s) for the initial management of septic shock (weak recommendation, low quality of evidence). 7. We suggest that combination therapy not be routinely used for ongoing treatment of most other serious infections, including bacteremia and sepsis without shock (weak recommendation, low quality of evidence). 8. We recommend against combination therapy for the routine treatment of neutropenic sepsis/bacteremia (strong recommendation, moderate quality of evidence). 9. If combination therapy is initially used for septic shock, we recommend de-escalation with discontinuation of combination therapy within the first few days in response to clinical improvement and/or evidence of infection resolution. This applies to both targeted (for culture-positive infections) and empiric (for culture-negative infections) combination therapy (BPS). Rhodes A, et al: Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. March 2017, Volume 43, Issue 3, pp 304–377
- 31. • All cause mortality - 44 trials - 5577 patients • Same β-lactam (13 studies n=1431): RR 0.97 (95% CI 0.73 – 1.30) • Different β-lactams: RR 0.85 ( 95% CI 0.71 – 1.01) (towards mono) • Nephrotoxicity: RR 0.30 (95% CI 0.23 – 0.39) (favouring mono)
- 32. • Death / Clinical Failure – 50 articles - 62 data subsets – 8504 patients • Overall: OR 0.865 (0.71 – 1.03) • Mortality < 15%: OR 1.53 (1.16 – 2.03) • Mortality 15-25%: OR 1.05 (0.81 – 1.34) • Mortality > 25%: OR 0.54 (0.45 – 0.66) Kumar et al. Crit Care Med 2010 Vol. 38, No 8
- 33. Subgroup analyses Sjövall et al Outcome measure Subgroups n Relative risk (95% CI) Test-of-interaction (p-value) All-cause mortality Surgical ICUs Mixed ICUs 271 1996 0.79 (0.48-1.31) 1.13 (0.96-1.33) 0.19 APACHE II ≥ 20 APACHE II < 20 1324 278 1.05 (0.87-1.26) 1.33 (0.81-2.18) 0.38 Trial conducted ≥ 2000 Trial conducted < 2000 1867 400 1.12 (0.95-1.32) 0.88 (0.55-1.39) 0.32 GI focus Not GI focus 98 1556 0.86 (0.31-2.37) 1.09 (0.89-1.34) 0.46 Secondary infections Surgical ICUs Mixed ICUs 308 904 0.75 (0.46-1.23) 0.99 (0.63-1.56) 0.49 APACHE II ≥ 20 APACHE II < 20 176 175 0.55 (0.11-2.69) 0.88 (0.29-2.72) 0.63 Trials conducted ≥ 2000 Trials conducted < 2000 724 558 0.96 (0.76-1.22) 0.89 (0.55-1.43) 0.78 GI focus Not GI focus 186 418 1.05 (0.5-2.23) 0.73 (0.37-1.42) 0.47
- 34. • Retrospective -4662 patients -Propensity-matched analysis Kumar, et al Crit Care Med 2010, Vol 38, No 9
- 35. Kumar, et al Crit Care Med 2010, Vol 38, No 9
- 36. Conclusion • As long as the causative pathogen is covered with a single empirical therapy. Additional agents will not give any additonal benefits
Editor's Notes
- Thank you for the invitation and giving me the opportunity to give this talk regarding antibiotic therapy in critically ill patients. As some of you can see I have chosen to alter the title a little bit to: antibiotics in the ICU, When What and How. I still believe though that the main concept of the title given in the program will be covered also with this disposition. My name is Fredrik Sjövall and I work primarily as an ICU consultant here in Malmö and I have a special interest in antibiotic therapy in the critically ill patient with a focus that I believe that we currently (most of us anyway) are over-treating our patients with antibiotics and that there is room for improvement. I also believe that this over treatment is driven by a somewhat understandable fear of not providing the best care and/or giving adequate therapy for our patients and that a little bit of extra antibiotics like an extra shot of aminoglycosides or a couple of extra days on antibiotics, just to be on the safe side, is good and doesn’t cause any harm to the patient. In my opinion this is not a good way of handling antibiotics in the era of increasing resistance and I’m not convinced that over treatment with antibiotics comes without collateral damage which can be detrimental to the patient. Of course, I cannot cover the whole area of antibiotic treatment to the critically ill in 15 minutes so I have focused on the two question when, how and will try and give you some highlights with regards to those.
- Here are my conflicts of interest
- First of all I would like to introduce the concept of optimal antibiotic therapy. It is not my own invention but was introduced by Jordi Rello et all some 10 years ago. The basic concept of choosing antibiotic treatment has been that we deem it appropriate if the causative bacteria is sensitive in vitro to the antibiotics we have prescribed. This is if you get an S as in sensitive from your microbiology department your home safe with your treatment. While this is a valid foundation and a prerequisite and for all antibiotic treatment there are also other factors to consider such as *are the antibiotics given at the right dose and right interval according to what we call pharmacodynamic and pharmacokinetic variables for this particular patient? * is the antibiotic given at the right time etc. * Do we stop the antibiotic at the right time If we optimize all this we will reach the adequate level of therapy. Moving up another step on the ladder, we finally reach the optimal antibiotic therapy. Here we also consider any non-bacterial effects of the antibiotics given such as immunomodulatory effects of antibiotics.
- It is obvious that there are many factors to take into consideration to be able to reach optimal antibiotic therapy. Many of the factors contributing to optimal antibiotic therapy can be clustered to the previously introduced questions of when, what and how (with slight variations). Where adequate coverage and penetration in to tissue falls under what. When relates to the timing of both when to start and when to stop. Then there are a lot of different hows which in turn can be sub divided regarding correct route, correct dose and correct administration.
- Lets start with the when. This might seem like a no brainer where the answer is just “As quickly as possible. I will just take a few moments to reflect upon this. The new surviving sepsis guidelines recommends that antibiotics should be administered within one hour of recognition of sepsis. These recommendations are largely based on two retrospective studies done by Kumar et al published in 2006 and a more recent study by Ferrer et al ppublished in 2014 and shown here as the mortality outcome.
- They analysed a large cohort of 18.000 patients in the surviving sepsis database and and made statistics on the outcome in regards to timing of antibiotics and shows that the later the antibiotic is given, the higher the mortality. Starting on app. 25% reaching 32% after a 6 hour delay The Kumar trial came to the same conclusion but with a much higher increase in mortality for every hour of delay. The problem of course with these studies are that they are retrospective. We don’t have any information with regards to appropriateness or adequacy of antibiotics given and we don’t know why there was a delay in the starting of antibiotics. Is this a confounding factor that also reflects a delay in other resuscitation measures that might be equally important such as giving fluids.
- To contrast, I would like to show this study, which is a meta analysis performed by Sterling et al and published in 2015 which includes these two aforementioned studies and I believ at the moment are the best evidence we have.
- As you probably can see despite including the two previously mentioned studies, (where the Kumar paper stands out quite extensively with its excess mortality) the actual result of the meta-analysis does not confirm that there is an mortality effect on the delays of antibiotics. You will then say to yourselves, Does it make any difference what it shows. We will not delay the antibiotics anyhow. A more hypothetical reasoning from me would be that, from a pathophysiological point of view we know that it mostly the reaction to the bacteria that causes the detrimental effects in sepsis and not the bacteria per se. This inflammatory response has been shown in several studies to transiently increase after antibiotics are given likely due to the killing of the bacteria and release of immune triggering substances. Therefore in the future if we want to fine tune our initial approach to patients with sepsis I’m not sure that antibiotics is the treatment that should come absolutely first but it might be that fluid resuscitation or even steroids or other immunomodulatory agents should be given before.
- So moving on to the question of how. We can divide that into correct dose and correct administration which somehow intermix.
- Why is it we can’t rely on the doses that is recommended in the normal pharmaceutical information sheets? There are some significant changes to the normal physiology in septic patients that are the reason for this. On one hand sepsis leads to endothelial dysfunction and vascular leakage with extravasation of fluids which leads to an increase in the volume of distribution. We increase this even further with the resuscitation fluids that we give to the patients. On top of this comes the decreasing albumin concentration that is usually seen in sepsis which alters the protein biding fraction of many antibiotics. The hyperdynamic state of sepsis with an elevated cardia output also increases the renal clearance of most water soluble drugs leading to lowered plasma concentrations. On the other side of the scale we have the patients with increasing severity of organ dysfunction, especially acute kidney injury which then decreases the clearance and leading to higher plasma concentrations. And of course, this is a continuum between the two that patients with sepsis move between.
- To illustrate what these alteration leads to. I will use a study we have just performed on concentrations of meropenem in patients with septic shock. We sampled 50 patients with septic shock 7 times over a dosing interval to get a concentration curve. These values then act as a base for a clearance formula which in turn is used in a so called Monte Carlo simulations where you simulate how the concentrations of your substance, in this case meropenem, would perform in 1000 patients with a variation in predefined variables. The variations that we tested were the effect of different renal clearances ranging from 30 up to 200 and different administration strategies ranging from intermittent infusion over 30 min, a prolonged infusion over 3 hours and continuous infusion. The first simulation tested what was required to reach a concentration 2 mg/L target of which is currently classified as being the breakpoint for a susceptible bacteria. The so called (MIC) minimal inhibitory concentration. What we found was that to achieve a concentration above 2 mg/L in 95% of patients with all creatinine clearances you needed to give 4-6 grams of meropenem if you are using intermittent infusion, this can be reduced to 2-3 g if given as prolonged infusion (depending on interval) and 2 g for continuous infusion.
- To put in to a more clinical context. We modulated how to reach sufficient concentrations when treating difficult to treat bacteria. That is bacteria that often shows high resistance to antibiotics. And as an example bacteria I want to show you the results for Acinetobacter baumanii. We performed simulations for both empirical therapy where you consider how the MICs are distributed for all the wild type bacteria choosen and then for targeted therapy. Logically it will require higher concentrations to kill all bacteria empirically compared to targeted where you only have to consider those that are found susceptible. And as shown before that concentration is 2 mg/L when dealing with meropenem. In this simulation we deem it clinically relevant if we reached concentrations that were above the MIC for more than 90% of the cases. So to reach this level in empirical therapy of A. baumannii, in all categories of renal function, a daily dose of 8000 mg of meropenem was required for intermittent boluses and prolonged infusion This could be reduced to a daily dose of 6000 mg for continuous infusion. As expected, lesser doses were required for targeted therapy where a dose of 6000 mg daily was required for intermittent dosing and 3000 mg daily was sufficient for prolonged infusion, which could be reduced to 2000 mg daily for continuous infusion. This was for all levels of creatinine clearance where the highest was set to 200. I we move down to more moderate levels of clearance we can see that the levels needed are substantially reduced and are closing in to what we normally se in daily practice with 1 g every eight hours for both intermittent an d prolonged infusion and 3g continuous infusion for empirical therapy and as low as 1g for prolonged and continuous infusion in targeted therapy
- So now you ask yourselves, What does all this mean? It means that if you are in doubt with regards to your patients renal clearance and you have to cover MDRS such as Acinetobacter you have to increase your doses very much to be able to be sure that you cover all of them However, if you have a nice looking resistance pattern and normal to slightly reduced renal function you can still go with the ordinary dosing regimens and if you want to save even more money/reduce the dose further you can go for continuous infusion.
- Some of you probably also ask yourselves how often you come across a patient with that high creatinine clearance and I will tell you that they are probable more common than you think. In this study by Andrew Udy et al from Australia they looked in to that. They looked at app. 280 critically ill patients with normal plasma creatinine concentrations to see how many had high clearance rates. The problem with plasma creatinine concentrations is that there is poor discrimination between these values and actual clearance, when reported within the “normal” reference range What they found was that around 65% of the patients had an augmented renal clearance defined as above 130 ml/min / 1.73 m2 So they are not that uncommon. But who are they
- In the same study they found that these patients where usually male and younger So these are the ones that you should look out for.
- There has now been a lot of talk with regards to renal function. What about obesity. I believe you all heard that obese patients must have increased doses. This is yet another study from our friends in Australia where they studied 19 patients, normal with BMI 19-30, obese BMI 30-40 and morbidly obese BMI > 40 What they found was that only the volume of distribution was effected by the increase in weight. For the other targets that they used which were essentially the same as in the previous study the weight had no influence. So what does this mean.
- You should use a loading dose. A loading dose is important since this is the first antibiotic dose that is typically administered when inoculum of infection is high and likely to harbor moderately or severely resistant subpopulations. Variable, fluctuating or suboptimal antibiotic concentrations during the first few days of therapy, especially in a critically ill septic patient, greatly increases the risk of selecting resistant subpopulations that later breakthrough in the patient with untreatable levels of resistance. A common misconception is that initial LDs need to be adjusted on the basis of the renal function of the patient. Although impaired drug clearance in a patient has relevance to prolonging the interval in between drug doses and adjustment of maintenance doses, renal function does not influence the LD required by the patient. Therefore, LDs are not adjusted or reduced in patients with impaired kidney function Also it is vital if your are giving prolonged or continuous infusion since it will take much longer time to reach a steady state level in this type of administration.
- All of a sudden I show you a Swedish reference. It is a Scandinavian meeting so I thought I could allow myself that. It is a nice review on the evidence if these different dosing has any impact on any relevant outcome. They come to the conclusion, as we all do, that this is a very compelling way of administer antibiotics and has many theoretical advantages but we lack firm evidence that it actually helps.
- From our friends in Australia (again) we have this meta-analysis which is a meta-analysis of individual patient data. Not that many patients. 630 isch. Demonstrating a significant survival benefit for continuous infusion.
- That is why they are now setting up the BLING III study that’s going to be a gigantic study of 7000 patient where they want to answer the question if continuous infusion is better than intermittent dosing.
- However, isn’t it better if we measure what we do? How many of you perform therapeutic drug monitoring on B-laktam? Raise your hands. I think more and more labs around the hospitals are setting these up for the most commonly used b-laktam antibiotics so it will be possible. The problem here also will be that we don’t know if it will help. Therefore my last rhetorical question is Do we need an RCT on this? I truly believe so. There are some under way in Germany and the UK. Because then we would get the answer if moving from appropriate therapy up the therapeutic ladder to adequate or even optimal antibiotic therapy will make any difference for our patients.