Therapeutic Guidelines Antibiotic Part 1

[Music] Welcome to the Australian Prescriber Podcast. An independent, no-nonsense podcast for busy health professionals.

I'm Dhineli Perera, your host for this episode and it's incredibly exciting to be chatting to Professor Allen Cheng today, about the much-anticipated Therapeutic Guidelines: Antibiotic update. Allen is the Director of Infectious Diseases at Monash Health, as well as Professor of Infectious Diseases and Epidemiology at Monash University. Amongst a long list of extracurricular activities, Allen is also a member of the Therapeutic Guidelines: Antibiotic expert group. Today, Professor Cheng and I will try to unpack some of the critical changes that have occurred in Therapeutic Guidelines: Antibiotic update. Some of these are particularly relevant to the hospital sector. Welcome to the program, Allen.

Thanks so much.

Before we start, we should preface this interview with the emphasis that this will not be an all-encompassing list of changes. We really encourage listeners to deep-dive into the updated guidelines, take the time to read the corresponding texts and not just skip to the blue boxes. It is clear that a lot of work has gone into making the guidelines as thorough and as detailed as possible. So Allen, would it be fair to say that community-acquired pneumonia, or CAP, as a topic, has probably undergone one of the biggest structural changes in the guideline?

Yeah. There are a lot of major changes – we’re going to skim over some of the highlights, but yes, community-acquired pneumonia is one of the more contentious topics in Therapeutic Guidelines when we come to discuss it; it has changed quite a lot in this edition.

Yeah. So what has happened to the severity scoring tools and why?

Yeah. I understand that the group was a bit concerned about the sensitivity and specificity of the various scores, in terms of predicting both deterioration and the need for intensive care, as well as mortality. And that was particularly true for younger patients. And so the approach that's really taken in this is now to say, does the patient need admission, so what are the red flags you look for (which actually are a lot of the elements of what we look for in the scoring system)? But also reinforcing that other factors, social situation, comorbidities, frailty and time, might factor into that decision. And then to look for red flags for intensive care admission. I think one of the important things to mention is that severity assessment is sort of a static measure in what can be a dynamic situation. So a lot of patients can present and may not look that sick at the start, but over the first 24 hours or 48 hours, they might deteriorate. And that's where clinical judgement is really important.

There's the recognition of the sick patient, which there's lots of different ways to do that and try to move away from scoring systems to red flags, and recognising the signs of deterioration. In terms of the investigation approach, I think the intensity of investigation is based on severity and just recognising low-severity pneumonia is probably mostly managed in the community, hopefully they'd never see the hospital and they have, for example, quite a low risk of bacteraemia, so don't need to do a blood culture. But as the severity does increase, there's really a need to intensify the investigation. So that's where Legionella antigens and serology and pneumococcal antigens have their role, particularly in severe pneumonia.

So Allen, then what was the evidence supporting the introduction of IV hydrocortisone to treatment recommendations in high-severity CAP? I sort of see this as one of the bigger changes in management for this syndrome.

So intravenous hydrocortisone was recommended in the guidelines now, if given within 24 hours of diagnosis for critically unwell adults with high-severity CAP that require high-flow oxygen or mechanical ventilation. And then obviously, if there's another indication for use like COPD [chronic obstructive pulmonary disease] or something like that. And the evidence for that really comes from the CAPE COD study published in the New England [Journal of Medicine] that suggests that hydrocortisone is likely to reduce hospital mortality in that group specifically, and then also has some benefits in some of the secondary outcomes, like the duration of mechanical ventilation and shock and the duration of staying in intensive care.

Right. So it really is for our sick and high-severity [adult] cohort. And so, where do we stand with viral CAP; are antivirals now recommended for this condition overall?

Yeah. I think there's now greater recognition that respiratory viruses may be the only cause of some cases of pneumonia. So I guess in times gone by we thought that pneumonia was bacterial and if a virus was detected, then there was a bacterium there somewhere. But I think there's an increased recognition that viruses can be the only pathogen, as well as obviously, co-infection with bacterial pathogens may also be possible. So in the current guidelines, there's advice on the approach for empiric antiviral therapy. So for example, for influenza, people that have either high-severity CAP or those who are at risk of complications where influenza is likely, there's a recommendation to use influenza antivirals. I think one of the things that we did struggle with, and particularly because it's such a dynamic evidence situation, was what to do about COVID antivirals. So the section actually points to other resources, but I think we now know that there's probably a gap in clinical recommendations, and that's something that I know Therapeutic Guidelines is thinking about.

Right. It comes back down to the clinical judgement at the time then as well, for these patients that might be getting treatment for viral CAP.

Yep.

So staying on the pneumonia train of thought, can you tell us what has changed in the definition for HAP [hospital-acquired pneumonia]? What did it move from and to, and why?

Yeah. So the definition of hospital-acquired pneumonia traditionally [is] about how long you've been in hospital. So the first 48 hours is still regarded as community-acquired pneumonia, and then after 48 hours, is hospital-acquired pneumonia. But the definition now includes patients that have been in hospital recently, so within the last 7 days – have they been in hospital for more than 48 hours? And that's something that's increasingly being recognised. For example, the FDA [US Food and Drug Administration] in the US has used that definition for clinical trials. And the evidence for that is really around the prevalence of Gram-negative colonisation in people that are hospitalised. And because most pneumonia is about aspiration from the oropharynx, that Gram-negative coverages are really required for people that meet this definition of either being in hospital for 48 hours or having been in hospital recently for 48 hours, because of that increased colonisation with Gram-negatives.

So moving on to aminoglycosides, the world of aminoglycosides has undergone quite a bit of a shake-up in late 2023. One of the main outcomes was that clinical microbiological labs were no longer reporting gentamicin susceptibility for Pseudomonas [aeruginosa]. Where have we landed with aminoglycosides in the Antibiotic update, and why?

This was one of the more difficult issues that we had to face. And there were a lot of meetings with clinical microbiologists and ID [infectious diseases] physicians about what we should do about this. And the main issue was around that EUCAST [European Committee on Antimicrobial Susceptibility Testing] and the clinical microbiology labs aren't reporting susceptibility data for gentamicin for Pseudomonas. The outcome really has been that tobramycin is recommended alongside gentamicin through most of the guidelines where Pseudomonas is a player. And in the end, it's probably a reasonable alternative as it has a similar spectrum of activity. But we do also need to think about how available, for example, tobramycin therapeutic drug monitoring would be, what systems each lab is using, whether EUCAST or other reporting systems, and also the cost of the drugs.

So in the current guidelines, tobramycin and gentamicin are ranked equally, except if Pseudomonas is suspected or proven, in which case, tobramycin is preferred because the MIC [minimum inhibitory concentration] for tobra[mycin] is slightly less than for gentamicin in vitro. And tobramycin is easy to get to target attainment with that. There is a section on interpreting microbiological results. I think the clinical ID people are a little bit uncomfortable with what we are able to treat with being dictated by what the microbiologists will test, but the microbiologists do have a good rationale for why they are preferring to report some things than others. So that's an ongoing tension that we're having to manage.

Yeah, absolutely. So moving on to sepsis now, Allen, can you tell us more about the new tiered approach to managing patients with suspected sepsis?

So here, there are 2 considerations. The first one is, how sick is the patient in front of you? And then the second one is, how likely is this due to infection? So clearly, there's a group where they're very sick and it's very likely to be infection and you just need to give antibiotics quickly. So that is people that you really think have septic shock, people who are likely to get septic shock because they are immunocompromised, or otherwise vulnerable to sepsis, or they've got organ dysfunction and you think it's due to infection. That is a clear group, severe infection, give antibiotics quickly. For the people that aren't in that group and you're not really sure whether it's due to infection or there might be something else going on, so immunocompetent patients, not vulnerable to sepsis, don't have septic shock, then you might want to delay your antibiotics a little, just to make sure that you've got time to assess what's going on.

And so in that group we say, ‘Well, if you can't work it out within 3 hours, then maybe you want to give antibiotics,’ but it's not that imperative to just give it straight away. And that really is trying to balance that tension between giving antibiotics to everyone who is sick versus not giving antibiotics to people where there's a bit less certainty that their symptoms are due to infection. And this has been something that's been discussed with the Australian Commission for Safety and Quality in Health Care, the Sepsis Clinical Care Standard. And then also, it's consistent with the Surviving Sepsis Campaign, international guidelines for management of sepsis and septic shock.

Yeah. Okay. Now, moving on to antimicrobial dosing, that's something that's close to most pharmacists' hearts. It's something we look at very closely. So I wanted to walk through first the piperacillin + tazobactam, as well as meropenem, continuous infusions. Starting with the BLING III study, a meta-analysis, what did we take from that, Allen, in terms of the guidelines?

Yeah. Look, this was a really important study and just a shout-out to all the Australian pharmacists and clinicians involved in that. So the study itself didn't show a clinically or statistically significant reduction in mortality, but it did show an increased rate of clinical cure in the group receiving continuous infusion. And when that was combined with all the previous data in the meta-analysis, it did suggest that there probably was a reduced risk of 90-day mortality with prolonged infusions. So I guess, what I take from this is that firstly, longer infusions for beta-lactams in general are better on theoretical grounds. And although I'm not completely convinced that [continuous] infusions are better, it probably does translate to better clinical outcomes. The evidence isn't rock solid on that, but it's probably as good as we're going to get.

So what does that mean practically for those prescribing? It probably means that you should use continuous infusions for piperacillin+tazobactam and meropenem specifically, where we can. If it can't be done for whatever reason, then it's probably okay, as long as they get it, so there's guidelines to allow for administration over 3 hours or 30 minutes. But probably the most important thing, and that was something that they did in the trials, was that they do need a loading dose. So when continuous infusions are given, the first dose is given over 30 minutes, just to make sure you get the level up there before you start the infusion and keep the level up there.

And do you see a difference in the need for these continuous infusions between ward and ICU settings?

Yeah. Look, it's probably more important for intensive care patients because they're the ones that are more likely to die and the evidence is around the outcomes for mortality. But again, from first principles, time over MIC [minimum inhibitory concentration] is probably what we're aiming for, and that's probably better achieved through [continuous] infusion. So, where we can do it, we probably should.

Great. And then with regards to the other beta-lactams, where does this leave them? Do we leave them be, as they are, or do we need to extend this principle across to them as well?

Yeah. So I think the feeling from the review group was that, although other beta-lactams were included in the meta-analysis, there wasn't as strong evidence for those that have not [been] studied adequately or not recommended for clinical illness in the guidelines. So theoretically, an extended or continuous infusion of other beta-lactams may have a theoretical benefit for people that are particularly sick or have Pseudomonas [aeruginosa] where the MIC might be a little higher, but the evidence really isn't quite the same for those other infections as it is for piperacillin [+tazobactam] and meropenem.

Okay. So now, moving on to IV amoxicillin+clavulanate, and I guess this has probably been one of the antibiotics that has seen the biggest change since the last edition of the guidelines, where it probably wasn't anywhere near as available as it is now, especially in some of the smaller regional hospitals across Australia. Now, it would be used a lot more and probably routinely for a lot of infections. I know at our institution, it is. When it comes to dosing, what are some of the changes that have been made with regards to IV amoxicillin+clavulanate? And why were these changes made?

Yeah, certainly. I think it was the last edition when amoxicillin+clavulanate IV was just becoming available and we weren't sure how commonly it was going to be used, and it was still finding its place in formularies. Now, it does seem to be, for example, a good alternative to piperacillin + tazobactam without necessarily being quite so broad, just noting it is still a relatively broad-spectrum antibiotic and we do need to be careful with its use.

So the new guidelines, there's now a recommendation for the 2.2 g formulation [2+0.2 g amoxicillin+clavulanate]. So that's 2 g of amoxicillin, 200 mg of clavulanate, and that's an alternative to the 1.2 g formulation [1+0.2 g amoxicillin+clavulanate] for adults and children weighing 40 kg or more. So both options, the 2.2 g and the 1.2 g dosing recommendations, are equally ranked because different hospitals will have different formulations in their formulary. And the rationale for this is really about the MICs [minimum inhibitory concentrations], particularly for Enterobacterales, which would be the group of organisms where this would be most useful. And there was some concern that the MICs were a little higher, so that the current 8-hourly dosing of 1.2 [g] may not quite attain some of those targets. So the dosing frequency has been increased for 1.2 g from 8-hourly to 6-hourly, to make sure that they're adequately treated. But the 2.2 g, the higher dose, still stays at 8-hourly because that's probably enough to achieve target attainment.

And I guess it still ends up being, across the day, a decent difference in the dosing, but you don't see that to be problematic. So for example, with the 1.2 [g] 6-hourly, it's 4 g essentially of amoxicillin versus 6 [g] when you're using the bigger dose. But essentially, both of them are going to achieve that time above MIC that you are after.

Yes, exactly.

Okay. And when using the amoxicillin+clavulanate IV for paediatric patients, have there been similar dose increases?

Yeah. For children that are less than 40 kg, then it's not recommended to use the 2.2 [g] formulation. It's probably too much amoxicillin for them. And the 1.2 g formulations are recommended 8-hourly for that group or 12-hourly for very young children, less than 3 months. Unless there's penetration issues, they need to use a very high dose such as an abscess or bone infection or something like that. So there's very little data on PK [pharmacokinetic] and safety and efficacy for the use of the 2.2 g formulation in children.

Okay. So then, moving on to penicillin hypersensitivity, the updated guidelines have included 2 validated allergy assessment tools. So that's PEN-FAST and the antibiotic allergy assessment tool. And so I thought, just to highlight some of the interest areas for this topic, one of the trickier but common questions to answer has been, or can be, so my patient has a penicillin allergy, but I'm not sure if they have a cephalosporin allergy. And if they can have it, which one?

So the first thing to do is to divide it up into, does the patient have severe delayed hypersensitivity? So that's the Stevens-Johnsons [syndrome] what we call SCAR [Severe Cutaneous Adverse Reaction]. So in that group, if they reported that [side effect] due to either penicillin or cephalosporin, they shouldn't get it, all of them, because it's such a severe side effect and the immunological mechanisms behind that aren't quite so well defined.

Yeah.

What we probably more commonly see is the immediate rash, so we're talking about anaphylaxis or rashes and so on, then this is where PEN-FAST and the allergy assessment tools have been developed for. So the 3 things we do know in that group is that most people that say they have a penicillin allergy, a lot of them won't have a reaction on rechallenge. And that's where PEN-FAST is helpful. So if it's more than 5 years ago and particularly, if it's a milder reaction, that evidence suggests that on rechallenge, they don't get any reaction the second time.

The second thing we know is that reactions are mediated mainly by side chains. And then the third thing to know is that the cross-reactivity between penicillin and cephalosporin is in the order of about 2%. So 98% of people that have a penicillin allergy, even a true penicillin allergy, if they get a cephalosporin, as long as it's not one that's got the same side chain, they won't get a reaction.

Yeah.

So the common one would be for severe immediate hypersensitivity, so they've got anaphylaxis to penicillins and you know that it's confirmed or recent and high risk, then they shouldn't get the penicillin obviously. For directed therapy, they could use a cephalosporin if a beta-lactam is preferred, and then we just need to check the table to make sure it's not one of the cross-reactive ones. And then for empiric therapy, then you might also consider a non–cross-reactive cephalosporin. Again, check the table if a beta-lactam is preferred.

Excellent. So for listeners that might be wanting to know what that table is that Allen is referring to, it's table 2.117 [Table: Examples of beta-lactam antibiotics with R1 side-chain similarity] in the updated Therapeutic Guidelines. And it's a really great reference to be used when answering this exact question because it has made it nice and clear what your likely cross-reactive beta-lactams are to be considered when dealing with this question.

Yeah, it's great to have it actually in a table, in a guideline. It's easily accessible.

100% agree. So when it comes to non-operative treatment of uncomplicated appendicitis, I feel like this may be more common than we realise. So, which cohort is this condition likely to apply to, Allen, and what is the total recommended duration of antimicrobial therapy for this group?

So for uncomplicated appendicitis, there is non-operative treatment. So treating with antibiotics is now discussed as an alternative to appendicectomy. And that's based on a series of studies that suggest that the risk of complications and quality of life are similar for people that have an appendicectomy compared to those that have non-operative treatment. But there are clearly risks and benefits on both sides, and that's something that needs to be discussed with the patient. There's a risk of recurrence; they may still need an appendicectomy in the future. And all of that needs to be talked about with the patient. So the total duration of antibiotic treatment is 7 to 10 days, and there's a new algorithm in there to both select who might be appropriate for non-operative treatment, as well as to compare the 2 treatment options, to work out which one might be best for your patient.

Yeah. I guess in practice, I've seen this situation pop up for a lot of the really elderly frail, and frail patients – getting them onto the table in itself is a risk. So I'm really grateful to see this appear in the updated guidelines because we're often stuck with making up our own treatment durations. So I think, acknowledging that this happens is really useful for clinical practice. So Allen, there has been some new content developed on the approach to skin and soft tissue infections and infective endocarditis in people who inject drugs. Could you briefly walk us through the updates in this space?

Yeah. So this is a really important group. And in fact, I reckon, half of the patients in my unit probably inject drugs. So it's a very common situation for infectious diseases physicians in many parts of Australia. So I think the first thing to say is that it is a risk factor for different pathogens. So for example, MRSA [methicillin-risistant Staphylococcus aureus] is more likely to be a risk and that's something that we need to think through. The second one is there's a really helpful section on patient information on harm reduction. So, what do we need to tell patients so that they don't get this infection the next time? And then more specifically for endocarditis, but I think this applies to skin soft tissue infections as well, is that there really needs to be a multidisciplinary approach. So obviously, endocarditis needs cardiology and cardiothoracics to be involved, but for all these patients, addiction medicine and pain, and making sure that a lot of their other concerns (other than infection) are addressed is really important.

There's a recommendation to assess their suitability for hospital in the home [ambulatory antimicrobial therapy]. And there are different models of hospital in the home. So I think a lot of concerns for hospital in the home programs is the safety of their staff going into difficult social situations. But there are other models where the patient can come to the hospital to get a daily dose of antibiotics. And the other changes have been the advent of oral therapies. Again, not all of them are appropriate, and then long-acting glycopeptides, for example, dalbavancin and oritavancin. So there's a whole lot of different treatment options both in how antibiotics are delivered, as well as oral options and long-acting glycopeptides. And then just reinforcing the importance of the multidisciplinary team to provide a sort of wraparound support for patients who are otherwise quite vulnerable.

Great. Definitely looks like it's a more holistic approach in this update, which has been really good to see. Finally, Allen, but excitingly, this update included voices from the largest number of paediatric specialists to date. What would you say are the top 3 key changes in antimicrobial prescribing for this paediatric cohort?

Yeah. So just to note, I'm not a paediatrician, but some of the things that have been highlighted to me that are different, are different recommendations for the dose of cefalexin. So for example, using a higher dose 8-hourly, instead of a normal dose 6-hourly, to try and improve adherence. Doxycycline has always been a topic of discussion and there's always been that question about the risk of tooth discolouration with tetracyclines. And I think it's now thought that it probably is not a risk with doxycycline specifically. So it's now recommended for short-term use for less than 21 days in children of all ages because there's now pretty good data for safety with regard to tooth discolouration, enamel hypoplasia and bone deposition. And then, I guess the other big change has been the recommendations for empiric therapy for hospital-acquired sepsis in children 2 months or older. And maybe just a fourth one, there's some new neonatal recommendations for directed therapy for some bloodstream infections.

Wonderful. Well, that's unfortunately all the time we've got for this really jam-packed episode. Many thanks for joining us today, Allen.

Thanks so much for having me.

[Music]

Professor Allen Cheng is a member of the Antibiotic expert group. The views of the hosts and guests on the podcast are their own and may not represent Australian Prescriber or Therapeutic Guidelines. I'm Dhineli Perera, and thanks for joining us on the Australian Prescriber Podcast.