I am really fortunate to work with a great team of diagnostic cardiologists who have a keen interest in infective endocarditis. We have an endocarditis multidisciplinary team and do a ward round of all the endocarditis patients every week, regardless of where they reside in the hospital. One of the big problems for these patients is the long courses of IV antibiotics in the current treatment guidelines, be they British, American or European. As a result patients have long periods of time where they have central venous catheters (CVC) for administering the antibiotics and prolonged hospital stays; both predisposing to further infections.
So when I saw an article in the New England Journal of Medicine from Denmark investigating whether oral antibiotics can be used in the treatment of this infection, my attention was stirred and I made the most of the present moment and ordered the paper from the library, “carpe diem”.
So when I saw an article in the New England Journal of Medicine from Denmark investigating whether oral antibiotics can be used in the treatment of this infection, my attention was stirred and I made the most of the present moment and ordered the paper from the library, “carpe diem”.
Infective endocarditis is infection of the endocardium of the heart. Untreated it is invariably fatal. Most antibiotic regimens currently used consist of 2-3 antibiotics given for 4-6 weeks. The antibiotics are often given up to six times a day. This means that patients need long-term intravenous access in the form of a CVC whose tip sits in the superior vena cava just before it enters the heart. Damage to the heart valves from endocarditis predisposes to further episodes of endocarditis and any bacteria that colonise the CVC will pass into the heart, therefore the combination of endocarditis and a CVC should raise concern for healthcare staff as well as patients.
In order to reduce the risk of infection and get patients home faster, a team from Denmark has undertaken a large randomized, non-inferiority, multicentre trial to compare IV followed by oral antibiotics with IV antibiotics alone to see if the outcome is the same. They have called the study the “Partial Oral treatment of Endocarditis Trial” or POET study. Being that infective endocarditis is invariably fatal if untreated, I was curious to see if this was “Dead Poet’s study!” I chose not to stand on a table to read the paper when it arrived, although this paper was definitely a different approach to infective endocarditis!! (If you haven’t seen the film Dead Poet’s Society then I would recommend it to you… it’s one of Robin William’s best performances in my opinion).
How was the study done?
The study selected 400 patients from an original sample size of 1954 (about 20%) and split them randomly into 2 groups; 199 received normal IV treatment and 201 received half of their treatment IV and half orally. Both groups were well matched in terms of the type of patient, age, sex, co-morbidities, bacterial pathogen, laboratory results, heart valve involved, etc.
In terms of outcome the study looked at all-cause mortality, the need for unplanned cardiac surgery, embolic events (clots coming off heart valve vegetations and causing strokes) and relapses in bacteraemias. These were essentially the markers used to say whether there was a significant difference between the two groups.
From a statistical point of view the study was well designed with careful attention paid to the number of patients required to give sufficient statistical power to answer the studies questions and the appropriate statistical tests for the study were used.
How were patients selected?
In order to be eligible for a switch to oral treatment patients had to fulfil a number of criteria:
What did the study show?
The study showed that IV followed by oral antibiotics were not inferior to IV antibiotics alone for the treatment of left-sided infective endocarditis caused by Streptococcus spp., Staphylococcus aureus, Enterococcus faecalis or Coagulase-negative Staphylococcus spp. There was no difference in terms of complications and deaths. This is really exciting because it shows that oral antibiotic therapy is possible for infective endocarditis and as one of my cardiology colleagues said “this is a real game changer”.
So can we start using these oral antibiotic regimens in the UK?
Woooaaaa there! Hold your horses! Not so fast!
What are the limitations to this study?
The main limitations to this study are that they only studied left sided endocarditis and did not include intravenous drug users (IVDUs). This means that the results may not be applicable to patients with right-sided endocarditis or IVDUs. Is this a big deal? Not really. It is unlikely that there would be any major difference in response in these patient groups so I suspect the results can be applied in real life.
The biggest technical limitation for me, is in the antibiotic sensitivity testing data. The study says that all oral regimens were based on “minimal inhibitory concentrations (MICs) for each bacterial species published by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)” but this is not true. There are no EUCAST MICs for some of the bacteria-antibiotic combinations they tested and in the supplementary data for the article they even say they used their own breakpoints, the laboratory cut off for saying if a bacterium is sensitive to a specific antibiotic or not; usually is an internationally standardised value.
They do not say how these breakpoints were calculated or tested and some are for combinations not necessarily considered effective such as Streptococcus spp. AND Rifampicin or Enterococcus faecalis AND Moxifloxacin OR Rifampicin. This doesn’t mean the results are invalid, I would just like to know how they chose these cut off values, it seems a clumsy omission from an otherwise robust article.
Why is this important to know? These breakpoint methods would need to be known in order for routine microbiology laboratories to perform these tests on the bacteria from their own patients.
There is another even bigger stumbling block to repeating or implementing the results of this study in most hospitals in the UK and that is that in the study patients started on oral antibiotics had their serum antibiotic levels measured on day 1 and day 5, 30 minutes, 1 hour, 2 hours, 4 hours and 6 hours after administration, to see if they had therapeutic antibiotic levels. These samples were tested using high-pressure liquid chromatography. The study changed patients dosing regimens based upon the serum antibiotic levels and without the ability to do that it just wouldn’t be safe to manage patients in this way. This is excellent microbiology BUT I don’t know of any routine microbiology laboratory in the country that would be able to do this.
We don’t have the resources in terms of nursing or doctor time or laboratory support. Most biochemistry laboratories have the equipment but it is all “plug and play” kit-based tests; the expertise in setting up in-house bespoke tests is no longer widely available. It would only become feasible if kits were developed to do the tests and were cost effective in small numbers as otherwise it would be too difficult to justify the cost for the small numbers involve; about 10 cases a year in my hospital. It just wouldn’t happen. Maybe we could team up multiple hospitals or start endocarditis networks which might make it cheaper and more cost effective, who knows. But essentially no! You cannot currently use oral antibiotics to treat infective endocarditis.
The current IV antibiotic regimens for endocarditis have been used for many years. There is lots of data to show that patients reach therapeutic levels and where levels might need monitoring e.g. Vancomycin, Teicoplanin, Gentamicin, these can be done routinely in most pathology departments. Until the same could be done for all of the other antibiotics used in the study it just isn’t possible to adopt the oral strategy just yet.
HOWEVER, as more big research units are able to repeat the study the more data about the pharmacokinetics and dynamics of these antibiotic combinations will become known and in the not too distant future regimens might be designed without the need for measuring levels. When that happens I’m all in… oral antibiotics for infective endocarditis…that really would be poetic and I’d stand on my desk for that!
Reference
Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis. Iversen K, Ihlemann N, Gill S, et al. NEJM August28,2018 DOI: 10.1056/NEJMoa1808312
In order to reduce the risk of infection and get patients home faster, a team from Denmark has undertaken a large randomized, non-inferiority, multicentre trial to compare IV followed by oral antibiotics with IV antibiotics alone to see if the outcome is the same. They have called the study the “Partial Oral treatment of Endocarditis Trial” or POET study. Being that infective endocarditis is invariably fatal if untreated, I was curious to see if this was “Dead Poet’s study!” I chose not to stand on a table to read the paper when it arrived, although this paper was definitely a different approach to infective endocarditis!! (If you haven’t seen the film Dead Poet’s Society then I would recommend it to you… it’s one of Robin William’s best performances in my opinion).
How was the study done?
The study selected 400 patients from an original sample size of 1954 (about 20%) and split them randomly into 2 groups; 199 received normal IV treatment and 201 received half of their treatment IV and half orally. Both groups were well matched in terms of the type of patient, age, sex, co-morbidities, bacterial pathogen, laboratory results, heart valve involved, etc.
In terms of outcome the study looked at all-cause mortality, the need for unplanned cardiac surgery, embolic events (clots coming off heart valve vegetations and causing strokes) and relapses in bacteraemias. These were essentially the markers used to say whether there was a significant difference between the two groups.
From a statistical point of view the study was well designed with careful attention paid to the number of patients required to give sufficient statistical power to answer the studies questions and the appropriate statistical tests for the study were used.
How were patients selected?
In order to be eligible for a switch to oral treatment patients had to fulfil a number of criteria:
- Endocarditis was due to Streptococcus spp., Staphylococcus aureus, Enterococcus faecalis or a Coagulase-negative Staphylococcus spp.
- Appropriate IV antibiotics had been given for ≥10 days
- Patients had shown good response to treatment e.g. afebrile >2 days, CRP <25% of highest level or <20mg/L and white blood cell count <15 x 109/L
- Transoesophageal echocardiography (TIE) performed within 2 days showed no abscess formation or indication for surgery
- Patients had no other infections requiring IV antibiotics, had a BMI <40 and had good gastrointestinal absorption
- Microbiological examination identified two different classes of antibiotics available for oral treatment
What did the study show?
The study showed that IV followed by oral antibiotics were not inferior to IV antibiotics alone for the treatment of left-sided infective endocarditis caused by Streptococcus spp., Staphylococcus aureus, Enterococcus faecalis or Coagulase-negative Staphylococcus spp. There was no difference in terms of complications and deaths. This is really exciting because it shows that oral antibiotic therapy is possible for infective endocarditis and as one of my cardiology colleagues said “this is a real game changer”.
So can we start using these oral antibiotic regimens in the UK?
Woooaaaa there! Hold your horses! Not so fast!
What are the limitations to this study?
The main limitations to this study are that they only studied left sided endocarditis and did not include intravenous drug users (IVDUs). This means that the results may not be applicable to patients with right-sided endocarditis or IVDUs. Is this a big deal? Not really. It is unlikely that there would be any major difference in response in these patient groups so I suspect the results can be applied in real life.
The biggest technical limitation for me, is in the antibiotic sensitivity testing data. The study says that all oral regimens were based on “minimal inhibitory concentrations (MICs) for each bacterial species published by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)” but this is not true. There are no EUCAST MICs for some of the bacteria-antibiotic combinations they tested and in the supplementary data for the article they even say they used their own breakpoints, the laboratory cut off for saying if a bacterium is sensitive to a specific antibiotic or not; usually is an internationally standardised value.
They do not say how these breakpoints were calculated or tested and some are for combinations not necessarily considered effective such as Streptococcus spp. AND Rifampicin or Enterococcus faecalis AND Moxifloxacin OR Rifampicin. This doesn’t mean the results are invalid, I would just like to know how they chose these cut off values, it seems a clumsy omission from an otherwise robust article.
Why is this important to know? These breakpoint methods would need to be known in order for routine microbiology laboratories to perform these tests on the bacteria from their own patients.
There is another even bigger stumbling block to repeating or implementing the results of this study in most hospitals in the UK and that is that in the study patients started on oral antibiotics had their serum antibiotic levels measured on day 1 and day 5, 30 minutes, 1 hour, 2 hours, 4 hours and 6 hours after administration, to see if they had therapeutic antibiotic levels. These samples were tested using high-pressure liquid chromatography. The study changed patients dosing regimens based upon the serum antibiotic levels and without the ability to do that it just wouldn’t be safe to manage patients in this way. This is excellent microbiology BUT I don’t know of any routine microbiology laboratory in the country that would be able to do this.
We don’t have the resources in terms of nursing or doctor time or laboratory support. Most biochemistry laboratories have the equipment but it is all “plug and play” kit-based tests; the expertise in setting up in-house bespoke tests is no longer widely available. It would only become feasible if kits were developed to do the tests and were cost effective in small numbers as otherwise it would be too difficult to justify the cost for the small numbers involve; about 10 cases a year in my hospital. It just wouldn’t happen. Maybe we could team up multiple hospitals or start endocarditis networks which might make it cheaper and more cost effective, who knows. But essentially no! You cannot currently use oral antibiotics to treat infective endocarditis.
The current IV antibiotic regimens for endocarditis have been used for many years. There is lots of data to show that patients reach therapeutic levels and where levels might need monitoring e.g. Vancomycin, Teicoplanin, Gentamicin, these can be done routinely in most pathology departments. Until the same could be done for all of the other antibiotics used in the study it just isn’t possible to adopt the oral strategy just yet.
HOWEVER, as more big research units are able to repeat the study the more data about the pharmacokinetics and dynamics of these antibiotic combinations will become known and in the not too distant future regimens might be designed without the need for measuring levels. When that happens I’m all in… oral antibiotics for infective endocarditis…that really would be poetic and I’d stand on my desk for that!
Reference
Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis. Iversen K, Ihlemann N, Gill S, et al. NEJM August28,2018 DOI: 10.1056/NEJMoa1808312
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