Welcome to the Deep Dive. We take the source
material, you share the research, the reports,
and really cut straight to the essential knowledge
you need. Fast. Trying to get to the heart of
it quickly. Exactly. Today, we're plunging into
a really critical area of surgical practice,
finding the best way to prevent infections during
hip and knee replacement surgery. It's a major
challenge. It is. And it involves this significant
trade -off, doesn't it? How do you maximize protection
against potentially devastating infections, but
also carefully manage the risk of, well, serious
drug side effects? Precisely. It's a constant
balancing act in clinical practice. Today is
a research paper. It's from the Royal National
Orthopaedic Hospital NHS Trust, published on
an official government website. It looks specifically
at changing the antibiotic protocol used, you
know, before and after surgery in primary joint
replacement. Total joint arthroplasty, yes. And
joining me is our expert guide, Prof. Mo Imam,
to help us navigate these complex findings and
understand what they really mean. Happy to be
here. Preventing prosthetic joint infection,
or PJI as we call it, is absolutely paramount
in orthopedics. I can imagine. It's a complication
that is truly devastating for the patient, and
it presents enormous challenges for the healthcare
system too. Choosing the right antibiotic prophylaxis
isn't straightforward at all. It needs a careful
balance of efficacy against those potential adverse
effects. Exactly. And this study gives us some
real world data on that very balance. So at this
hospital, they changed their standard antibiotic
regimen, what was the old approach, and what
did they switch to, and crucially, what were
they actually measuring, both the good and the
bad, so to speak. Right, so the standard prophylaxis
was initially cifroxam only, a three -dose regimen.
Okay. They then switched, they moved to a single
preoperative dose combining two drugs. Tegoplanin
plus gentamicin. A combination therapy. Yes.
And the main goal, of course, was trying to reduce
the rate of prosthetic joint infection, PGI.
Makes sense. On the flip side, the primary potential
harm they were specifically tracking was acute
kidney injury, AKI, which is a known risk associated
with aminoglycosides. Gentamicin is one of those.
OK. Let's unpack how they actually studied this
change, then. What kind of approach did they
take? How did they collect the data to compare
these two regimens? Well, this was a retrospective
study looking back at what happened. Using past
records. Exactly. Comparing outcomes in two distinct
time periods, but at the same hospital. They
looked back at all patients undergoing primary
hip and knee replacements. The pre -intervention
group, that was patients from the 18 months before
the antibiotic change. They have to see for oxy.
Right. The post -intervention group were patients
from the 18 months after the change. So they
received the ticoplanin plus gentamicin. Got
it. And how many patients are we talking about?
They analyzed data from just under 2 ,000 patients
in total, about 1 ,100 in the C. feroxan period
and around 880 in the ticoplanin plus gentamicin
period. And importantly, all the information
came from routinely collected clinical records,
real world data. And to ensure consistency, which
is vital, They used standard, widely accepted
definitions for the outcomes. The European Bone
and Joint Infection Society criteria, EBJIS for
diagnosing PJI. Right. And the kidney disease,
improving global outcomes. KDIGO criteria for
defining and staging AKI. So, established definitions,
real -world results. Precisely. A pragmatic look
at what happened after the change. That approach,
using the hospital's own data, it feels very
relevant. But whenever you compare groups from
different times like this, you have to wonder
if the patients were, well, truly comparable.
Absolutely. Were there any significant differences
between the group getting Siferoxim and the group
getting the new combination? That's a very important
point, and the authors definitely addressed it.
They compared a whole range of baseline characteristics.
Like what? Things like age, BMI. the ASA grade,
which is a measure of overall health co -morbidities,
how long the surgery took, whether it was a hip
or knee. And for most of these, the groups were
actually quite similar. But not identical. Not
quite. There were two statistically significant
differences they found. The Cifroxime group,
the earlier group, had a higher proportion of
female patients. and also more cemented arthroplasties.
Ah, cemented versus uncemented, that can matter,
can't it? It can sometimes influence risk profiles,
yes. So because of these differences, sex and
cement use, they couldn't just do a simple comparison
of the raw numbers, they used statistical modeling.
Cox regression analysis specifically. To adjust
for those factors. Exactly. To adjust for the
potential confounding effects of sex and cement
use, which allows for a more sort of like -for
-like comparison of the PGI risk that you can
attribute to the antibiotic regimen itself. Good.
So they tried to level the playing field statistically.
Right. Let's get to the core question then. The
infection rates. How did the two antibiotics
actually compare? This is where we see the potential
benefit, presumably. Absolutely. And the results
here were, well, pretty striding. OK. Across
the entire group, nearly 2 ,000 patients followed
for two years. The overall PGI rate was 1 .50%.
So 30 patients in total. OK. Overall. But by
group. That's where the difference shows up.
The citroxine group, the ones on the older drug,
had a PGI rate of 2 .24%. That's 25 infections
out of about 1 ,100 patients. Right. Two and
a quarter percent. Then. The ticoplanum plus
gentamicin group, their PGI rate was just 0 .57%.
0 .57. Yes. Only five infections out of 880 patients.
Wow. That is a dramatic reduction just looking
at the raw numbers. It is. A very noticeable
drop in the observed infection rate. So after
they did that statistical adjustment you mentioned
for the differences in the groups, what was the
estimated size of that risk reduction? Well,
after adjusting for sex and cement use, the analysis
showed that the ticoplankton -plustion -tambosin
group had a 75 .2 % lower risk of developing
PGI compared to the c -feroxime group. 75 % lower
risk? Yes. The hazard ratio was .248. Okay, explain
the hazard ratio a bit. What does .248 mean,
practically? It means that patients getting the
new combined regimen were, at any given time
point during the follow -up, only about a quarter
as likely to actually experience a PGI compared
to those on ciferoxam, once you've accounted
for those other factors like sex and cement type.
Right. So a four -fold reduction in likelihood,
roughly. Roughly, yes. And this difference was
highly statistically significant. The P value
is 0 .004. Very unlikely to be due to chance.
A 75 % reduction is really substantial. Was this
benefit seen across the board? for all types
of infections or was it particularly effective
against certain bacteria or maybe infections
appearing at specific times after the surgery?
That's a critical insight from the source actually.
The risk reduction was, and I'm quoting here,
most pronounced for early onset and delayed infections.
So infections happening relatively soon after
surgery or within the first year or so? Typically,
yes. And specifically those caused by two groups
of bacteria. coagulase -negative staphylococci
connes, and sephiroxine -resistant enterobacteriaceae.
Okay, connes and resistant enterobacteriaceae.
Why those particularly? Well, it makes perfect
sense when you look at the antibiotics. Sephiroxine,
it's a second -generation cephalosporin. Its
activity against many strains of connesse is
limited, and it often has poor activity against
enterobacteriaceae that have developed resistance
mechanisms. So it had known weaknesses? Exactly.
Tycoplanet, on the other hand, gives excellent
coverage against gram -positive bacteria, including
staph like connesse. And gentamisin provides
strong coverage against many gram negatives,
including most enterobacteriaceae. Ah, so the
new combination directly targeted the bugs that
the old drug wasn't hitting effectively. Precisely.
It covered the gaps. And these are common causes
of PGI. So the new combination addressed pathogens
the previous single agent was less effective
against. That's a really key point. It wasn't
just a general improvement. It seems specifically
effective where the previous antibiotic perhaps
had a blind spot. So connecting this back, what's
the main implication for why the infection rate
dropped? The authors conclude that this change
in the antibiotic prophylaxis is the most likely
reason for the lower infection risk. Because
of that better coverage? Primarily, yes. Better
coverage of key pathogens often picked up around
the time of surgery. And this was alongside the
hospital maintaining consistent general infection
prevention and control practices throughout both
study periods. That's important too. Right, it
wasn't just the drugs changing in isolation.
No. It's also interesting they note this finding
contrasts with some older studies, trials that
didn't necessarily show one regimen being clearly
better than another. Why might that be? The source
suggests it might be because those older trials
often compared regimens with only minor differences
in their spectrum of activity, whereas this switch
involved a much more substantial change in coverage,
specifically targeting resistance patterns relevant
to PJI. So a bigger change led to a bigger effect,
potentially. Potentially. They also raised another
possibility about ziferoxam dosing, particularly
in obese patients. Flender dosing. Maybe. They
noted that a really striking 96 % of the infections
in the ziferoxam group occurred in obese patients,
compared to only 40 % in the ticoplanin plus
gentamicin group. 96%. That's huge. It is. It
highlights that maybe dose adequacy for certain
patient groups. against specific bugs, could
have played a role in the higher infection rate
seen with Cifroxime in the study. Fascinating.
So a significant drop in infections likely due
to better targeting of common and sometimes resistant
pathogens. Okay, let's look at the other side
of that balance sheet now, the potential harms.
What about the acute kidney injury, the AKI?
Yes, the AKI. As you'd perhaps anticipate with
using an amyoglycoside like Tentamacin, the rate
of AKI was higher in the group getting the combined
regimen. How much higher? Well, the overall AKI
rate across the whole study was just under 2%,
1 .9%. In the Sviroxin group, it was low 0 .8%,
only 9 patients. Okay. But in the take -a -plan
and plus gentamicin group, it was significantly
higher, 3 .3%. That's 29 patients. And that difference
was statistically significant. Right. So a definite
increase. But you mentioned earlier that AKI
has different stages of severity based on those
KDIGO criteria. Was this mostly severe kidney
injury or milder cases? That's a crucial distinction.
And the source is clear on this. The vast majority
of the AKI cases, they saw 84 % of them, in fact,
were stage one AKI. Stage one being the mildest
form. Yes, the mildest form. And the rate of
stage one AKI was significantly higher with the
tekaplanin plus gentamisin. Three point zero
percent versus only point five percent with sephiroxam.
That drove the overall difference. OK, mostly
stage one. What about more severe stages? Importantly,
the study found no difference in the rate of
stage 2 AKI between the groups. And critically,
no patients developed stage 3 AKI, the most severe
form, in either group. That's reassuring. Yes.
And furthermore, no patients required renal replacement
therodialysis for their kidney injury during
the follow -up. So, more common, but generally
less severe and seemingly reversible kidney issues.
That's what this study found. And it's consistent
with findings from some other studies using similar
combined antibiotic regimens. An increase, but
predominantly in mild AKI. Were there other significant
potential harms discussed in the source? Yes,
anaphylaxis. A severe allergic reaction. It was
highlighted as a critical perioperative risk.
And antibiotic -related anaphylaxis is certainly
a known, though rare, concern. Right. The source
references data from the UK's sixth National
Audit Project, NAP6, which estimates anaphylaxis
incidents during anesthesia. And what did that
show for these drugs? Well, for the antibiotics
we're discussing, NEP6 estimated incidences per
100 ,000 procedures. Tycoplanin actually had
a highest estimate at 16 .4. Compare that to
sephiroxam at 0 .9 and gentamicin at 0 .6. So
Tycoplanin potentially carries a higher background
risk according to that national data. According
to NEP6, yes. But what's particularly notable
from the source, from this paper, is that their
own observational data within their hospital
suggested the actual rate for Tycoplan and anaphylaxis
might be even higher. Really? Higher than the
national estimate? Potentially up to three times
higher than the NAP6 estimate. Your local data
suggested a range between 1 in about 2100 and
1 in about 1650 cases. Wow! That raises questions
about under -reporting, perhaps. It does raise
questions. The source does point out, though.
that administering Tycoplanin slowly, usually
over 30 minutes, is the recommended practice.
That helps minimize infusion -related reactions,
which can sometimes mimic or contribute to anaphylaxis
symptoms. This really brings us to the central
question, doesn't it? You weigh that substantial
reduction in devastating infections. Which are
terrible for patients. Absolutely. Against the
increase in mostly milder kidney issues and this
potentially higher risk of a very serious, albeit
still rare, allergic reaction like anaphylaxis,
how do those benefits and harms actually stack
up? How did the paper frame it? They provide
a calculation, sort of a thought experiment,
to help put this trade -off into perspective.
based on treating 10 ,000 patients undergoing
primary joint replacement. Okay, per 10 ,000
surgeries. Switching from sepharoxin to tycoplan
and plus gentamicin could lead to an estimated
125 fewer PJIs over two years. That's 125 fewer
major complications. Yes. However, it could also
result in approximately 220 more stage 1 AKEIs.
Okay, 220 more cases of mild kidney injury. Predominantly
mild, yes. And using a combination of the NAP6
data and their own higher local estimate for
tico plane and risk, potentially five more cases
of life -threatening anaphylaxis. Five more anaphylaxis
events per 10 ,000. That's the estimate based
on their data. and an AP6. So what's fascinating
here is seeing that balance laid out with numbers
derived from their real -world practice. It certainly
is. It presents a very clear clinical decision
point for hospitals and clinicians. Reducing
one significant risk appears to come with increasing
others, albeit potentially less severe ones in
the case of AKI, but very severe in the case
of anaphylaxis, even if rare. That really sharpens
the perspective on the decision. Every medical
intervention involves that risk -benefit analysis.
What were the limitations of the study that the
authors themselves acknowledged? Well, as is
typical for a retrospective study, looking back
in time, they noted several limitations. Such
as? The inherent nature means you can't control
all variables, like in a prospective trial. While
they adjusted for those key differences like
sex and cement use, They acknowledge that minor
unmeasured differences in patient comorbidities
or even maybe changes in the prevalence of certain
bugs over the two time periods can't be entirely
ruled out. Right. You can't control everything
historically. Exactly. They also mentioned it's
impossible to completely isolate the effect of
the antibiotic change from other potential historical
effects, maybe other subtle changes in practice
at the hospital during that time. Although they
did state that general infection prevention practices
remain consistent. OK. And finally, the incidence
of some very specific resistant bacteria, things
like vancomycin -resistant enterococci VREA,
was just too low on their data set to draw firm
conclusions about the impact of the new regimen
on those particular pathogens. Understood. So
given these findings, the clear benefits and
the clear risks, and acknowledging those limitations,
what's the main takeaway message for professionals,
say orthopedic surgeons or hospital pharmacists
reviewing their own prophylaxis protocols? I
think the key conclusion from this single -center
observation study is pretty clear. The change
to tycoplan and plus gentamisin was associated
with a significant reduction in the overall rate
of prosthetic joint infection. And particularly,
it targeted those early and delayed infections
caused by conness and sephiroxam -resistant enterobacteriaceae.
That seems key. What? But this benefit came with
a statistically significant increase in acute
kidney injury, mostly the milder stage one cases.
And it requires very careful consideration. of
the potentially increased risk of anaphylaxis,
especially given the local risk estimate for
take -a -plan and being higher than national
figures. So the decision for other hospitals
really involves carefully weighing these specific
quantifiable benefits against these specific
quantifiable harms, all within their own local
context, their own patient population, their
own resistance patterns. And linking this to
the bigger picture, the source mentions the importance
of prospective multicenter studies following
this kind of single -center data. Why is that
next step Well, prospective studies are really
essential to confirm these findings in a more
controlled environment, across multiple different
centers, which would include varying patient
populations and potentially different local bacterial
resistance patterns. You get a broader view.
Exactly. They can provide more robust data on
less common outcomes, like severe AKI or anaphylaxis.
And importantly, they offer a better opportunity
to monitor the impact of these antibiotic changes
on wider trends in antimicrobial resistance over
time. Which is, of course, a major global health
concern. So this study provides compelling real
-world evidence from one place. Yes, strong observational
evidence. But confirmation and broader applicability
really need those larger prospective trials.
That would be the ideal next step to inform wider
practice changes confidently. Okay, so we've
taken a deep dive into this really interesting
study comparing two different antibiotic approaches
for hip and knee replacements. We've seen that
switching the regimen at this particular hospital
led to a significant reduction in those dangerous
prosthetic joint infections, especially hitting
the bugs that the previous antibiotic struggled
with. A clear benefit on the infection front.
But we also saw that clear increase in kidney
issues, mostly milder, thankfully, and that potentially
higher risk of a severe allergic reaction anaphylaxis.
The trade -off is very evident. This study powerfully
illustrates that real -world balancing act, that
trade -off that hospitals and clinicians have
to navigate constantly when deciding on the best
strategy to protect patients. If you found this
deep dive valuable, it really helps other professionals
discover these insights if you consider rating
and sharing the show. Getting the knowledge out
there. Indeed. Thanks for joining us for this
deep dive. And just a final thought to leave
you with. Thinking about the specific bacteria
that this new regimen was particularly effective
against those resistant to the previous antibiotic,
does this study really hint that tailoring antibiotic
prophylaxis strategies much more closely to local
resistance patterns is perhaps the most impactful
way forward, even if it means consciously accepting
and managing different types of risks? Something
to perhaps consider as you review protocols in
your own clinical setting.