Discussion
Bacterial septic arthritis is a life-threatening cause of severe
lameness in the horse, often resulting from a penetrating injury (Baxter
2004). There is limited literature discussing the involvement of fungal
organisms(Riley et al. 1992, Madison et al. 1995, Swerczeket al. 2001, Sherman et al. 2006, Cohen et al.2008, Doyle et al. 2013). The literature reports treatment using
a combination of synovial debridement and lavage with systemic and IA
antifungal chemotherapy. Cohen et al., (2008) report the first case
using intravenous regional perfusion of antifungal chemotherapeutics.
Wickerhamomyces anomalus (formerly Candida pelliculosa ) is
widespread within nature often found in soil and on plant material and
is considered a level 1 biosafety organism, safe for healthy humans
(Satora et al. 2014). It is an opportunistic pathogen of humans
and animals(Kurtzman 2011) and has been isolated from infected human
lungs (Kurtzman 2011), involved in neonatal fungemia (PAUL et al.2020) and ocular keratitis(Kamoshita et al. 2015) cases.Candida species are well known to colonise the skin and mucosal
surfaces of humans and often form biofilms making their eradication
challenging (PAUL et al. 2020).
Cohen et al., (2008) report a 3-year-old standard-bred filly that
developed bacterial metacarpophalangeal joint septic arthritis following
IA medication with hyaluronic acid. Subsequent fungal septic arthritis
developed due to Candia utilis which was isolated on culture.
Cytology revealed a TNCC of 15x109cells/L, TP 18g/L.
The filly was managed with systemic and IA fluconazole in combination
with IVRP amphotericin B and arthroscopic lavage. A lytic subchondral
bone lesion was identified on radiographs. The filly developed a
recurrence of the fungal infection 8 weeks following discharge that was
managed similarly. Eleven months after discharge from the hospital the
filly was pasture sound(Cohen et al. 2008). Similarly, Doyle et
al., (2013) report a case of fungal septic arthritis (Candida
glabrata) of a 2-year-old gelding that was suspected to have had IA
medication of the right metacarpophalangeal joint with corticosteroids.
Cytology revealed a TNCC of 17.2x109cells/L, TP 69g/L.
The gelding was euthanised due to a poor prognosis and evidence of lytic
radiographic changes on the proximal sesamoid bones. There were
significant findings reported on post-mortem (Doyle et al. 2013).
Swerczek et al., (2001) report the case of a 6-year-old Thoroughbred
gelding with a Scedosporium prolificans infection of the left
metacarpophalangeal joint with a recent history of intralesional
hyaluronic acid and antimicrobials to treat an inflammatory interosseous
tendon injury. The horse was treated with IA corticosteroids and
antimicrobials before being euthanised 10 days later(Swerczek et
al. 2001). In 1995, Riley et al., reported a case of fungal arthritis
caused by Candida famata in a 4-year-old Thoroughbred that
sustained a laceration to the left metacarpophalangeal joint. The
laceration appeared to heal well with systemic anti-microbials. However,
21 days after the initial injury the horse was markedly lame at the walk
with subchondral lucencies evident on radiography. Subsequent treatment
consisted of systemic antimicrobials, systemic amphotericin-B and
potassium iodine. The mare was retired from racing and was clinically
normal after 1 year with a normal foal.
The case reported here and that reported by Cohen et al., (2008) and
Doyle et al., (2013) both received IA corticosteroid therapy in the days
leading up to the development of lameness. The use of IA corticosteroids
has been associated with fungal and bacterial arthritis in human
patients and this is likely a result of local immunosuppression(Habibet al. 2010, Cohen 2011, Bufalari et al. 2016, Leclere
2017, Fang et al. 2019). Further to the immunosuppression caused
by corticosteroids, if combined with antimicrobials this may well
increase the risk of fungal infection further. In one human study,
Candida albicans was the most common fungal organism involved in
prosthetic synovial sepsis with recent (within 90 days) antimicrobial
administration as a significant risk factor(Riaz et al. 2020).
This re-enforces the need for responsible antimicrobial use especially
given the evidence suggests that concurrent antimicrobial administration
with corticosteroids does not significantly reduce the risk of
iatrogenic synovial sepsis (Braid 2019) and could increase the risk of
fungal septic arthritis (Fang et al. 2019, Riaz et al.2020). The incidence of septic arthritis following intra-articular
injection is reported to be <0.1% following injection of more
than 300,000 joints (Pezzanite et al. 2022).
The literature is sparse concerning the safe use of anti-fungal
chemotherapeutics within synovial structures with some extrapolating
treatment regimens from ophthalmic cases on the basis that if it is safe
to use in the eye it is likely safe to use in a synovial structure.
Voriconazole and fluconazole were used IA without any noted adverse
effects in this case. Amphotericin-B is a well-documented model for
inducing arthritis in the horse and for this reason, was not a
first-line treatment choice (McIlwraith et al. 1979, McIlwraith
and Van Sickle 1981). The authors did consider intravenous regional
perfusion as reported by Cohen et. al., 2008, but felt there was little
advantage over IA use given that a therapeutic concentration was
required within the joint and thus still presented the risk of
chemically induced arthritis. Amphotericin -B was later used in
combination with hyaluronic acid intra-articulary which resulted in a
transient but marked increase in lameness post-administration.
The initial management of this case reflects the standard approach to
bacterial synovial sepsis with arthroscopic lavage, and systemic and
local antimicrobials (Pille and Martens 2009). Within 6 days of the
initial surgery, the causal organism had been identified as aCandida species which then underwent further typing. This rapid
identification of a fungal organism allowed prompt anti-fungal treatment
to be initiated. Unfortunately, it took 3 days to source an appropriate
anti-fungal chemotherapeutic for IA use. The initial choice was made
whilst awaiting fungal sensitivity results which did not arrive until
day 23 and revealed only intermediate sensitivity to voriconazole. It
should be noted that the initial 24-hour fungal culture obtained on
blood agar was significant and somewhat surprising given the frequently
unrewarding (Dumoulin et al. 2010) results of synovial fluid
culture without enrichment. Culture and sensitivity in this case were
pivotal as they guided treatment from the more commonly encountered
bacterial synovial sepsis to one of fungal origin. It is also valuable
in prognosticating given what we already know about fungal septic
arthritis and the poor prognosis associated.
Antimicrobial therapy was continued despite a negative bacterial culture
since bacterial isolation without enrichment is often not achieved with
rates of isolation as low as 25% (Robinson et al. 2016) and
there was potential that a bacterial component may have been missed
particularly given the heavy fungal growth. It is considered that
bacterial colonisation of this already severely compromised joint may
have further complicated the management of this already challenging
case. On reflection, the use of a blood culture enrichment technique may
have been useful and allowed the cessation of antimicrobials at an
earlier time in the interest of anti-microbial stewardship. There are
complex relationships between many commensal organisms including
bacteria and fungi. These relationships may be synergistic, saprophytic
or antagonistic and due to their opportunistic nature co-infection is
possible (Soll 2002, Peleg et al. 2010). However, there are
certain gram-negative bacteria (Escherichia coli ,Pseudomonas aeruginosa, Acinetobacter baumannii and Burkholderia
cepacia) that have shown an ability to kill or attenuate someCandida species. The exploitation of these attenuation
mechanisms is likely to prove advantageous in the treatment of
infections in the future particularly given the increasing problem of
antimicrobial resistance(Peleg et al. 2010).
There were financial constraints and anti-fungal chemotherapeutic
availability issues that dictated some of the clinical management, in
this case, resulting in a delayed 2nd surgery.
However, by day 23 the owners had reviewed their financial situation and
an extension of the budget allowed for a 2ndarthroscopic lavage and injectable fluconazole was then available.
An interesting feature of this case was the persistently low TNCC values
despite a worsening clinical picture. The authors cannot offer a
definitive explanation as to why this may have occurred, although it
does seem consistent across other reports that TNCC is generally lower
than in bacterial cases with values pre-lavage frequently reported in
the mid-teens(Sherman et al. 2006, Cohen et al. 2008,
Doyle et al. 2013). In the human literature, it is reported that
corticosteroid use can dampen the inflammatory response(Kohli and Hadley
2005) and whilst that is certainly possible pre-lavage it is hard to
believe potent immunosuppression persists thereafter. Another feature
exhibited by this case is the slow insidious onset of clinical signs
similar to that reported in other cases within the literature with
lameness not present until days and sometimes even weeks after the
initial suspected causal event(Cohen et al. 2008, Doyle et
al. 2013), this too could be linked to the anti-inflammatory properties
of the corticosteroids. However, is more likely representative of the
indolent nature of fungal arthritis(Kohli and Hadley 2005). This case
highlights the importance of monitoring the response to treatment for
synovial sepsis using not only the synovial fluid parameters but also
the clinical presentation of the horse, the degree of lameness and the
physical appearance of the joint (Murray 2012).
Regarding fungal sensitivity testing, it is important to note that there
are no veterinary-specific clinical breakpoints for fungal species
(Sellon and Long 2013). Instead, human-derived clinical breakpoints are
used. It is important to consider this as several distinct aspects
determine these clinical breakpoints: minimum inhibitory concentration
(MIC) distribution of the fungal species against the drug of interest,
the pharmacokinetics (PK) and pharmacodynamics (PD) of the drug of
interest in the body and the clinical outcomes of treatment (Toutainet al. 2017).
The MIC distribution of a particular fungal species is unlikely to
differ between human and animal origin but the PK/PD data can vary
greatly between humans and animals and even between animal species.
Consequently, human-derived breakpoints may not be entirely appropriate
for use in animals.
A further issue is that, even in human medicine, fungal-species-specific
breakpoints for W. anomalus have not yet been described(Kiddet al. 2021). Therefore, breakpoints for other Candida
species are used for interpretation but there may be
fungal-species-specific differences which might influence the
appropriateness of these (Procop et al. 2020).
In this case, the isolate of W. anomalus was categorized as
intermediate to voriconazole using human-derived breakpoints for otherCandida species . This is the best estimate of the status of that
isolate but does not guarantee that it was truly sensitive or resistant.
However, as the voriconazole treatment was administered
intra-articularly (i.e. at an increased concentration), the
concentrations achieved may have been sufficient for the inhibition of
fungal growth. Recently the European Committee on Antimicrobial
Sensitivity Testing (EUCAST) reclassified the intermediate categories in
some cases to “Susceptible, Increased Exposure” to allow for such
situations (Arendrup et al. 2020). Although, we do not know how
the intra-articular environment, with cellular infiltration and debris,
might have impacted the activity of the drug.
The gross post-mortem and histological findings, in this case, were
extensive and beyond the previous expectations of the authors. The fact
that the joint space was almost occluded by synovial proliferation
highlights the severity of the inflammatory process. Additionally, it
begs the question: had the fungal infection been cleared, how would the
authors resolve this marked inflammatory response within such a
high-motion joint? Ultimately, the answer is likely that it wouldn’t
have been possible to fully resolve and return this horse to athletic
soundness irrespective of the significant osseous changes. This supports
the outcome reported by Cohen et al., (2008) where 11 months after
hospital discharge the filly only achieved pasture soundness.