Antimicrobial therapies for Gram-positive infections

pharmaceutical-journal.com/research/antimicrobial-therapies-for-gram-positive-infections/20203363.article

Clinical Pharmacist12 SEP 2017By Christopher Eades, Stephen Hughes, Katie Heard, Luke SP
Moore

Abstract: Gram-positive bacteria are among the most common human pathogens associated with
clinical infections, which range from mild skin infections to sepsis. In an era defined by
antimicrobial resistance (AMR) and an increasing drive toward delivering patient care via
ambulatory pathways, the paradigm for the management of infections is changing. Methicillin-
resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), the best
known cases of Gram-positive resistance, are increasingly prevalent and may be associated with
significantly worse clinical outcomes versus wild-type strains using current therapeutics. This article
reviews the spectrum of antimicrobial agents currently available for the treatment of Gram-positive
infections with a special focus on AMR, and outpatient antimicrobial therapy (OPAT). Also reviewed
are agents currently in development, and renaissance roles for older antimicrobials in cases
complicated by AMR.
Keywords: Antimicrobials, antimicrobial resistance, bacteria, Gram-positive,Enterococcus, MRSA,
Staphylococcus, Streptococcus.
Original submitted: 01 June 2017; Revised submitted: 26 July 2017; Accepted for
publication: 28 July 2017.

Source: Science Photo Library

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 Methicillin-resistant Staphylococcus aureus (MRSA, red) is a Gram-positive, round (coccus) bacterium. It is
resistant to many commonly prescribed antibiotics. S. aureus is carried by around 30% of the population
without causing any symptoms. However, in vulnerable people, such as those that have recently had
surgery, it can cause wound infections, pneumonia and blood poisoning.

Key points:

Gram-positive bacteria are among the most common causes of infection.

The prevalence of drug-resistant strains of Gram-positive bacteria (including
methicillin-resistant Staphylococcus aureus and glycopeptide-resistant
enterococci) is increasing.
An increasing proportion of specialist infection care is being delivered in
ambulatory settings, including outpatient antimicrobial therapy (OPAT).
A number of new antimicrobials with activity against drug-resistant Gram-
positive organisms have been licensed recently; a number of these are novel
examples of existing classes.
A number of existing antimicrobials have important activity against drug-
resistant Gram-positive organisms. Such agents are likely to become
increasingly useful, particularly in cases where oral therapy is appropriate.

Introduction
Gram-positive organisms (including bacteria of the genera Staphylococcus,
Streptococcus and Enterococcus) are among the most common bacterial causes of
clinical infection. This is primarily due to their association with a diverse spectrum of
pathology, ranging from mild skin and soft tissue infections (SSTIs) to life-threatening
systemic sepsis and meningitis[1]. Although a number of antimicrobial agents already
exist for the treatment of such diseases, emerging issues such as antimicrobial
resistance (AMR) and innovations in healthcare delivery have created a need for
antimicrobials with novel spectra of activity and pharmacokinetic (PK) profiles.

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Although recent global attention has focused on the issue of multi-drug resistance
(MDR) in Gram-negative bacteria in particular detail, Gram-positive AMR is also a
serious concern[2]. Methicillin-resistant Staphylococcus aureus (MRSA) is perhaps the
paradigm example, and is of high global importance as a cause of community-acquired
and healthcare-associated infection[3],[4]. MRSA is a pathogen of concern due to its
inherent resistance to almost all β-lactam antimicrobials (i.e. penicillins,
cephalosporins and carbapenems), with present exceptions being some of the novel
cephalosporins discussed later in this review. Given the superior comparative efficacy of
first-line β-lactams in staphylococcal infection, such as flucloxacillin and cefazolin, this
is particularly problematic in the context of severe infections, for which the use of
second-line agents confers a proven loss of survival-benefit[5],[6],[7],[8]. Similarly,
glycopeptide-resistant enterococci (GRE) are recognised as emerging pathogens,
particularly in immunocompromised or hospitalised patients, and have been associated
with outbreaks in healthcare facilities globally[9],[10] .

The management of clinical infection must also be considered against the changing
landscape of healthcare delivery[11]. Increasingly, novel approaches are being
implemented globally to deliver inpatient-level care to patients in ambulatory settings,
including outpatient antimicrobial therapy (OPAT). The OPAT approach has
demonstrable efficacy in numerous infections, including serious conditions previously
managed exclusively in hospital settings[12],[13]. The cost-effectiveness of this approach
has been demonstrated across a variety of healthcare systems[14],[15],[16]. Moreover, an
OPAT service can improve patient autonomy by facilitating earlier discharge and, as
such, is associated with high levels of patient satisfaction[17]. In order to deliver OPAT,
there has been heightened interest in the development of antimicrobials with dosing
regimens compatible with ambulation. This encompasses the development of novel
agents with suitable PK profiles, together with innovative strategies to administer
existing agents in the outpatient setting. The aim of this article is to review the evidence
informing the treatment of Gram-positive infections, including resistant strains. The
impact of OPAT-compatible regimens and administration strategies is also considered.

Sources and selection criteria

A focused literature review of online biomedical databases (PUBMED, EMBASE and the
Cochrane Library) was undertaken, considering published journal articles and
conference abstracts relevant to each subject heading. Citations available via the above
sources on or before 26 July 2017 were considered for inclusion.

Glycopeptides

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The glycopeptides, vancomycin (VANC) and teicoplanin (TEIC), are bactericidal
antimicrobials with activity against Gram-positive bacteria only. Their shared
mechanism of action is similar to that of the β-lactams, except that their action on cell
wall synthesis is effected via an interaction with the D-alanyl-D-alanine (DADA) moiety
of peptidoglycan precursors, thus inhibiting the cross-linking stabilisation step in
bacterial cell wall formation[18]. All glycopeptides available to date have negligible oral
bioavailability and must therefore be administered parenterally for the treatment of
systemic infections — usually via the intravenous (IV) route. TEIC, and the newer
lipophilic glycopeptides, have emerging roles in the delivery of OPAT; these will be the
focus of this section.
TEIC is a highly protein-bound glycopeptide with a terminal half-life in the region of
150 hours[19]. In keeping with other highly protein-bound drugs, loading is necessary in
order to achieve a rapid plasma steady state: twelve-hourly dosing for three to five
doses, followed by once-daily dosing thereafter is usually recommended[20]. Adequate
dosing is critical to the efficacy of TEIC, particularly in deep-seated or severe infections.
Current guidelines now recommend doses of 12mg/kg as lower doses have been shown
to be significantly inferior to comparator agents for deep-seated or complex infections,
and associated with failure [21]. Owing to this shift in dosing advice, the European
Medicines Agency (EMA) has mandated that additional safety monitoring studies be
undertaken, and has placed black triangle (▼) status on all TEIC-containing products
marketed in European countries[22]. TEIC is generally well tolerated with fewer renal-
or infusion-related reactions than VANC, although it must be acknowledged that this
observation is largely derived from early data and lower dosing regimens. Indeed,
elevated TEIC levels may be associated with fatigue, and reversible neutropenia has
been described with prolonged use[23]. Therapeutic concentrations may also be
achieved with three-times weekly dosing; successful outcomes have been reported with
this regimen for a number of infections, including MRSA osteomyelitis [24]. TEIC is not
active for the majority of infections caused by GRE, with the exception of those
expressing TEIC-susceptible phenotypes, including vanB and vanC[25]. A proportion of
coagulase-negative staphylococci are also resistant. Close liaison with a medical
specialist in infectious diseases or microbiology is strongly suggested to obtain advice
on the interpretation of in vitro susceptibility tests.

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The new lipoglycopeptides, oritavancin (ORI) and dalbavancin (DAL), are currently
licensed in Europe for the treatment of SSTIs only, whereas telavancin (TELA) holds a
licence for the treatment of hospital-acquired/ventilator-acquired pneumonia
(HAP/VAP). In the United States (US), the Food and Drug Administration (FDA)
licence for TELA differs in that it is also licensed for the treatment of SSTIs. All of these
lipoglycopeptides contain an additional lipophilic side chain to the parent glycopeptide
structure, which is thought to confer additional benefit over TEIC and VANC in two
ways. First, this moiety interacts closely with hydrophobic components in the
phospholipid bilayer of the bacterial plasma membrane, thus anchoring the
glycopeptide molecule to the membrane — in close proximity to the peptidoglycan
targets[26]. This phenomenon is thought to result in superior comparative bactericidal
activity. Second, the lipophilic nature of these agents increases cellular penetration; in
conjunction with high levels of plasma protein binding, this is thought to account for the
significantly longer biological half-lives of these agents, particularly when compared
with VANC.

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ORI is licensed (Orbactiv®; The Medicines Company, UK) within Europe and the US
for acute bacterial SSTIs in adult patients from the double-blind randomised controlled
trials (RCTs) SOLO I and II, which suggest the non-inferiority of single-dose (1.2g IV
infusion) ORI versus a seven-to-ten-day course of twice-daily VANC for the treatment of
SSTIs[27],[28]. Although concerns have been raised about the potential for severe side
effects in susceptible patients because of the significant systemic exposure following a
single dose, these data suggest that ORI is well tolerated for this indication, with an
adverse effect profile largely indistinguishable from VANC [27],[28]. The one-off dosing
schedule is unprecedented in the treatment of severe infections and may be highly
beneficial for patients for whom compliance or indwelling IV cannula insertion may be
less suitable[29]. ORI is also unique in its class for its activity against GRE expressing
both vanA and vanB phenotypes, and therefore may be an emerging option for the
treatment of complex GRE-associated infections, including endocarditis[30]. DAL is
licensed (Xydalba®, Correvio UK Ltd) for administration as a single 1.5g IV dose, or as
two doses (1g and 500mg) administered on days one and eight[26]; both regimens
appear to be of equivalent efficacy for this indication[31]. Data from the double-blind
RCTs DISCOVER 1 and 2 suggest that DAL was non-inferior to at least three days of IV
VANC, either continued or followed by oral linezolid (LZD) to complete 10–14 days of
therapy for acute bacterial SSTIs. Efficacy was maintained in patients with
MRSA[32],[33]. DAL is inactive for vanA GRE, but retains activity in the vanB and vanC
(low-level VANC resistance) phenotypes[26]. Indications for DAL are likely to be similar
to ORI for the foreseeable future given their similar PK profiles and licensing
indications. TELA is licensed (Vibativ®, Clinigen Healthcare Ltd) for the treatment of
HAP (including VAP) that is known (or suspected) to be caused by MRSA, at a daily
dose of 10mg/kg[26]. In the ATTAIN 1 and 2 trials, TELA (in conjunction with suitable
Gram-negative cover, where required) was non-inferior to VANC in patients with
HAP/VAP[34]. However, concerns regarding the nephrotoxicity of TELA have arisen
from the study data; patients with renal impairment had elevated excess mortality in the
TELA arm versus VANC in an unpublished post-hoc analysis [35]. This is reflected in the
European and US licensing, which exclude use in these patients. It is questionable
whether this relates to intrinsic excess toxicity, or whether it merely reflects the
considerable body of data informing safer VANC prescribing in such patients. Given the
availability of cheaper and potentially safer agents, the role of TELA for its licensed
indication remains unclear. Further RCT data may be helpful in determining whether
this agent has a therapeutic niche not otherwise satisfied by other antimicrobials.

Daptomycin

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The cyclic lipopeptide Daptomycin (Cubicin®; Merck, Sharp & Dohme Ltd; DAPT) has
a broad spectrum of activity against Gram-positive bacteria, including GRE and MRSA.
Structurally, DAPT comprises a 13-member hydrophobic polypeptide with a lipophilic
side chain[36]. It is believed that this structure confers a unique mechanism of action,
albeit one that is not fully understood. It is suggested that the lipophilic region inserts
into the bacterial cell membrane, oligomerising into pore-like structures, through which
significant efflux of potassium ions occurs[37]. Immediate arrest of DNA, RNA and
protein synthesis occurs downstream of the membrane depolarisation, resulting in
rapid bacterial cell death. The drug is highly protein-bound, and has a biological half-
life in the region of nine hours in patients with normal renal function — compatible with
once-daily dosing. DAPT is licensed in Europe and the US for the treatment of SSTIs (at
4mg/kg once daily) and right-sided infective endocarditis (RIE) and/or bacteraemia
secondary to S. aureus (at 6mg/kg once daily). Treatment of respiratory tract infections
is contra-indicated given that DAPT is bound and inactivated by pulmonary surfactant
resulting in minimal penetration into the lung parenchyma[38]. Results from the initial
open-label study on which DAPT received approval for the RIE indication included
insufficient data from patients with left-sided (i.e. aortic or mitral valve) infective
endocarditis (LIE) receiving DAPT, with a trend towards negative outcomes in this
subset[39]. However, limited data suggest that this may relate to insufficient dosing in
LIE as successful outcomes have been achieved with higher doses in the range of 10–
12mg/kg once daily[40]. This is perhaps intuitive given that DAPT exhibits
concentration-dependent bactericidal activity but is also highly protein-bound,
resulting in lower levels of free, active drug at lower doses[41]. However, the major
adverse effect of DAPT is dose-dependent muscle toxicity. Asymptomatic elevations in
creatine kinase (CK), myalgia and, more rarely, rhabdomyolysis have been reported,
particularly in patients with renal impairment. Regular CK monitoring, at least weekly,
is therefore recommended for patients receiving long-term DAPT; patients should be
counselled to report any muscle-related symptoms immediately. Co-prescription with
other drugs associated with myopathy (including statins) should be avoided. DAPT
resistance has been reported in Gram-positive cocci, but is relatively uncommon at
present. Nevertheless, resistance has been reported during the prolonged treatment of
infections with a high microbial burden, such as deep-seated abscesses or infective
endocarditis. The mechanisms underlying DAPT resistance are currently poorly
understood, but unrelated mutations largely involved with cell wall precursor synthesis
have been postulated in a number of Gram-positive organisms, including staphylococci
and enterococci[42],[43]. Although an attractive once-daily option for the OPAT
treatment of complex infection, pharmacists must take care to ensure the risks of
myopathy are balanced against the very real risks of treatment failure if DAPT is under-
dosed. Careful monitoring of appropriate clinical parameters, alongside careful patient
selection, is likely to be critical to ensure successful outcomes in such cases.

Oxazolidinones

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The oxazolidinones (OXAs) are the newest class of antimicrobials to be licensed for
human use. OXAs possess broad-spectrum bacteriostatic activity, predominantly
against Gram-positive bacteria including MRSA and vancomycin-resistant enterococci
(VRE). OXAs are believed to abrogate bacterial protein synthesis by inhibiting the
formation of the ‘initiation complex’ — a composite structure of the 30S and 50S
ribosomal ribonucleic acid (rRNA) sub-units, transfer RNA (tRNA) and messenger RNA
(mRNA). OXAs bind to the 23S portion of the 50S rRNA sub-unit, thus inhibiting
mRNA translation at the earliest stage[44] . This is in contrast to other agents with
protein synthesis inhibitor activity (such as the macrolides and the lincosamide,
clindamycin), which prevent elongation of the nascent peptide chain[45]. A number of
major OXA resistance mechanisms have been identified to date, the most common of
which is class-specific involving the G2576T/U mutation of the 23S rRNA sub-unit[46] .
The second mechanism of resistance involves the plasmid-encoded cfr gene, an enzyme
with 23S rRNA methyltransferase activity, which confers a pan-resistant phenotype
involving chloramphenicol, clindamycin and LZD[47]. Similarly, OXA pan-resistance
mediated by the transmissible transporter-gene, optrA, has been observed in both
human and veterinary specimens throughout China, including from food-producing
animals[48]. Given the propensity of plasmid-transfer between strains, cfr and optrA are
perhaps the most concerning OXA resistance mechanisms observed to date.
Nevertheless, OXA resistance remains relatively uncommon in both staphylococci and
enterococci, and their unique mode of action preserves activity in the presence of
mutations conferring resistance to other protein synthesis inhibitors.

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LZD was the first OXA to gain a European product licence in 2000 for empirical use in
severe pneumonia and complicated SSTIs, where alternative agents are unsuitable.
Nevertheless, there is considerable experience supporting the use of LZD in bone and
joint infections, endocarditis and bacteraemias despite some concerns regarding the use
of a bacteriostatic agent in such settings[49],[50]. Indeed, for GRE-associated infections,
LZD is usually first-line treatment, irrespective of infection site or severity. In contrast
to the European licence, this indication has been reflected in FDA labelling since the
outset [51]. Similarly, FDA labelling also recognises the value of LZD for the treatment of
infections caused by MDR Streptococcus pneumoniae (pneumococcus) and
Streptococcus agalactiae (Group B streptococcus). More recently, European and US
regulatory authorities approved tedizolid (Sivextro®, Merck Sharp & Dohme, UK;
TZD), a second-generation OXA, for the treatment of acute skin and skin structure
infections (SSSIs) in adult patients. Data from ESTABLISH-1 and ESTABLISH-2, both
double-blind phase-III RCTs demonstrating non-inferiority of TZD versus LZD for the
treatment of SSSIs, underpinned the licensing decisions[52],[53]. Importantly, the
methodology of the above trials determined that a six-day course of once-daily TZD was
equivalent to a ten-day course of twice-daily LZD for this indication — probably
reflecting a biological half-life approximately twice that of LZD[54]. Common to LZD,
TZD is available in both IV and oral formulations, and has near-total enteral
bioavailability. TZD may also be effective against LZD-resistant organisms, including
those harbouring the cfr gene[55]. Taken together, TZD may be used for short-course,
ambulatory treatment of SSSIs, particularly in patients for whom compliance or the use
of IV therapy may be problematic. However, the cost implications of TZD are
considerable, particularly as LZD is now available as a generic preparation in many
parts of the world, including the UK. Accordingly, LZD is now used extensively in UK
OPAT settings for the ambulatory treatment of infections, including SSTIs, in which IV
therapy would normally be indicated. Further data are required to answer the issue of
superiority in this class of antimicrobials, and the use of TZD is likely to be valid only on
an individual condition-by-condition basis.
Due to their inhibitory effect on protein synthesis, the OXAs are particularly useful for
attenuating infections and para-infectious phenomena caused by polypeptide exotoxins.
Panton-Valentine Leukocidin (PVL) is a highly virulent exotoxin produced by some
strains of methicillin-sensitive S. aureus (MSSA) and MRSA that is associated with
severe SSTIs, necrotising pneumonia and fulminant systemic sepsis[56],[57]. LZD is
among the treatments of choice in severe PVL-positive MRSA infections, usually in
combination with another effective agent (i.e. a glycopeptide and/or rifampicin), as both
overt and inducible clindamycin resistance is relatively common in this situation[58].
Similarly, LZD can play an important role in the treatment of infections caused by
toxigenic strains of Streptococcus pyogenes (Group A streptococcus; GAS), responsible
for scarlet fever, necrotising fasciitis and systemic sepsis[59].

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Despite the clear advantages offered over other agents, the side-effect profile of the
OXAs can be problematic. The most serious among these include myelosuppression and
neurological toxicity, including severe and sometimes irreversible, optic and peripheral
neuropathies in up to 0.1% of patients[60],[61]. It is hypothesised that such adverse
effects relate to an inhibitory effect on mitochondrial protein synthesis in a manner
broadly similar to certain nucleoside analogues, such as zidovudine (AZT) and
stavudine (d4T), used in the treatment of HIV infection[62]. The impact of the OXAs on
bone marrow and nerve function appears to be cumulative, although severe side effects
after minimal exposure have been observed. Therefore, prolonged use of LZD in excess
of four weeks is strongly discouraged without specialist supervision[61]. Most
international guidelines mandate weekly full blood count monitoring for all patients
receiving LZD, and careful patient counselling regarding the symptoms and signs of
neurological dysfunction. Trial data suggest that TZD may offer a more favourable
adverse effect profile versus LZD, but given the six-day treatment restriction it is
unclear of the validity of such findings in the context of longer-term therapy[52],[53]. The
other issue of concern is the interaction between OXAs, certain foods and medications.
Both LZD and TZD possess reversible monoamine oxidase inhibitor (rMAOI) activity,
and are therefore generally contra-indicated for concomitant use with
sympathomimetic or serotonergic agents due to the risk of hypertensive crisis or
serotonin (5-hydroxytryptamine) syndrome, respectively[63]. Similarly, excessive
consumption of foods and beverages high in tyramine (including mature cheeses, cured
meats, soy products and brewed beers) are best avoided during a treatment course to
reduce the risk of hypertension[64] . Pharmacists are likely to play a key role in the
counselling process, to ensure patients receiving these drugs are fully aware of these
important interactions.

Novel cephalosporins

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Ceftaroline (Zinforo®, AstraZeneca UK Ltd; CTA) and ceftobiprole (Zevtera®, Basiliea
Pharmaceutica International, UK; CBA) are fifth-generation cephalosporins, both
possessing a unique spectrum of bactericidal activity among β-lactams. CTA and CBA
bind with high affinity to the penicillin-binding proteins (PBPs) 2A, 2X and 5—the
transpeptidases conferring β-lactam resistance in MRSA, penicillin-resistant
pneumococci and Enterococcus faecium, respectively[65],[66],[67]. CTA is licensed in
Europe and the US for the treatment of complicated SSTIs and community-acquired
pneumonia (CAP) in adults. Data from the double-blind RCTs CANVAS 1 and 2
suggested the non-inferiority of CTA versus VANC (plus aztreonam) for the treatment of
complicated SSSIs in a modified intention-to-treat (mITT) analysis[68],[69]. Concordance
of efficacy was demonstrated between the mITT and clinically evaluable populations; a
reassuring finding. Indeed, this was despite the presence of MRSA in around a third of
patient cultures. However, given the relatively poor efficacy of the comparator arm (i.e.
VANC) for the treatment of complicated staphylococcal infection, such results are
perhaps unsurprising. Nevertheless, CTA may play a role in the treatment of MRSA-
positive SSTIs for whom VANC and other agents are unsuitable or ineffective. For the
CAP indication, FOCUS 1 and 2, both double blind, placebo-controlled RCTs,
determined that CTA was non-inferior to IV ceftriaxone (CRO) 1g once daily for the
treatment of CAP in the absence of atypical pathogens[70],[71]. Moreover, in the crude
analysis of the mITTE population, the cure-rate for cases positive for pneumococci was
markedly higher in the CTA arm (88.9% versus 66.7%). While the numbers are small
and preclude firm conclusions, this is possibly due to the superior efficacy of CTA for
penicillin-resistant strains. However, the inference of any overall benefit may be
difficult to generalise to areas with lower rates of pneumococcal resistance, such as the
UK, and may not justify the additional cost versus standard first-line therapies.
Additionally, it is noteworthy that both studies used a relatively low dose of CRO in the
comparator arm (1g once daily). Pneumococci with elevated penicillin minimum
inhibitory concentrations (MICs) may be treated successfully by increased β-lactam
exposure, and it is therefore unclear whether CTA would confer similar benefit over
larger doses of CRO in such patients, arguably in keeping with standard clinical
practice[72]. Despite these reservations, CTA may be a useful salvage agent for the most
difficult-to-treat infections, with early data suggesting a potential adjuvant benefit in
recalcitrant MRSA bacteraemia and MDR enterococcal infections[73],[74].

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CBA has a pan-European licence for the empirical treatment of CAP and HAP,
excluding VAP[75]. Licensing was supported by data from two double-blind, placebo-
controlled RCTs, which suggested the non-inferiority of CBA versus CRO±LZD (for
CAP) and ceftazidime (CFZ) ± LZD (for HAP) among the clinically evaluable and mITTE
population[76],[77]. For the CAP study, rates of MRSA and MDR pneumococci were low,
thus indicating that the optional adjuvant LZD in the comparator arm was redundant in
most cases. Therefore, where local epidemiology is such that MRSA or penicillin-
resistant pneumococci are uncommon causes of CAP, CBA is non-inferior to CRO, but
where rates are higher, it remains to be seen whether CBA offers a clinical cure benefit
over CRO. This is in direct contrast to the HAP study, in which MRSA was present in
around 10% of the study population. In these patients, CBA conferred additional benefit
over the comparator arm in terms of subjective clinical improvement by day four of
therapy (94.7% versus 52.6%; difference: 42.1%; 95% CI: 17.5–66.7). It is possible that
this observation relates to the bactericidal properties of CBA on MRSA — a high
virulence pathogen — in comparison to the bacteriostatic LZD [46] . However, at the test-
of-cure (TOC) visit, there was no difference in cure rate in MRSA-infected patients.
Thus, the clinical relevance of the highlighted finding is unclear. CBA may therefore be
of benefit for patients with MRSA-associated pneumonia; the combination with LZD
could be a viable salvage option for patients with severe PVL-MRSA-associated
infection. It is important to state that the European and US licences for CBA explicitly
preclude its use for the VAP indication. This relates to the observation from subgroup
analysis of the aforementioned trial, in which CBA failed to meet the primary efficacy
endpoint for this indication (37.7% versus 55.9%; difference: –18.2%; 95% CI: 36.4;0).
The reasons for this are unclear but may relate to CBA’s lack of anti-pseudomonal
activity, as Pseudomonas was isolated in respiratory secretions in around a fifth of VAP
cases.

The side-effect profiles of CTA and CBA are relatively bland, a class phenomenon, and
are generally well tolerated by patients. However, clinical pharmacists and prescribers
must be mindful of the association between cephalosporins and Clostridium difficile
infection, which applies equally to CBA and CTA as with other drugs in the class.

Elastomeric pumps: using flucloxacillin in outpatient settings

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Flucloxacillin is a narrow-spectrum, second-generation penicillin derivative with
superior comparative efficacy for the treatment of infections caused by MSSA and
penicillin-sensitive streptococci versus most other antimicrobials[5],[6]. In subjects with
a normal glomerular filtration rate (GFR), the biological half-life of flucloxacillin is in
the region of 1.6 hours, necessitating a six-hourly dosing regimen (by intermittent IV
infusion) to ensure sufficient systemic exposure[78]. The administration of β-lactams,
including flucloxacillin, by continuous IV infusion has been recognised for around 20
years. Initially, this was intended to capitalise on the established relationship between
systemic area-under-the-curve (AUC) exposure and bactericidal activity of β-lactam
antimicrobials[79],[80] . More recently, elastomeric infusion pumps have been used to
facilitate OPAT administration of antimicrobials, including flucloxacillin. These
portable devices are worn by the patient, usually in a pouch around the waist, and are
designed to deliver the infusion automatically following attachment to a suitable IV
cannula. Published outcome data for this approach appear to be highly favourable[81].
However, there are no RCT data comparing flucloxacillin IV infusions with more
established therapies, including IV CRO. In principle, any antimicrobial may be
delivered in this fashion, provided that robust safety and stability data exist for the
agent in question. However, it is clear that the current evidence base for antimicrobial
stability in portable devices does not meet the prescribed national guidelines; at least in
the UK[82]. Thus, the unique knowledge base and skillset of clinical pharmacists
— including expertise in the safe delivery and procurement of medications — is likely to
remain central to the governance structure of a high quality OPAT service in future.

Horizon-scanning in Gram-positive antimicrobial therapy: from

novel compounds to renaissance drugs
The growing problem of global AMR has led to heightened interest in the use and
development of antimicrobials with novel resistance properties. Solithromycin (SOL) is
a novel antimicrobial of the fluoroketolide class; a derivative of existing macrolides
including erythromycin[83]. In common with its structural homologues, SOL possesses
bacteriostatic activity by inhibition of the 50S ribosomal sub-unit[84]. This confers a
relatively broad spectrum of activity against many Gram-positive bacteria (including
MSSA and pneumococcus)[85]. Resistance appears to be uncommon, with preserved
activity against MDR strains of pneumococcus, including those with high-level
macrolide resistance[86]. Indeed, data from two double-blind RCTs confirmed the non-
inferiority of oral and IV SOL (versus moxifloxacin) in the treatment of CAP, including
in cases caused by macrolide-resistant pneumococcus[87],[88]. However, SOL has high
structural similarity to telithromycin, a ketolide withdrawn in 2007 by the FDA
following significant hepatic and neurological safety concerns[89],[90]. Similar concerns
have arisen with SOL, and the FDA have recently refused to approve the drug pending
further data — an outcome likely to prevent widespread use of this agent for the
foreseeable future[91].

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A number of next-generation fluoroquinolones (FQs), with key activity against Gram-
positive organisms, are in development. FQs possess potent bactericidal activity via
their interactions with bacterial DNA gyrase and topoisomerase IV, both essential for
DNA replication[92]. Delafloxacin has broad-spectrum coverage against important
Gram-positive pathogens, including MRSA and GRE. Data from phase II studies suggest
that delafloxacin is safe and efficacious in the treatment of SSTIs, as compared with
VANC, tigecycline (TIGE) and LZD[93],[94] . Experimental data also suggest a potential
role for lower respiratory tract infections (RTIs)[95],[96]. Similarly, nemonoxacin and
zabofloxacin are related FQs with data to support their use in infective exacerbations of
chronic obstructive pulmonary disease (COPD) and CAP[97],[98]. Topical ozenoxacin
possesses potent in vitro activity against MRSA and MSSA, including ciprofloxacin-
resistant strains, and appears to be efficacious for the empirical treatment of superficial
skin infections, such as impetigo or infected eczema[99]. Thus, ozenoxacin may also play
a future role in MRSA decolonisation protocols, where resistance or allergy precludes
the use of mupirocin (Bactroban®, GlaxoSmithKline UK) or chlorhexidine/neomycin
(Naseptin®, Alliance Pharmaceuticals) nasal cream. However, the development of new
FQs must be taken in context of concerns regarding toxicity. Given the potentially
serious side-effect profile of existing FQs (including tendon rupture, cardiac
dysrhythmia and retinal detachment), new agents of this class are likely to be subject to
intense pre- and post-licensing scrutiny. Further data will be necessary to satisfy the
requirements of the US and European regulatory authorities, but these agents may have
a role to play in the treatment of MDR infections, where existing agents are unsuitable.

In keeping with the concept of antimicrobial cycling and mixing, clinical pharmacists
must be aware of the value older antimicrobials may have in the treatment of MDR
infections and as components of OPAT-compatible regimens: these are discussed in this
section. Furthermore, the use of oral antimicrobials with high bioavailability is likely to
increase given the preliminary data from OVIVA — a multi-centre RCT comparing the
efficacy of oral versus IV antimicrobials for adults with bone, joint or orthopaedic
metalwork-associated infections[100]. Early data from this study intimate non-inferiority
of oral agents in this setting. However, it is very important to recognise the
heterogeneity of the OVIVA study population, incorporating a diverse spectrum of
demographic, infection-type and microbiological characteristics. Therefore, subgroup
analysis will be crucial to understanding the optimal management at the individual-
patient level, and firm conclusions cannot be drawn at present. It is particularly
important to note that susceptibility testing is essential to guide oral therapy in this
setting. Staphylococci, in particular, are variably susceptible to oral agents with high
levels of heterogeneity between isolates[101]. Clindamycin, doxycycline and
trimethoprim-sulfamethoxazole (co-trimoxazole) possess good efficacy against sensitive
strains of staphylococci, including MRSA and coagulase-negative staphylococci. These
agents are highly bioavailable orally, and with prolonged use, penetrate skin and
musculoskeletal (MSK) tissues well[102]. Similarly, oral fusidic acid (sodium fusidate)
and rifampicin may be useful for the adjunctive treatment of deep-seated MSK
staphylococcal infections, including MRSA. Neither agent should ever be used as
monotherapy; resistance occurs readily, even on treatment[103],[104]. Rifampicin may
14/26
also be useful for preventing biofilm formation in patients with infected prostheses, or
to prevent colonisation in bacteraemic patients with indwelling devices (e.g. permanent
cardiac pacemakers or prosthetic cardiac valves)[105],[106]. Regular monitoring of liver
function tests is essential, as drug-induced hepatitis is relatively common and can be
life-threatening. Fosfomycin (FOS), an agent first synthesised in 1969, was previously
available in the UK only as an unlicensed oral preparation for the treatment of
uncomplicated urinary tract infections (UTIs)[107] . In the era of increasing AMR, IV FOS
has recently received a European licence for the treatment of a wide range of deep-
seated infections including bacteraemia, osteomyelitis and meningitis. Indeed, data for
its successful use in a diverse range of severe infections are emerging[108],[109]. FOS
inhibits the bacterial enzyme, UDP-N -acetylglucosamine-3-enolpyruvyltransferase
(MurA), involved in the synthesis of peptidoglycan cell wall components in both Gram-
positive and Gram-negative organisms[110]. Accordingly, FOS possesses broad-spectrum
bactericidal activity, including some activity against Pseudomonas aeruginosa. This
unique mode of action makes FOS a potential option for the treatment of infections
caused by MDR Gram-positive organisms, including MRSA and VRE. FOS is generally
considered to possess a low barrier to the development of resistance, with mutant
strains developing readily in vitro[111]; to a lesser extent, this may occur in vivo even
during therapeutic dosing[111],[112]. This may be circumvented to a certain extent by
using FOS in combination with other agents, such as DAPT[109]. Given its high
predisposition to resistance and unique activity against highly resistant organisms, FOS
should be reserved as a drug of last resort when other agents are contra-indicated due
to resistance or allergy. While the oral preparation (fosfomycin trometamol) is now also
licensed within the EU, it has unproven efficacy outside the indication of uncomplicated
UTI, and therefore should not be used in complex infections or as an oral step-down
agent following IV therapy. TIGE, a semisynthetic tetracycline analogue, possesses
activity against MRSA and VRE, and currently holds an EU licence for the treatment of
complicated SSTIs and intra-abdominal infections. TIGE is bacteriostatic and is
therefore less suitable for the treatment of bacteraemia where rapid bacterial killing is
desirable. Normally administered as a 100mg IV loading dose, followed by 50mg twice
daily, TIGE may be a useful treatment option for the OPAT management of patients
with organisms caused by MDR organisms, or where allergy to β-lactams precludes the
use of first-line agents. Emerging data suggest a once daily regimen (at the 100mg dose)
appears to be feasible and well tolerated, and may be advantageous for OPAT
administration[113].

The paradigm of clinical infection practice, of which the treatment of infections caused
by Gram-positive organisms is but one component, is liable to change in the era of
increasing use of OPAT, together with the major issue of AMR. Pharmacists are likely to
play a significant role in the safe and effective use and delivery of anti-infective
therapeutics via a multi-disciplinary team approach. Taken together, it will be critical
that clinical pharmacists maintain and drive an awareness of the principles of
antimicrobial stewardship and the importance of involving the infection specialist team
in the care of complex patients.

15/26
 Author disclosures and conflicts of interests

Christopher Eades has received an honorarium from Basiliea Pharmaceuticals

(2017); Stephen Hughes has received educational grants from Pfizer Inc. (2014) and
Baxter Healthcare UK (2017); Katie Heard has no interests to declare; Luke SP
Moore has received consulting fees for BioMérieux UK & Ireland (2013, 2014), and
DNA Electronics (2015). He also received a research grant from Leo Pharma UK
(2015), and received financial support to attend educational activities from
Eumedica SA (2016).

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Citation: Clinical Pharmacist, September 2017, Vol 9, No 9, online | DOI:
10.1211/CP.2017.20203363

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