MENACE OF RISING MDR GRAM POSITIVE INFECTIONS IN ICU. NEWER ANTIBIOTIC APPROACHES

1. Gram Positive Infections In ICU –
Emerging Resistance Patterns &
Newer Treatments
Dr. Pankaj Omar
Head Of Critical Care
Prof & Head for Superspeciality critical care course
SNH Raipur.
1

2. • Definition:
– microorganisms, predominantly bacteria, that are
resistant to one or more classes of antimicrobial
agents
• Importance:
– Limited options for treatment
– Increase the length of stay and cost of
hospitalization
– Increase admission to and stay in ICU
– High mortality rates
2
Multi-Drug Resistant Gm +ve
Organisms

3.  Transmission:
◦ Mainly person to person through hands of
healthcare personnel (HCP)
◦ Contact with contaminated environmental surfaces
◦ Transmission depends on
 Availability of vulnerable patients
 Antimicrobial pressure
 Colonization pressure
 Adherence to infection control measures
 Frequent movement among healthcare facilities
3
Multi-Drug Resistant Gm +ve
Organisms Epidemiology

4.  Reservoirs
◦ Infected and colonized patients
◦ Contaminated environmental surfaces & patient
care equipment
 Risk factors
◦ Colonization, age > 65, ICU admission, long
hospital stay, frequent hospitalizations, invasive
procedures, indwelling devices, underlying
diseases, enteral feeding, LTCFs, antimicrobial
exposure
4
Multi-Drug Resistant Gm +ve
Organisms – Epidemiology

5. • Infected: a person who has culture-positive
for an organism and displays signs or
symptoms of infection
• Colonized: a person who has culture-
positive for an organism but has no signs or
symptoms of infection
5
Multi-Drug Resistant Gm +ve
Organisms – Epidemiology

6. Enterococcus faecium (VRE)
Staphylococcus aureus (MRSA)
Clostridium difficile (C. Diff)
RARELY--
Actinomycete, (order Actinomycetales), member of
a heterogeneous group of gram-positive, generally
anaerobic bacteria noted for a filamentous and
branching growth pattern that results, in most forms, in
an extensive colony, or mycelium.
i.e. nocardiosis,
6
Important Multi-Drug Resistant Gm
+ve Organisms

7. Gram Positive Infections In ICU –Emerging
Resistance Patterns & Newer Treatments
• Gram-positive bacteria are among the most
common human pathogens (ICU+COMMUNITY)
• associated with clinical infections, which range
from mild skin infections to sepsis.
• The prevalence of drug-resistant strains of Gram-
positive bacteria (including- methicillin-resistant
Staphylococcus aureus and glycopeptide-resistant
enterococci) is increasing.

8. Gram Positive Infections In ICU –Emerging
Resistance Patterns & Newer Treatments
• 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

9. Gram Positive Infections In ICU –Emerging
Resistance Patterns & Newer Treatments
• 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 .
• superior comparative efficacy of first-line β-lactams in
staphylococcal infection, such as flucloxacillin and cefazolin
• 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

10. • In recent years, S. aureus with elevated vancomycin
MICs have emerged. S. aureus with intermediate
susceptibility to vancomycin (MIC 8 mg/L) were first
identified in Japan in 1996 ,and subsequent isolates
have been identified in other parts of the world,
including the USA and France
Probable mechanism of resistance is peptidoglycan
overproduction. Hetero-VISA has also been reported.
Hetero-VISA strains are suscept-ible to vancomycin but
contain subpopulations, at a frequency of 10)6 CFU/mL
or higher that grow at a vancomycin concentration of 4
mg/L and have MICs of >4 mg/L.

11. • Following the development of VISA and SARV,
vancomycin-resistant MRSA (VRSA) has now emerged.
Three isolates have been identified to date in the USA,
from Michigan, Pennsylvania and more recently, New
York . The Michigan isolate had a vancomycin MIC of
1024 mg/L, was also resistant to teicoplanin, and was
positive for vanA. The gene appeared to have been
acquired from an enterococcus
• A study from the SENTRY surveillance programme in
2001 reported that 1.2% (35/3052) of S. aureus isolates
collected from European hospitals were non-
susceptible to quinupristin/dalfopristin (MIC ‡2 mg/L) .

12. • In addition, clinical failures have been
reported for the oxazolidinone linezolid,
involving both susceptible (linezolid MIC 4
mg/L) and resistant (linezolid MIC ‡8 mg/L)
isolates

13. Enterococci
• Enterococci are part of the normal intestinal flora.
• However, the presence of virulence genes has meant they have become
an important consideration in the treatment of serious Gram-positive
infections . Of great concern is the acquired resistance of Asuch as
Enterococcus faecium and Enterococcus faecalis. In these species, several
genes mediate resistance, the most common of which are vanA and vanB.
Isolates that carry the vanA gene typically demonstrate high vancomycin
and teicoplanin MICs, whereas those isolates that carry the vanB gene are
resistant to vancomycin (but with a lower MIC than vanA isolates) and
susceptible to teicoplanin.
• The prevalence of vancomycin-resistant enterococci(VRE) is highly variable
across Europe and seems to be high in Italy (because of local epidemics)
and the UK (Fig. 3).
• VRE is a particular problem in large hospitals and the risk factors
commonly associated are severe underlying disease, prolonged hospital
stay and previous antibiotic therapy.

14. Enterococci
• Treatment options are limited as VRE are typically multi-drug resistant,
with vancomycin-resistant E. faecium known to be very often resistant to
high concentrations of aminoglycosides,to ampicillin and to the
fluoroquinolones in addition to the glycopeptides.
• Recently, the transfer of the vancomycin resistance genes from the
enterococci into other species has been realised with the emergence of
vancomycin-resistant MRSA.

15. In the case of infections caused by intermediate S.
pneumoniae isolates, agents such as ceftriaxone or
cefotaxime can be used as treatment as long as the patient
does not have meningitis.
Treatment options are further complicated as penicillin
non-susceptible S. pneumoniae are typically resistant to
multiple drugs such as erythromycin, tetracycline and co-
trimoxazole.
Penicillin non-susceptible S. pneumoniae are a problem all
over the world, both in the community and hospital setting.
In 2002, the EARSS project reported five countries with a
prevalence of penicillin non-susceptible S. pneumoniae of
greater than or equal to 30%.

16. Viridans group streptococci
• Viridans group streptococci are particularly important
pathogens causing bacteraemia in febrile neutropenic
patients, a particularly severe clinical syndrome.
• streptococcal infection was associated with diarrhoea,
use of non-absorbable antifungal agents, high-dose
cytarabine and gut decontamination with colistin.
• Complications that commonly arise in neutropenic
patients with viridans streptococcal bacteraemia
include pneumonia (3–31%), acute respiratory distress
syndrome (3–33%), hypotension (5–37%), shock (7–
18%) and endocarditis (7–8%). Mortality is reported
tooccur in 6–30% of the patients.

17. STRATEGY
• Today, it is necessary to deal with infections caused by multidrug-
resistant organisms, particularly methicillin-resistant staphylococci,
penicillin- and erythromycin-resistant pneumococci, and
vancomycin-resistant enterococci (VRE). The emergence and rapid
spread of strains of methicillin-resistant Staph. aureus (MRSA),
which are resistant not only to all b-lactams, but also to the other
main antibiotic classes, has resulted in an increased use of
glycopeptide antibiotics, i.e., vancomycin and teicoplanin.
• As a result of these developments, there is an urgent need for
effective new antimicrobial agents, as well as for prudent use of
existing agents. Linezolid, quinupristin–dalfopristin,
daptomycin,tigecyline, new glycopeptides and ceftobiproleare the
main new agents that have recently become available for use or are
underclinical development.

18.  Staph aureus (SA) resistant to beta‐lactams.
 Nasal colonization  general population
◦ 25-30 % for SA
◦ < 2% for MRSA
 Other colonization sites: rectum, axilla, throat, wounds
 Higher carriage among HCP, dialysis patients, diabetics, IV
drug users
 Reservoirs: ……. and……...
 Transmission…… and………
18
MRSA – Epidemiology

19.  49-65 % of HA-Staph infections NHSN
◦ 94,360 invasive MRSA infections annually/US
◦ 18,650 associated deaths
◦ 86% of all invasive MRSA are HAIs
 Staphylococcus aureus
◦ Intrinsic virulence
◦ Cause a wide range of life threatening infections
◦ Adapt to different environmental conditions
◦ Can survive in the environment 1-56 days
19
MRSA – Epidemiology

20.  MRSA colonization generally precedes infection
 Risk of developing MRSA infection among
colonized individuals is 29% in 18 months
 Rationale for prevention
◦ Prevent transmission from colonized to un-colonized
individuals
◦ Prevent infection in colonized individuals
 MRSA-specific strategies (Decolonization)
 Non MRSA-specific strategies (reduce device-
associated infections)
20
Prevention and Control

21.  Aerobic Gram positive cocci that inhabitant of GI tract
and female genital tract
 Endemic in most U.S. hospitals
 25% all enterococcal isolates are VRE
 Resistance is commonly seen in isolates of E. faecium
than E. faecalis
 Risk factors (Host, Healthcare facility, Antimicrobial
exposure)
21
Vancomycin‐Resistant Enterococci
(VRE) Epidemiology

22.  Reservoirs: ….. and ……..
 Transmission: ……and ……
 Common sites of infection: urinary tract, surgical
wound, blood stream
 Mortality rate is 2 times higher in VRE than VSE
infections
 Survives on environment  days – weeks
22
VRE Epidemiology

23.  Gram positive spore forming bacillus (rods)
 Obligate anaerobe
 Part of the GI Flora in
◦ 1-3% of healthy adult
◦ 70% of children < 12 months
 Some strains produce toxins A & B
 Toxins-producing strains cause C. diff Infection
(CDI)
 CDI ranges from mild, moderate, to severe and
even fatal illness
23
C. difficile : Epidemiology

24. Transmission
 Fecal – oral route
◦ Contaminated hands of healthcare workers
◦ Contaminated environmental surfaces.
 Person to person in hospitals and LTCFs
 Reservoir:
◦ Human: colonized or infected persons
◦ Contaminated environment
 C. diff spores can survive for up 5 months on environmental
surfaces.
24
C. difficile Epidemiology

25.  A common cause of nosocomial antibiotic-
associated diarrhea (AAD)
 Most common infectious cause of acute
diarrheal illness in LTCFs
 The only nosocomial organism that is anaerobic
and forms spores
 Infective dose is < 10 spores
25
C. difficile: Epidemiology

26. Number of
annual
cases
Cost Number of annual
deaths
Hospital-onset, hospital acquired
(HO-HA)
165,000 $ 1.3 B 9000
Nursing home-onset 263.000 $ 2.2 B 16,500
26
CDI: Impact

27. • Illness caused by toxin-producing strains of
C. difficile ranges from
– Asymptomatic carriers = Colonized
– Mild or moderate diarrhea
– Pseudo membranous colitis that can be fatal
• A median time between exposure to onset of
CDI symptoms is of 2–3 days
• Risk of developing CDI after exposure ranges
between 5-10 days to 10 weeks
27
Clinical Manifestations

28. 28
Rationale for Preventive strategies
Antimicrobial
stewardship
Admitted to
healthcare facility
Antimicrobials
C Diff exposure & acquisition
Colonized
no symptoms
Infected
Symptomatic
Optimizing Environmental
cleaning and Hand Hygiene

29. Supplemental Measures
 Extend (CP) beyond
duration of diarrhea (48
hours)
 Presumptive isolation for
symptomatic patients
 Implement soap and water
for HH before exiting room
of a patient with CDI
 Implement universal glove
use on units with high CDI
rates
 Use sodium hypochlorite
(bleach) - containing agents
for environmental cleaning
 Implement an antimicrobial
stewardship program
29
Preventive Strategies: C. Diff
Core Measures
 Surveillance
 Contact Precautions (CP)
for duration of diarrhea
 Hand hygiene (HH)
 Dedicated equipment
 Cleaning and disinfection of
equipment and environment
 Laboratory-based alert
system for immediate
notification
 Educate HCP,
housekeeping, admin staff,
patients, families, visitors,
about CDI
 Monitor compliance

30.  Patient placement (factors to consider)
 Hand hygiene (HH)
 Gloves
◦ Don gloves upon room entry
◦ Change gloves after contact with infectious materials
◦ Change gloves when moving from contaminated to non contaminated
site
◦ Remove gloves and HH before leaving the room or caring for another
patient
 Gowns
◦ Don gown upon room entry
◦ Remove and discard gloves before removing gown
◦ Discarding gown before exiting the room
 After gown and gloves removal HH make sure not to touch any
potentially contaminated environmental surface in the room
 Dedicated equipment (BP cuff, stethoscope, thermometer, etc.)
30
Contact Precautions (CP)

31.  Challenges of implementing CP in LTCFs
 Contact Precautions should be used for the following
residents with MDROs
◦ Dependent on HCP in their activities of daily life
◦ Ventilator-dependent
◦ Incontinent of stool
◦ Wound with difficult to contain discharge
 Contact Precautions can be relaxed for all others
residents with MDROs (consider resident’s mental
status and personal hygiene)
 Standard precautions should be observed all times
 Dedicated equipment
 Signage for HCP and visitors
31
Contact Precautions in LTCFs

32. NEWER ANTIBIOTICS

33. Glycopeptides
• 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
• 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.
• 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

34. Glycopeptides
• TEIC is not active for the majority of infections caused
by GRE, with the exception of those expressing TEIC-
usceptible phenotypes, including vanB and vanC
• A proportion of coagulase- negative staphylococci are
also resistant
• 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).

35. Glycopeptides
• 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
• DAL is inactive for vanA GRE, but retains activity in the vanB
and vanC (low-level VANC resistance) phenotypes
• 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
• 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

36. GLYCOPEPTIDE
• Like teicoplanin, dalbavancin is active against
vanB-positive enterococci, as well as
staphylococci and other important species.
• The pharmacokinetic profile of dalbavancin is
characterised by a long half-life of c. 7 days.

37. GLYCOPEPTIDE
• Oritavancin is active against most isolates of streptococci and
staphylococci, as well as Peptostreptococcus spp.,
Propionibacterium acnes, Clostridium perfringens and
Corynebacterium jeikeium.
• Its activity against enterococci is not affected by the presence of
vanA-, vanB- and vanC-encoded vancomycin resistance, or by
aminoglycoside resistance.
• Its activity against pneumococci and viridans streptococci is not
affected by the presence of intermediate- or high-level penicillin
resistance.
• In addition, the presence of methicillin resistance does not affect
the activity of oritavancin against Staph. aureus or
coagulasenegative staphylococci.
• Oritavancin is inactive against Gram-negative aerobes and
anaerobes

38. Daptomycin
• The cyclic lipopeptide Daptomycin (Cubicin®; Merck,
Sharp & Dohme Ltd; DAPT) has a broad spectrum of
activity against Gram-positive bacteria, including GRE
and MRSA.
• 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

39. Daptomycin
• 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. 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
• 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
• 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 .

40. DAPTOMYCIN
• Daptomycin is the first of a new class of cyclic lipopeptides.
This agent is derived from the fermentation of a strain of
Streptomyces roseosporus.
• Daptomycin attaches to the cytoplasmic membrane of
Gram-positive bacteria, forming a channel that allows the
efflux of potassium, causing depolarisation of
themembrane, along with dysfunction of macromolecular
synthesis and collapse of the organism without lysis.
• It has been used successfully to treat bone and joint
infections . Successful results have also been reported for
the treatment of bacteraemia and right-sided infective
endocarditis, but not for the treatment of community-
acquired pneumonia

41. Daptomycin
• The lack of efficacy of daptomycin in treating community-
acquired pneumonia is thought to be a consequence of a
reduction of daptomycin activity in the presence of lung
surfactant .
• Resistance to daptomycin is rare. Spontaneous resistance is
uncommon, resistance can be induced by serial passage in
increasing concentrations of the antibiotic .
• There have been several reports of daptomycin resistance
emerging in clinical isolates of MRSA from patients who
received prolonged treatment . The once-daily dosing
schedule and the favourable safety profile (except for some
concerns regarding rhabdomyolysis and neuropathy) make
daptomycin an attractive option for the treatment of Gram-
positive infections

42. Oxazolidinones
• The oxazolidinones (OXAs) are the newest
class of antimicrobials .
• OXAs possess broad-spectrum bacteriostatic
activity, predominantly against Gram- positive
bacteria including MRSA and vancomycin-
resistant enterococci (VRE).

43. Oxazolidinones
• 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
• 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
• 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 .
• 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.

44. Oxazolidinones
• 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 . 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
• 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

45. LINEZOLID
• depending on the organism and the linezolid concentration, has a
bacteriostatic or bactericidal effect by inhibiting protein synthesis at
the ribosomal level and by preventing the formation of the protein
initiation complex [9].
• Linezolid is active against most Gram-positive bacteria, including
methicillin-sensitive Staph. aureus (MSSA) and MRSA,
Streptococcus pneumoniae (including multidrug-resistant strains),
Streptococcus pyogenes and Streptococcus agalactiae.
• Rare occurrences of linezolid resistance among VRE in North
America (0.8–1.8%), caused by a G2576U ribosomal mutation, have
been reported, and an intrinsic resistance gene rendering a clinical
strain of MRSA resistant to linezolid has been described. Although
resistant strains of Staph. aureus have been reported, linezolid
remains highly active against MRSA (MIC90 2 mg⁄ L)

46. LINEZOLID
• Linezolid is reported to be equally effective or even superior to
vancomycin for the treatment of pneumonia and soft-tissue
infections . However, recent meta-analyses have suggested that
linezolid’s apparent superiority for the treatment of pneumonia and
bone and joint infections has limitations. Cases of MRSA
endocarditis that failed to respond to linezolid treatment have also
been reported
• Like many other antibiotics, it may predispose to pseudo-
membranous colitis following the overgrowth of Clostridium
difficile . Myelosuppression (including anaemia,leukopenia,
pancytopenia, and thrombocytopenia)has been reported in patients
taking linezolid.
• Lactic acidosis, peripheral neuropathy and optic neuropathy are
other adverse effects of linezolid treatment.

47. TIGECYCLINE
• Tigecycline is a new, semi-synthetic glycylcycline, which is a
new class of antimicrobial agent. Glycocides are derivatives
of tetracyclines, and have broad-spectrum activity against
susceptible and multidrug-resistant strains of bacteria.
• Tigecycline, the first glycylcycline, demonstrates potent in-
vitro activity against a wide range of Gram-positive and
Gram-negative bacteria,including MRSA and tetracycline-
resistant Staph. aureus, as well as many multidrug-resistant
Gram-negative pathogens and anaerobes .
• The potent in-vitro activity of tigecycline resulted in its
approval by the FDA for the treatment of skin,soft-tissue
and intra-abdominal infections .

48. QUINUPRISTIN–DALFOPRISTIN
• Quinupristin–dalfopristin (Synercid_) is a fixed mixture (30:70) of semi-
synthetic streptogramin derivatives. These compounds enter bacterial
cells by diffusion and bind to different sites on the 50S ribosomal subunit,
resulting in an irreversible inhibition of bacterial protein synthesis.
• Dalfopristin blocks the reaction catalysed by the peptidyl transferase
catalytic centre of the 50S ribosome by inhibiting substrate attachment to
the P-site and A-site of the ribosome.
• Quinupristin inhibits peptide chain elongation. The synergic effect of this
drug combination appears to result from the fact that it targets both early
and late stages of protein synthesis .
• Thus, quinupristin–dalfopristin is bacteriostatic against E. faecium and
bactericidal against MSSA, MRSA and Strep. pyogenes.
• It is ineffective against Enterococcus faecalis.
• In the USA, the only FDA-approved use of quinupristin–dalfopristin as an
anti-staphylococcal agent is for the treatment of adults with complicated
skin and skin-structure infections caused by MSSA.

49. QUINUPRISTIN–DALFOPRISTIN
• The drug is approved for complicated skin and
skin-structure infections caused by Strep.
pyogenes, and for serious VRE infections
associated with bacteraemia
• Resistance in E. faecium was reported by
theSENTRY antimicrobial surveillance
programme in Europe and North America to
be 10.0%and 0.6%,respectively .

50. QUINUPRISTIN–DALFOPRISTIN
• Drug elimination is through bile into faeces, but clearance may be slightly impaired
in patients with renal insufficiency.
• The drug has significant toxicity problems, including arthralgia–myalgia syndrome
and venous intolerance.
• Pain and inflammation at the infusion site is experienced by up to 74% of patients .
• Hyper-bilirubinaemia and liver toxicity can also occur.
• Quinupristin–dalfopristin has been shown to be a major inhibitor of the activity of
the cytochrome P450 3A4 isoenzyme, and drug interactions (especially with
cyclosporine) should be monitored carefully during therapy.
• Drug itself does not induce QTc prolongation, it can interfere with the metabolism
of other drug products that are associated with QTc prolongation.
• Quinupristin–dalfopristin is the first parenteral streptogramin and offers a unique
alternative treatment for infections caused by multidrug resistant Gram-positive
bacteria, but the broad spectrum of adverse effects makes it an inferior choice to
other agents.

51. CEFTOBIPROLE
• Ceftobiprole is a novel broad-spectrum b-lactamase-stable parenteral
cephalosporin with strong affinity for the penicillin-binding proteins PBP2a
and PBP2x, responsible for resistance in staphylococci and pneumococci,
respectively.
• Ceftobiprole can also bind to relevant penicillin-binding proteins of
resistant Gram-positive and Gramnegative bacteria, and appears to have a
low ability to select for resistance . In-vivo screening models suggest good
activity of ceftobiprole against Gram-positive and Gram-negative bacteria.
• Several animal models have been used in the evaluation of ceftobiprole,
including mouse sepsis, abscess and pneumonia models, rat endocarditis
and tissue cage models, and a rabbit endocarditis model . These models
suggest that ceftobiprole should have clinical efficacy as an empirical
treatment for severe clinical infections.
• The broad-spectrum activity of ceftobiprole may allow it to be used as
monotherapy for serious nosocomial infections for which combination
therapy would otherwise be required.

52. Novel cephalosporins
• 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

53. Novel cephalosporins
• CTA is licensed in Europe and the US for the treatment of complicated SSTIs and
community-acquired pneumonia (CAP) in adults.
• Double-blind RCTs CANVAS 1 and 2 suggested non-inferiority of CTA versus VANC
(plus aztreonam) for the treatment of complicated SSSIs.
• CTA may play a role in the treatment of MRSA-positive SSTIs for whom VANC and
other agents are unsuitable or ineffective.
• 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
• CBA has a pan-European licence for the empirical treatment of CAP and HAP,
excluding CBA has a pan-European licence for the empirical treatment of CAP and
HAP, excluding VAP
• 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

54. IV FOSFOMYCIN
• 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 .
• 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 .
• 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 ; to a lesser extent, this may occur in vivo even
during therapeutic dosing
• This may be circumvented to a certain extent by using FOS in combination with other agents,
such as DAPT .
• 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.

55. OTHER AGENTS
• 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.
• 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 .
• Rifampicin may 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)

56. MDROs represent a major clinical and
infection control challenge particularly in
LTCFs
You cannot do it alone  Regional approach
Aggressive infection control approach works
Appropriate antimicrobial use
Training and education (HCP, Patients,
Families)
Communications (intrafacility and
interfacilities)
56
Conclusion

57. • SHEA/APIC Guideline: Infection Prevention and Control in the Long-
Term Care Facility
http://www.dhhr.wv.gov/oeps/disease/AtoZ/Documents/SHEA%20Guide%20to%20LTCF%20Infec
tion%20Control%20Jul08.pdf
• Guideline for Isolation Precautions: Preventing Transmission of
Infectious Agents in Healthcare Settings
http://www.cdc.gov/hicpac/pdf/isolation/Isolation2007.pdf
• Management of Multidrug-Resistant Organisms In Healthcare
Settings, 2006 http://www.cdc.gov/hicpac/pdf/MDRO/MDROGuideline2006.pdf
• DIDE Website http://www.dhhr.wv.gov/oeps/disease/HAI/Pages/default.aspx
• CDC Healthcare-Associated Infections http://www.cdc.gov/hai/
• CDC SHEA “Train the Trainer” May 2011
• Epidemiology and Prevention of Common Emerging MDROs
“Alex Kallen, MD, MPH” DHQP, CDC
57
Resources and References