Professor Laurie Walsh - GP CMEgpcme.co.nz/pdf/2017 South/Fri_Room4_1400... · •New forms of antibiotic resistance spread between continents with ease. •Many forms of resistant

Professor Laurie WalshProfessor of Dental Science

University of Queensland School of Dentistry

Brisbane

14:00 - 14:55 WS #26: Strategies Behind Overcoming Antimicrobial Resistance

15:05 - 16:00 WS #36: Strategies Behind Overcoming Antimicrobial Resistance

(Repeated)

Strategies behind overcoming antimicrobial resistance

Professor Laurence J. WalshBDSc(Hons), PhD, DDSc, GCEd, FRACDS, FFOP(RCPA)

Specialist in Special Needs Dentistry

© 2017

WS 26; WS 36

• Candida albicans is at present the fourth most common cause of healthcare-associated bloodstream infections in the US, and in some hospitals it is the most common cause.

• These infections tend to occur in the sickest of patients. • Some Candida strains are increasingly resistant to first-line and second-line antifungal

treatment agents. • Recent data demonstrate a marked shift among infections towards Candida species with

increased resistance to antifungal drugs including azoles and echinocandins.

Antifungal drugs

Nystatin Amphotericin

Nystatin drops have a bitter taste and patient compliance is usually poor.

Azole resistance

2008+

AntibioticsAlongside improved sanitation and vaccines, antibiotics are arguably

the most life-saving medical technology ever developed.

They have been used widely since the early 1940’s.

Transfer of resistance to other

microorganisms

Development of new ABT

Development of ABT Resistance

A global problem

• New forms of antibiotic resistance spread between continents with ease.

• Many forms of resistant bacteria spread from person to person, or from the non-human sources in the environment, including food.

• Antibiotics are also commonly used in food animalsto prevent, control, and treat disease, and to promote the growth of food-producing animals. The use of antibiotics for promoting growth is no longer regarded as necessary.

The number of new antibiotics developed and US FDA approved has steadily decreased in the past three decades, leaving fewer options to treat resistant bacteria.

Unwarranted use of ABT

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Factors influencing choice of ABT for ABT for healthy young adult male with carious lower molar in pain and some mild localized swelling.

This patient does not NEED any ABTs, yet 75% of govt and 64% of private clinicians recommended ABT

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AMS : Definition

• An ongoing effort by a healthcare institution or facility to optimise antimicrobial use in order to improve patient outcomes, ensure cost-effective therapy and reduce adverse sequelae of antimicrobial use (including antimicrobial resistance.

• Change antimicrobial prescribing to reduce unnecessary use and promote the use of agents less likely to select resistant bacteria. This is done in line with treatment guidelines and with consideration of the demonstrated local incidence of resistant pathogens.

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Prophylactic ABT for dental implant placement in healthy patients

• Park et al. Aust Dent J – August 2017

• Systematic review of prospective human clinical trial studies investigating antibiotic usage during implant placement studies conducted between 2005-2016

• ABT use does not play a major role in the early incidence of prosthesis failure, implant failure, adverse events, and postoperative complications.

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Antimicrobial prophylaxis for removal of third molar teeth• Large retrospective studies show that in general, antimicrobial

prophylaxis offers no advantage despite its use in protocols for over 25 years.

• When all appropriate precautions are taken, the routine administration of prophylactic antibiotics to healthy patients before third molar removal appears to be unnecessary.

• Lawler B, Sambrook PJ, Goss AN: Antibiotic prophylaxis for dentoalveolar surgery: Is it indicated? Australian Dental Journal 2005; 50 (Suppl 2): S54.

Key points

• Prescribing antibiotics for any indication should only come after a thorough clinical examination and be determined according to clinical need on a case-by-case basis, not a blanket rule.

• As a profession, we need to reduce the overprescribing of antibiotics that is occurring.• Dose-dependent and idiosyncratic adverse reactions, antibiotic

resistance and emergence of multi-drug resistant bacteria may arise as a result of misuse of ABT.

• When ABT are improperly prescribed it produces greater difficulties in treating legitimate infections.

• Do the benefits outweigh the risks when antibiotics are being prescribed for surgical procedures?

ABT prophylaxis for patients with prosthetic joints undergoing dental Tx

• There is no evidence that prophylaxis prevents late prosthetic joint infections from transient bacteraemias induced by dental treatment.

Metro South HHS

ABT as an adjunct in managing oro-dental infections

• E.g. Acute dento-alveolar (periapical) abscess• where there are systemic symptoms or the host is compromised

• In all cases, ABT are used in combination with other PHYSICAL measures (as appropriate to the condition). The patient must be seen urgently by a dentist for physical treatments, such as • drainage of pus (sunset rule)• Tooth extraction• Endodontic (root canal) treatment• mechanical debridement

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Important issue

• Up to 50% of all the antibiotics not optimally effective as prescribed.

• Inactivation of penicillin-based drugs by beta lactamase produced by some bacteria such as some anaerobes in the oral cavity• Cleaves beta lactam ring

• To address this problem, add in clavulanic acid (a beta lactamase inhibitor) = “Augmentin”

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1. Use the narrowest spectrum antimicrobial to treat likely pathogen(s) –and so kill less “good bacteria”. Thus usually single drug unless combination therapy is evidence-based

2. Use adequate dose appropriate to site / Type of infection – consider the weight of the patient

3. Review patient after 2 or 3 days - check for adverse effects, effectiveness and decreasing symptoms (STOP ABT if improving). Do not exceed 7 days without a proven cause (5 days is sufficient to sort most odontogenic infections)

4. Obtain specimens of Exudate / Pus wherever possible to culture and sensitivity tests (M+C+S)

5. Oral route is preferred. IV reserved for severe infections and life threatening or patient swallowing / GIT absorption problems.

How to use antibiotics

Infective endocarditis:More daily bacteraemia with gingivitis or periodontitis

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How safe is that ABT cover, used for IE?

• In April 2015 new data were published quantifying the risk of adverse drug reactions following use of antibiotic prophylaxis in the UK (Thornhill et al. 2015 J Antimicrob Chemother 2015; 70: 2382–2388. )

• This confirmed earlier data showing that there has never been a reported death in the UK from the use of amoxicillin antibiotic prophylaxis, and showed that the risk of non-fatal adverse reactions is much lower than previous

• Lee P, Shanson D. J Antimicrob Chemother 2007; 60: 1172–1173

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How safe is that ABT cover?

•Clindamycin antibiotic prophylaxis had a worse adverse reaction profile than amoxicillin and resulted in approximately one death every three years in the UK.

•Whilst worse than expected, this is still comparatively low.

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New methods of meeting the microbial challenge

Rethinking antimicrobial strategies

Novel strategies which are being examined

• There is no one panacea for the problems of antimicrobial resistance, so combinations of strategies and materials will be needed for future.

Biocides

• Large group of diverse chemical agents that inactivate a variety of microorganisms.• Inhibit a variety of microbial cellular processes.

• Multiple sites of action on target cells (bacteria, fungi, viruses)

• Broader spectrum than antibiotics thus resistance is rare

• (NB: innate resistance to CHX for some Gram negatives such as Pseudomonads and enterobacteriacae)

Erythematous candidosis associated with MX dentures

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Biocides for lowering candidal load

• Biocides: mouthrinsing

• CHX

• Povidone iodone

• Essential oils: Listerine and T4O

• (Some less marked effects from Triclosan or Quats (CPC))

• Soak denture in NaOCl after physical cleaning to reduce candidal load – this also works because of its high pH

Listerine decreases the viability of Candida albicans and causes a significant

reduction in palatal inflammation and candidal colonization of dentures and

palatal mucosa

EO (Listerine) as an antifungal

Chlorhexidine

Disinfection of appliances and removable prostheses with sodium hypochlorite

• Soak denture in NaOCl after physical cleaning to reduce candidal load – this also works because of its high pH (11)

• Immerse for 5 minutes in diluted (1:10) NaOCl bleach

• Don’t leave overnight (corrodes metal clasps)

• Rinse well afterwards

Denture hygiene• Clean the denture physically to remove biofilm (particularly the

fitting surface) using a detergent/surfactant

• Then disinfect the denture by immersion for 5 minutes in diluted (1:10) NaOCl bleach

• Wash thoroughly afterwards

• Keep the denture out at night (keep it hydrated!)

• Chlorhexidine gel can be used as a smear inside the denture

Use of NaOCl or microwaves for dentures

Microwave Tx

Range of biocides

• Quaternary Ammonium compounds• CPC, benzalkonium chloride

• Phenolics• Natural Products

• Essential Oils• Gallates• Polyphenols

• Synthetic (Triclosan)

• Non-Ionic Detergents

• Bisguanides• CHX

• Enzymes

• Halogens• Fluoride (Stannous/Amine)• Iodine, Povidone iodine

• Metal Ions/nanoparticles• Zn, Sn, Ag, Au

• Oxygenating Agents • Peroxides, ozoner, chlorine dioxide

• Natural Products/Derivatives• Lysins• Antimicrobial peptides

Phytochemicals

Lysins

• Produced by bacteriophage viruses (~1031 entities reported), to enable the release of the replicating virus following the lysis of the bacterial host.

• Attractive for next generation antibiotics. • High specificity, rapid action, lack of reported resistance

development, high biosafety • Work on planktonic and biofilm bacteria

Lysins

• Possible to develop novel ‘designer lysin’ sets, e.g. using microalgae as the production unit

• cell binding domain: targets the selected pathogen

• catalytic domain cleaves the bacterial cell wall: at least four different catalytic domains, which can cleave peptidoglycan layers at different positions

Antimicrobial peptides• Natural AMPs have attracted considerable interest as a potential new

class of antimicrobial agent because their major mechanism of action is to permeabilize the cytoplasmic membranes of bacteria.

• The problems of natural AMPs (haemolytic activity, poor stability and poor bio-availability) can be overcome by developing new class of synthetic AMP molecules which have a suitable safety profile and are able to eliminate multi-drug resistant bacteria, even in a quiescent state within biofilms.

de novo series of synthetic lipopeptides that have the essential characteristics of AMPs

AMP mode of action -disrupting the bacterial cell membrane

Novel silver nanoparticles

• Pure silver electrodes in ultrapure water; Direct current 500 uA and 300 volts @ 1 cm.

• Ag leaves the anode (+), and turn ionic. To prevent these cations from reaching the cathodes, high luminosity irradiation by 420 nm violet light causes the cations to combine with hydrated electrons to form AgNPs in an electrostatic suspension in water as clusters of 2 or more Ag atoms.

Proof of concept

• Colloidal silver (AgNPs) – 4 preparations

• Positive controls• Ionic silver - 25mg/ml AgNO3

• Ionic gold - 30mg/ml AuCl3• 0.12% CHX

• 0.4% NaOCl

• 4 day mixed species oral biofilm treated for 20 min or 24 hours; XTT assay of viable biofilm

20 min contact

• Colloidal silver almost as effective CHX and NaOCl in decreasing XTT conc.

24 hrs contact

• Colloidal silver almost as effective CHX and NaOCl in decreasing XTT conc.

No resistance possible

Physical

• Shockwaves/cavitation

• Heat – photothermal lasers

Chemical

• High pH

• Membrane solvents (Essential oils, CHX)

• Enzyme inhibitors (Zn, Sn, nano silver or gold)

• ROS – peroxides, ozone etc, generated as needed by electrolytic or photodynamic processes (PAD)

Photothermal disinfection

Diode, KTP or Nd:YAG laser

• Accompanying cavitation possible

Er:YAG or YSGG laser

Hydrogen peroxide, ozonated water

• Alternative oxidants

• Form similar reactive oxygen species in water

• Low concentrations (<6% HP) not irritant

• ROS release is enhanced by physical agitation with ultrasonic instruments or pulses from water-absorbing lasers

Microbial susceptibility to Ca(OH)2 pastes:Gomes et al. JoE 2002

Gram positives

Gram negatives

Most resistant to alkaline pH

Bactericidal effects of Ca(OH)2 mechanism

• High OH ions affect enzyme systems in cytoplasmic membranes of bacteria thus affecting normal functions of cell growth, metabolism, cell wall integrity. This is a reversible process depending on the pH (11.1 threshold)

• Ca(OH)2 has a similar effect on aerobic, anaerobic, Gram-positive and Gram-negative bacteria.

• Inactivates bacterial toxins: i.e. lipopolysaccharide (LPS) found in the outer membrane of gram-negative bacteria.

Walsh LJ, Athanassiadis B. Influence of PEG 400 vehicle on calcium hydroxide medicaments. IADR 2016.

MBC (mg/ml)

Medicament tested

E. faecalis Candida albicans

PEG 400/3350 base

No effect No effect

Calmix 7.80 7.80

Calasept 7.80 125.00

Pulpdent 7.80 62.5

Odontocide 31.25 31.25

Results are the mean of three replicates.Assays done by a commercial microbiology lab using blinded samples.

Antimicrobial testing:Lower MBCs mean greater effectiveness

Least effective on EF.

Calmix is better against fungi than the other calcium hydroxide pastes.

TIME KILL STUDY( Log reduction following 1 hour contact time with medicament)

Medicament E. faecalis C. albicans

PEG paste only 0.1, 0.0 0.5, 0.3

Ledermix No effect 0.1, 0

Pulpdent >5.6, >5.6 2.9, 2.7

CalMix >5.6, >5.6 >4.1, >4.2

• Greater effectiveness

against Candida

species compared to

Pulpdent

Reduction factor is approx. 400,000 fold from 1 hr contact time