antibiotics update antibiotics update

Antibiotics UpdateAntibiotics Update

Dr Kieran Hand C l Ph i A i I f iConsultant Pharmacist ‐ Anti‐Infectives

University Hospital SouthamptonNHS Foundation Trust

38th UK Medicines InformationPractice Development Seminarp

University of Warwick, 13th – 14th September 2012

A game of two halvesA game of two halves

• First half– An interesting anecdote

• Second half– Ask the audience

Prize-winning schoolgirls take quantum leap from babies’ bottoms to dairy cows’ udders

By Jimmy Woulfe, Mid-West Correspondent

Thursday, May 03, 2012

Two Co Limerick schoolgirls have found a widely-used cream for soothing g y gbabies’ bottoms is a great remedy for dairy cows with sore udders caused

by mastitis.

Both girls did their research on the family farms run by their dads. They f d th t t b f S d ti €4 l titi i d ifound that a tub of Sudocrem costing €4 can clear mastitis in a dairy cow

just as quickly as widely-used veterinary injections which cost €60 per treatment.

Evaluating appropriateness: what factors influence choice / dose / route / duration of therapy?

• Presenting complaint / signs & • Previous antibiotics• Presenting complaint / signs & symptoms

• Evidence of infection (+SIRS)• Past medical history (e.g. prosthetic

• Previous antibiotics• Biochemistry / haematology results /

urine dipstick• Allergy / intolerancePast medical history (e.g. prosthetic

valve, epilepsy)• Immune status/immunosuppressants• Family / social contacts

Allergy / intolerance• Pregnancy / breastfeeding• Organ dysfunction• GI absorption / swallowing

• Occupation / hobbies• Travel history• Pets / animal contact

p / g• Expert advice• Source control• Local pathogen epidemiology and

• DIAGNOSIS and likely pathogens• Severity of infection• Prescriber’s training / experience

P d i / lt t f

resistance• Antibiotic spectrum• Site of infection (penetration)

D i i (PK/PD)• Peer advice / consultant preference• Local guidelines / policy• Recent contact with healthcare• Recent or previous microbiology /

• Dosing regimen (PK/PD)• Interacting drugs (e.g. iron and

doxycycline)• Ethnicity (e g G6PD deficiency)• Recent or previous microbiology /

serology investigations.Ethnicity (e.g. G6PD deficiency).

Skin & soft tissue infections: in vitro sensitivities from Southamptonin vitro sensitivities from Southampton

GPs 11/12

90100

607080

tive

PenicillinFlucloxacillin

405060

% s

ensi

t

ErythromycinDoxycyclineRifampicin

102030

% RifampicinFusidic acidCiprofloxacin

010

Staph aureus

Southampton GP isolates 2011/12

Take a chance on meTake a chance on me

• Trust me I’m a doctor

• I have a remarkable memory for facts

• I’m going to start youI m going to start you on ‘Cefanmet’

• My rabbit’s foot has• My rabbit s foot has never failed me

Ebbinghaus’ forgetting curve (try to remember it)

Which of these two men would you send to the supermarket?

There is another wayThere is another way…

• Bear with me while I consult our treatment guidelines

• Hmm, they don’t seem to cover your particular circumstances

• I think I will get some expert advicep

Hospital pharmacist knowledge of ibi i d i f iantibiotics and infection

Assessment results by subject area (ITT)

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Hand K & Jubraj J 2005 (MSc)

What do patients deserve?What do patients deserve?

• Option one: Parachute in a micro/ID doctor

• Option two: Provide an IT system for decision‐

(and pharmacist) support 24/7

From maps to AppsFrom maps to Apps2008 2011

Guiding treatment choiceGuiding treatment choice

Protecting patients from harmProtecting patients from harm

Tailoring treatment to patientsTailoring treatment to patients

• “Existing guidance on the management of some infections may be too long and complex for many doctors to have time y g p yto absorb, according to the Healthcare‐Associated Infections (HCAI) Working Group at the RCP. The group have now produced a handy one page summary of guidelines to helpproduced a handy one‐page summary of guidelines to help busy doctors identify what is most important for them in their routine clinical practice.”

De‐skilling?

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Audience empowermentAudience empowerment

• Option A

• Revision of the basics –

• Option B

• Heads‐up on the latest choosing an antibiotic regimen that may save

trends in resistance / prescribing and

a patient’s life (or intervening if a regimen

advances in science of infection management

is likely to fail)

Four main groups of bacteria

1. Gram positive2 G ti2. Gram negative3. Anaerobes4. Atypical

Even Ebbinghaus could remember this!

Groups are defined by their response to antibiotics

Gram -veGenerally speaking...

Gram ve GI-tract

RespiratoryAnaerobesMouth, teeth, Peritonitisthroat, sinuses & lower bowel

PeritonitisBiliary infection

PancreatitisUTIAbscesses UTIPID

PneumoniaDental infection

Peritonitis Appendicitis

Gram +ve Skin & Chest

AtypicalsChest and

genito-urinaryPneumonia g yPneumoniaSinusitisCellulitis

Wound infection

Pneumonia Urethritis

PIDWound infectionLine infection

(Osteomyelitis)

Antibiotic spectrumAntibiotic spectrumLegionella,

Chl di &Anaerobic Streptococci & Clostridia

Streptococcus pneumoniae &

Group A, B, C, G

Pseudomonas aeruginosa

Chlamydia & Mycoplasma pneumoniae

Bacteroides fragilis

Gram positive Gram negative Atypicals

MRSA Staphylococci Streptococci EF Anaerobes Coliforms Resp Pyo ESBLMRSA Staphylococci Streptococci EF Anaerobes Coliforms Resp Pyo ESBL

Antibiotic

MRSA and Coagulase-

Enterococcus faecalis &

Enterococcus

Gut bacteria

E li

Respiratory Gram -ve e.g.Haemophilus

Extended-spectrum beta-

lactamase negative Staph. Enterococcus

faeciume.g. E. coli

pinfluenzae &

Moraxella catarrhalis

producers & other resistant Gram

negatives

Green = Generally Sensitive; Orange = Unreliable; Red = Generally Resistant

1. Narrow-spectrumpGram-positive agents

(Staphs and Streps)• Penicillin V/G*, FlucloxacillinPenicillin V/G , Flucloxacillin• Erythromycin• Clindamycin• Fusidic acid RifampicinFusidic acid, Rifampicin• Vancomycin, Teicoplanin

MRSA cover• Linezolid• Daptomycin

MRSA cover

* No Staph aureus cover

Daptomycin

Gram-positive coverAntibiotic Gram Positive Gram Negative Atypicals

MRSA Staph Strep pneumo

Streptococci EF Anaerobes Resp Coliforms Pyo ESBL

Benzylpen / P i illi V

R R G G G G A A R R R R

Penicillin V

Flucloxacillin R G G G R R R R R R R R

Cefalexin R G G G R A R R A R R R

Vancomycin & Teicoplanin

G G G G G G R R R R R R

Linezolid G G G G G G A A R R R R

Daptomycin* G G R* G G G R R R R R R

Septrin® G G G G G R R A A A A

Clarithromycin R G G A R A R G R R R G

*Inactive in the lung

y

Clindamycin R G G G R G A R R R R A

2 Narrow spectrum2. Narrow-spectrum Gram-negative agentsGram negative agents

• Ciprofloxacin• Gentamicin, Tobramicin, Amikacin• Ceftazidime• Ceftazidime• Aztreonam• Colistin

All active against pseudomonas

Gram-negative coverAntibiotic Gram Positive Gram Negative Atypicals



Nitrofurantoin* G G G G G R R R G R G R

Ciprofloxacin R A A A R R R G G G A GCiprofloxacin R A A A R R R G G G A G

Gentamicin / Tobramycin /

Amikacin

A G R R A R R G G G G R

Ceftazidime R A A A R A R G G G R R

Aztreonam R R R R R R R G G G R R

Colistin R R R R R R R G G G A R

*Only active in urine

3. Anti-anaerobe agents

• Metronidazole• Clindamycin• Co amoxiclav (“above the diaphragm”)• Co-amoxiclav ( above the diaphragm )• Piperacillin-tazobactam• Ertapenem, imipenem, meropenem

Moxifloxacin• Moxifloxacin

Anaerobic coverAntibiotic Gram Positive Gram Negative Atypicals



Metronidazole R R R R R G G R R R R R

Clindamycin R G G G R G A R R R R A

Co-amoxiclav R G G G G G A G G R R R

Pip-taz R G G G G G A G G G A R

Ertapenem R G G G A G G G G R G R

Imipenem R G G G G G G G G G G R

Meropenem R G G G A G G G G G G RMeropenem R G G G A G G G G G G R

Tigecycline G G G G G G G G G R R G

Moxifloxacin A G G G G G G G G R A G

4. Anti-atypical agents

• Macrolides– erythromycin, clarithromycin etc.

• TetracyclinesTetracyclines– oxytetracycline, doxycycline etc.

• Fluoroquinolones– ciprofloxacin, ofloxacin, levofloxacin etc.c p o o ac , o o ac , e o o ac e c

Atypical coverA ibi i G P i i G N i At i lAntibiotic Gram Positive Gram Negative Atypicals



Tetracyclines

D li G G G A R G A G A R A GDoxycycline G G G A R G A G A R A G

Minocycline G G G G R G A G A R A G


Macrolides

Erythromycin R A G A R A R A R R R G

Clarithromycin R G G A R A R G R R R G

A ith i R G G A R A R G A R R GAzithromycin R G G A R A R G A R R G

Chlor-amphenicol

G G G G A G G G G R A G

Ciprofloxacin R A A A R R R G G G A G

Levofloxacin R G G G G A A G G G A G


Broad spectrum coverAntibiotic Gram Positive Gram Negative AtypicalsAntibiotic Gram Positive Gram Negative Atypicals



Co-amoxiclav R G G G G G A G G R R R

Cefuroxime R G G G R A R G G R R RCefuroxime

Ceftriaxone & Cefotaxime

R G G G R A R G G R R R

Timentin R G G G A G G G G G A R

Pip-taz R G G G G G G G G G A R

R G G G A G G G G R G RErtapenem R G G G A G G G G R G R

Imipenem R G G G G G G G G G G R

Meropenem R G G G A G G G G G G R

Chlor-amphenicol

G G G G A G G G G R A G

Levofloxacin R G G G G A A G G G A G



Most important slide!Patient risk \P th

Low-risk patient•Mild-to-moderate infection•No prior antibiotics

High-risk patient•Severe or life-threatening infectionPathogen

group•No prior antibiotics•No recent healthcare exposureN hi t f lti i t t

infection•Prior antibiotics•Healthcare exposureHi t f lti i t t•No history of multi-resistant

pathogens•History of multi-resistant pathogens

Gram +ve Flucloxacillin or Vancomycin or Linezolid Clarithromycin or Doxycycline

(MRSA cover)

Gram –ve Trimethoprim, Co-amoxiclav, Gentamicin or Pip-tazp , ,Doxycycline, Ciprofloxacin

p

Anaerobe Metronidazole or Co-amoxiclav

Metronidazole or Pip-tazamoxiclav

Atypical Doxycycline or Clarithromycin

IV Clarithromycin or Ciprofloxacin

Treatment failure? Is your patientTreatment failure? Is your patient circling the DRAInSg

• D = Dose I th d d t ? I th ti t tti d ?– Is the dose adequate? Is the patient getting doses?

• R = Resistance– MRSA, Clostridium difficile, ESBL-producing Gram-negativep g g– Virus, fungi, TB, parasite (malaria, opportunistic infection)

• A = Allergy– Drug fever = unexplained fever despite improvement of other– Drug fever = unexplained fever despite improvement of other

symptoms and CRP/WBC• In = Interaction

– e.g. doxycycline absorption reduced by up to 90% by iron• S = SOURCE CONTROL

– Antibiotic therapy alone may not cure infectionAntibiotic therapy alone may not cure infection– Incision & drainage, debridement, removal of line or

prosthetic device

Thank you for your attention

Happy to answer questionsHappy to answer questions

[email protected]

Microbiota

Antibiotics alter epithelial homeostasis in the gut and enhance host susceptibility to incoming pathogens

Willing BP Nature Reviews Microbiology 2011

host susceptibility to incoming pathogens

Nature Reviews Microbiology: April 2011Nature Reviews Microbiology: April 2011

The average child in a developed country has received 10 20 f tibi ti b th f 18

Blaser M, Nature, August 2011

10-20 courses of antibiotics by the age of 18.

Antibiotic “collateral” damageAntibiotic collateral damage

“O f ibi i• “Overuse of antibiotics could be fuelling the dramatic increase indramatic increase in conditions such as obesity, type 1 diabetestype 1 diabetes, inflammatory bowel disease, allergies and , gasthma, which have more than doubled in many populations (see graph)?” Blaser M, Nature 2011

Prescribing

Antibiotic use risingAntibiotic use rising

Hospital prescribing trends: EnglandHospital prescribing trends: England

Ashiru Oredope D, JAC 2012

Hospital prescribing trends: ScotlandHospital prescribing trends: Scotland

SAPG Report 2010

Unintended consequences?Unintended consequences?

Courtesy Prof Jonathan Cooke and IMS Health Inc

Resistance threats

Staphylococcus aureus bloodstream infections in England

Health Protection Agency

Trends in bloodstream infections in England

Health Protection Agency

The ebb and flow of resistanceThe ebb and flow of resistanceAntibiotic resistance in E. coli from bacteraemia isolates for England & Wales

(Health Protection Agency)

25

20

e

CEPH

CIP

10

15

% resistance CIP

0

5

0

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Courtesy of Dr Alan Johnson, HPA

ESBLs waxing and waning?ESBLs waxing and waning?

DH ARHAI ESBL report, February 2012

How to select out ESBL producersHow to select out ESBL‐producers

Carbapenem resistance in pseudomonas i Ein Europe

www.rivm.nl/earss/

New Dehli Metallo‐betalactamase 1 (NDM‐1) carbapenemase: August 2010

Running out of optionsRunning out of options

Health Protection Report, June 2011 (n=333 in 2010)

Carbapenem‐resistant coliforms resported to the HPA

• Stool samples tested from 200 patients in Pakistan• Stool samples tested from 200 patients in Pakistan

• Prevalence of NDM‐1 positive coliform carriage/ ( ) f– 18/130 (14%) of outpatients

– 19/70 (27%) of inpatients

Clostridium difficile epidemic curveClostridium difficile epidemic curve

Health Protection Report, February 2012

Clostridium difficile risk & antibiotics: new insights

2009/10 CDRN (national reference laboratory in Leeds) processed2009/10 CDRN (national reference laboratory in Leeds) processed 5,720 faecal samples (C diff positive) from 172 healthcare facilities. 3,209 reported patient exposure to antibiotics.

Therapeutics

New contra‐indications, warnings and interactions for antimicrobials

• Trimethoprim and hyperkalaemia– An 18‐year case‐control study found that 1.7% of patients concurrently treated with spironolactone and Septrin were admitted to hospital with hyperkalaemia within 2 weeks.

Thi i k i 12 hi h th f i l t ith– This risk is 12x higher than for spironolactone with amoxicillin.• Antoinou T et al University of Toronto BMJ 2011• Antoinou T et al, University of Toronto, BMJ 2011

• Azithromycin and cardiovascular deathDuring a 5 day course risk of cardiovascular death was– During a 5‐day course, risk of cardiovascular death was 2.5‐fold higher with azithromycin vs amoxicillin

– Risk of death from any cause was 2 fold higher– Risk of death from any cause was 2‐fold higher• Ray WA et al, N Engl J Med 17 May 2012


S di f id t d t ti• Sodium fusidate and statins– Systemic fusidic acid should not be given with statins because of a risk

of (potentially fatal) rhabdomyolysis I i f h h f i f idi id i i l– In patients for whom the use of systemic fusidic acid is essential, statin treatment should be temporarily discontinued throughout the duration of fusidic acid treatment To ensure clearance of systemic fusidic acid statin therapy may be– To ensure clearance of systemic fusidic acid, statin therapy may be reintroduced 7 days after the last dose of systemic fusidic acid • MHRA Drug Safety Update, September 2011

– Mechanism is unknown. Fusidic acid is not a known inhibitor of enzymes or transporters involved in statin metabolism.

– Seven published cases with atorvastatin (3 fatal) and six withSeven published cases with atorvastatin (3 fatal) and six with simvastatin. All had risk factors for myopathy or rhabdomyolysis.

– An interaction between fusidic acid and the statins is not established.• Stockley’s Drug Interactions April 2012Stockley s Drug Interactions, April 2012


C b d di l t• Carbapenems and sodium valproate– A clinically significant interaction between carbapenems and valproic

acid/sodium valproate results in reduced valproate plasma concentrations with potential for inadequate seizure controlconcentrations with potential for inadequate seizure control

– Given the large magnitude and rapid time course of this interaction, monitoring of sodium valproate levels or making dose adjustments are unlikely to manage this interactionunlikely to manage this interaction

– Concomitant use of carbapenems in patients taking valproic acid/sodium valproate is not recommended, and prescribers should consider alternative antibacterial therapy py• MHRA Drug Safety Update, May 2010

– Plasma levels of valproate fall by 66% (34‐92%) within 24 hours of starting meropenem, associated with worsening seizures or EEG in 55%

– Mechanism possibly altered protein binding and increased glucuronidation with enhanced renal excretion

kl ’ l• Stockley’s Drug Interactions, April 2012

Worrying WarningsWorrying Warnings

Ti li (T il▼) i d li i li i l• Tigecycline (Tygacil▼): increased mortality in clinical trials – use only when other antibiotics are unsuitable (Drug Safety Update 04Apr11)unsuitable (Drug Safety Update 04Apr11)

• Daptomycin: risk of eosinophilic pneumonia (DSU 10Feb11)10Feb11)

• Moxifloxacin (Avelox ▼) : Because of evidence of an increased risk of life threatening liver reactions andincreased risk of life‐threatening liver reactions and other serious risks (such as QT interval prolongation), oral moxifloxacin should be used only when otheroral moxifloxacin should be used only when other antibacterials are inappropriate or ineffective (DSU Jan11))

New antimicrobials 1: fidaxomicinNew antimicrobials 1: fidaxomicin

N (G i i ) fi i l li• Narrow‐spectrum (Gram‐positive), first‐in‐class, macrocyclic antibiotic that has minimal absorption from the GI tract

• Activity against Clostridium difficile but little effect on faecal• Activity against Clostridium difficile but little effect on faecal microbiota

• Bactericidal, inhibits RNA polymerase• 1,000 patients evaluable in two Phase 3 studies. Cure rate

after 10 days was 88% in the FDX group versus 86% in the oral vancomycin groupvancomycin group.

• Clinical recurrence rates were 13% after FDX vs 24.5% after vancomycin per protocol (NNT = 8.7). At £1,350 per treatmentvancomycin per protocol (NNT 8.7). At £1,350 per treatment course, this puts the cost of preventing one recurrence at £11,750 (exc VAT).

New antimicrobials 2: ceftarolineNew antimicrobials 2: ceftaroline

N l h l i i h i i i l i• New parenteral cephalosporin with activity against multi‐drug‐resistant Gram‐positives including MRSA, VRE and penicillin‐resistant Streptococcus pneumoniaep p p

• 600mg IV infusion 12‐hourly• Not active against Pseudomonas aeruginosa or other non‐

fermenter Gram‐negatives• Ceftaroline non‐inferior to vancomycin for skin and skin

structure infections (91 6% vs 92 7% cure)structure infections (91.6% vs 92.7% cure).• Ceftaroline non‐inferior to ceftriaxone for community‐

acquired pneumonia (86.6% vs 78.2% cure).acquired pneumonia (86.6% vs 78.2% cure).• Two cases of C. difficile in Phase 3 ceftaroline arms.• May be less expensive than linezolid or daptomycin.y p p y

Renaissance of older antimicrobials 1: fosfomycin

i d i h• Discovered in the 1970s• Inhibits a transferase enzyme that catalyses y ythe first step of bacterial cell wall synthesis

• Retains activity against many resistant Gram‐Retains activity against many resistant Gramnegative bacteria including ESBL‐producers

• Licensed in the UK but no UK stock available• Licensed in the UK but no UK stock available so imported

• Given as 3g oral sachet single dose or q48h for lower UTI

Renaissance of older antimicrobials 2: colistin

• We underdose colistin• Loading dose of 10MU required for 70kg patientLoading dose of 10MU required for 70kg patient• Followed after 24h by 5MU 12‐hourly (CrCl 60mL/min)

Pharmacokinetics / Pharmacodynamics / (Toxicodynamics)(Toxicodynamics)

PK/PD parameters affecting antibiotic efficacy in vivo

ConcentrationCmax:MIC

Concentration

AUC:MIC

MICT>MIC PAE

0T MIC

Time (hours)

PAE

( )

PK/PD relationships for different antibiotics

Roberts J Crit Care Med 2009

PK/PD dosing of meropenemPK/PD dosing of meropenem

M PK f diff t IV b l d i iMeropenem PK for different IV bolus dosing regimens

60

40

50

(mg/

L)

20

30

um le

vels

1 gram 8-hourly500mg 6-hourlyBreakpoint (4mg/L)

10

20

Seru

72

00 1 2 3 4 5 6 7 8 9 10 11 12 13

Time (hours)

Equivalent response of PK/PD dosing in neutropenic patients

73

Arnold H, Pharmacotherapy 2009; 29(8): 914-923

Thank you for your attention

Happy to answer questionsHappy to answer questions

[email protected]

antibiotics update antibiotics update

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