Antibiotics- A Quick Overview

Ged Hawthorn Jan 2014

Ben P

en

Flu

clo

x

Am

p/ a

mox

Am

ox-C

lav

Tic

-Cla

v

Pip

- Taz

Cephazolin

Cefa

clo

r/

cefu

roxim

e

Ceftria

xone

Cefta

zid

ime

Gram Positive Strep A,B,C,G

Strep Pneumonia

MSSA

MRSA

CA-MRSA

enterrococcus faecalis

s

Listeria monocytogenes

Gram Negative

H. Influenzae

E. Coli

Klebsiella

Kleb/ Ecoli ESBL

Pseudomonas

legionella

ESCAPPM

MISC

m. Pneumoniae

Anaerobes

Baceroides Fragilis

C. Diff

usually effective or >60% susceptible

S synergy

trials lacking or 30-60% susceptible

Sensitive but resistance develops rapidly

Ben P

en

Flu

clo

x

Am

p/ a

mox

Am

ox-C

lav

Tic

-Cla

v

Pip

- Taz

Cephazolin

Cefa

clo

r/

cefu

roxim

e

Ceftria

xone

Cefta

zid

ime

Gram Positive Strep A,B,C,G

Strep Pneumonia

MSSA

MRSA

CA-MRSA

enterrococcus faecalis

s

Listeria monocytogenes

Gram Negative

H. Influenzae

E. Coli

Klebsiella

Kleb/ Ecoli ESBL

Pseudomonas

legionella

ESCAPPM

MISC

m. Pneumoniae

Anaerobes

Baceroides Fragilis

C. Diff

usually effective or >60% susceptible

S synergy

trials lacking or 30-60% susceptible

Sensitive but resistance develops rapidly

Genta

mic

in

Azith

rom

ycin

Doxycyclin

e

Metro

nid

azole

Clin

dam

ycin

Vancom

ycin

Cip

roflo

acin

Moxiflo

xacin

Mero

penem

Lin

ezolid

Gram Positive Strep A,B,C,G

Strep Pneumonia

MSSA

MRSA

CA-MRSA

enterrococcus faecalis s

Listeria monocytogenes s

Gram Negative

H. Influenzae

E. Coli

Klebsiella

Kleb/ Ecoli ESBL

Pseudomonas

Legionella

ESCAPPM

MISC

m. Pneumoniae

Anaerobes

Baceroides Fragilis

C. Diff

orally

usually effective or >60% susceptible

trials lacking or 30-60% susceptible

s used synergistically

Genta

mic

in

Azith

rom

ycin

Doxycyclin

e

Metro

nid

azole

Clin

dam

ycin

Vancom

ycin

Cip

roflo

acin

Moxiflo

xacin

Mero

penem

Lin

ezolid

Gram Positive Strep A,B,C,G

Strep Pneumonia

MSSA

MRSA

CA-MRSA

enterrococcus faecalis s

Listeria monocytogenes s

Gram Negative

H. Influenzae

E. Coli

Klebsiella

Kleb/ Ecoli ESBL

Pseudomonas

Legionella

ESCAPPM

MISC

m. Pneumoniae

Anaerobes

Baceroides Fragilis

C. Diff

orally

usually effective or >60% susceptible

trials lacking or 30-60% susceptible

s used synergistically

Pharmacodynamics of

Antibacterials BACTERIAL KILLING/PERSISTENT

EFFECT

DRUGS THERAPY GOAL-

PK/PD Parameter

Concentration-dependent/Prolonged

persistent effect

Aminoglycosides; daptomycin;;

quinolones; metronidazole

High peak serum concentration

Peak/MIC

Time-dependent/No persistent effect Penicillins; cephalosporins;

carbapenems; monobactams

Long duration of exposure

Time above MIC

Time-dependent/Moderate to long

persistent effect

Clindamycin; erythro/azithro/clarithro;

linezolid; tetracyclines; vancomycin

Enhanced amount of drug

24-hr AUC1/MIC

Initial serum

peak level Died Survived

< 5mcg/ml 21% 79%

>= 5mcg/ml 2% 98%

Aminoglycoside response rate

Beta Lactam Pharmacodynamics

24h-AUC/MIC ratio Satisfactory Unsatisfactory

< 125 4 (50%) 4

> 125 71 (97%) 2

Vancomycin Outcome vs 24h-AUC/MIC ratio

Duration of Therapy Site Diagnosis Duration in Days

Bone Osteomyelitis: acute

Chronic

42

Until ESR normal often > 3 months

Endocardium Infective endocarditis, native valve

Viridians Strep

Enterrococci

Staph

14-28

28-42

14-28

Gastrointestinal Shigellosis/ travellers diarrhoea

H Pylori

C. Diff

3

14

10

Joint Septic Arthritis 14-28 (recent study suggests 10-14)

Kidney Cystitis

Pyelonephritis

3

14

Lung Penumonia- pneumococcal

Pseudomonas or enterobacteriacae

Staph

Legionella, mycoplasma, chlamydia

Minimum 5 days and until afebrile 2-3

days

21, often up to 42

21-28

7-14

Sinuses Acute Sinusitits 5-14

Skin Cellulitis Until 3 days after acute inflammation

disappears.

Bacteraemia/ Sepsis Site with removable focus (ie. not

endocarditis)

10-14

Problem Bugs- VRE

• Enterrococcus Faecalis/ faecium- UTI, Bloodstream, Wound

• 85% of infections caused by Faecalis

MRSA by Region

Coombs et al., Australian Group for Antimicrobial Resistance (AGAR), Staphylococcus aureus Program 2008 (SAP 2008)

Community Survey MRSA Epidemiology and Typing Report, 2009

ESBL

Gram Negative Survey 2011 Antimicrobial Susceptibility Report: Report from the Australian Group on Antimicrobial Resistance

•E.Coli, Klebsiella spp, other Enterobacteracaie

•E coli ESBL 5-10% in Aus

•Klebsiella ESBL 10-15% in Aus

•Much higher overseas

•Associated with use of 3rd gen cephalosporin

•In vitro appear to be sensitive to cephalosporins, but have resistance in vivo

•Plasmid mediated resistance to penicillins and cephalosporins and…

Species Category Ciprofloxacin Gentamicin Trimethoprim

E Coli %I 1.7% 0.9% -

%R 51.1% 42.6% 55.1%

Klebsiella %I 27.1% 0% -

%R 29.2% 66.7% 79.2%

Co-resistance Percentages in Strains With Confirmed ESBLs

Antibiotic E Coli Aus 2011

Cat

%

Ampicillin %I 0.9

%R 50.5

Amox-clav %I 16.1

%R 7.7

Tic- Clav %R 8

Cephazolin %R 22.3

Ceftriaxone %NS 9.6

Ceftazidime %NS 5.8

Cefepime %NS 1.8

Meropenem %NS 0.1

Ciprofloxacin %NS 10.6

Gentamicin %R 8.2

Trimethoprim %R 23.4

Source AGAR 2012

2006 2006

Antibiotic Kleb spp Aus 2011

Cat

%

Ampicillin %R Intrinsic

Amox-clav %I 7.6

%R 7.1

Tic-Clav %R 9.7

Cephazolin %R 31.1

Ceftriaxone %NS 11.4

Ceftazidime %NS 8.2

Cefepime %NS 1.7

Meropenem %NS 0.4

Ciprofloxacin %NS 6.1

Gentamicin %R 8.4

Trimethoprim %R 14.9

Source AGAR 2012

Pan Resistant Bugs

• Klebsiella Pneumonia Carbapenemase (KPC).

• KPC-producing bacteria are often misidentified by routine microbiological

susceptibility testing and incorrectly reported as sensitive to carbapenems

• Organisms with detected KPC enzyme- Citrobacter,Pseudomonas, Escherichia coli,

Enterobacter, aerogenes, Acinetobacter spp Klebsiella pneumoniae, Klebsiella

oxytoca, Proteus mirabilis, Salmonella, Serratia marcescens

• Treatment- Colistin and Tigecycline

• New Delhi metallo-Clactamase 1 (NDM-1)

• An enzyme that produces resistance to a broad-range of beta-lactam antibiotics

• Produces a carbapenease

• Bacteria involved: E. coli, Klebsiella pneumoniae, Acinetobacter baumanni

• Can spread to other bacteria through horizontal gene transfer (via plasmids)

• Treatment: tigecycline and colistin

Intrinsic and associated resistance to antimicrobial agents

Bacteria Intrinsic Resistance Associated Resistance

MRSA All beta-lactams, beta-

lactam/beta-lactamase

inhibitor combinations

Common: erythromycin,

clindamycin,

aminoglycosides,

cotrimoxazole,

fluoroquinolones

VRE Glycopeptides, cotrimoxazole,

clindamycin,

aminoglycosides

Common: ampicillin,

carbapenems,

fluoroquinolones, high level

aminoglycoside resistance

ESBL enterobacteriaceae

All cephalosporins including

third generation

cephalosporins, (variable

activity against fourth

generation

cephalosporins), all

penicillins and

monobactams

Common: fluoroquinolones,

aminoglycosides,

cotrimoxazole

Carbapenem-resistant

Enterobacteriaceae

All beta-lactams including

carbapenem (except

monobactam)

Common: fluoroquinolones,

aminoglycosides,

cotrimoxazole

Associated resistance to aztreonam

is associated with other co-

existing enzymes (AmpC

beta-lactamase)

Strep Pneumoniae

• 2005 AGAR data

• 28.0% penicillin resistant

• 22.7% erythromycin resistant

• 15.6% clindamycin resistant

• 18.4% tetracycline resistant

• 31.0% trimethoprim-sulphamethoxazole resistant

• Seventeen point three per cent of isolates were multi-resistant (acquired resistance to more than 2 drug classes).

• North American data: may be between 40-80% penicillin resistant

• normal resistance: penicillin MIC < 0.1microgram/mL

• intermediate resistance: MIC 0.1-1microgram/mL (treat with high dose penicillin)

• high resistance: MIC > 2.0micrograms/mL

How do we compare?

Vancomycin Dosing and Monitoring

Loading dose and subsequent doses •Maximum infusion rate is 10 mg/minute to avoid Red Man syndrome (e.g., for 1.5 g, at least 2.5 hrs)

•Initial dose is a loading dose of 25 mg/kg of actual body weight

•Subsequent dosing and monitoring is based on the GFR calculated by the Cockroft Gault equation

Following the loading dose of 25 mg/kg (all patients):

Monitoring of target levels:

Timing of first level is per the table above

Target trough level is 15-20 mg/L

Only measure trough levels; peak levels aren’t measured

Do not delay regular dosing while waiting for a level

If levels are therapeutic and renal function stable, then repeat ~ weekly

Repeat more frequently with changing renal function, hemodynamic instability or concurrent nephrotoxins

Adjusting dosing and repeating levels:

Ensure that the trough level taken was a “true trough” taken pre-dose

Adjustment of vancomycin dosing is directly linear

e.g., for a trough of 12 and an existing dose of 1 g: 18/12 x 1 = 1.5 g

Re-check at same intervals as per table above if an adjustment is made

Indications

Empiric o <48 hours with investigations

pending, there is no need for levels

if use is less than 48 hrs o Gram negative pathogens

Directed o Infections when resistance to other

microbials shown o Combo therapy for Pseudomonas

aeruginosa and brucellois o Low doses as synergistic treatment

for streptococcal and enterococcal

endocarditis

Contraindications

Previous vestibular or auditory toxicity

due to an aminoglycoside

Hypersensitivity reaction to an

aminoglycoside

Precautions

Hearing problems

Vestibular problems

Neuromuscular disorders

Chronic liver disease, severe cholestasis

(serum bili >90)

Chronic renal failure or deteriorating

renal function

10-29 years 30-60 years >60 years

6mg/kg STAT

(up to 560mg)

5mg/kg STAT

(up to 480mg)

4mg/kg STAT

(up to 400mg)

Creatinine

Clearance

<30mL/min 30-40mL/min 40-60mL/min >60mL/min

Approach Seek expert

advice –

contact

Infectious

Diseases

Repeat same

dose in 48

hours

Repeat same

dose in 36

hours

Repeat same

dose in 24 hours

(can have a total

of 3 doses at

0,24 & 48 hrs)

Empirical or

Directed Therapy

Severe Sepsis Intermittent Dosing (only

when used synergistically)

7mg/kg STAT

(up to 640mg)

1mg/kg every 8 hours

(monitor trough levels

and UEC daily)

Single/Initial

Dose

Continued dosing for 48 hours without

need for drug monitoring (if indicated)

Gentamicin Dosing and Monitoring

IV to Oral Antibiotic Step Down

Inclusion Criteria:

Tolerating oral medications

Has received 2 days of IV therapy

Temperature <38 C over 24 hours

Respiratory Rate <20 or at baseline

Mental Status at baseline

Decreased WBC Count

Oxygenation >90% at room air or at

baseline

Exclusion Criteria:

In critical care area

Bone and joint infections

Endocarditis

Meningitis or other CNS infections

Bacteremia

Neutropenia

Legionella pneumonia

Malabsorption/Short Bowel syndrome

Severe diarrhoea

Uncontrolled nausea and vomiting

Patient on Total Parenteral Nutrition

When and when not to switch from IV to PO

antibiotics

IV ORAL

Antimicrobial Standard Dose* Antimicrobial Standard Dose*

Ampicillin 1-2g q6h Amoxycillin 500mg-1g TDS

Azithromycin 500mg daily Roxithromycin 300mg daily

Benzylpenicillin 1.2g q4-6h Amoxycillin 500mg-1g TDS

Ceftriaxone 1g daily

Cephazolin 1g q8h Cephalexin 500mg QID

Ciprofloxacin 200-400mg q12h Ciprofloxacin 250-500mg BD

Flucloxacillin 1g q6h Flucloxacillin 500mg QID

Lincomycin 600mg q8h Clindamycin 450mg TDS

Fluconazole 200-400mg daily Fluconazole 200-400mg daily

Metronidazole 500mg q12h Metronidazole 400mg TDS

Moxifloxacin 400mg daily Moxifloxacin 400mg daily

Piperacillin + Tazobactam^ 4.5g q8h Amoxycillin + Clavulanate 875/125mg BD

Ticarcillin + Clavulanate^ 3.1g q6h Amoxycillin + Clavulanate 875/125mg BD

Antimicrobial Oral Bioavailability

Ciprofloxacin 70-90%

Clindamycin 90%

Fluconazole >90%

Metronidazole 80%

Moxifloxacin 90%

Trimethoprim +

Sulfamethoxazole 98%

IV TO ORAL SWITCH Suggested Conversion Regimens *Dose adjustments may be required in renal impairment

^Consult ID Physician if pseudomonas or resistant negative Gram bacteria

Surgical Prophylaxis

Common Ups

• Timentin and Tazocin are penicillin based antibiotics- check allergies

• Give decent doses of gentamicin 4-7mg/kg

• Can give 48 hrs of gentamicin without needing to take a level (ie. 3 doses in normal renal function).

• Don’t use ceftriaxone 1st line for everything, has no enterrococcus or pseudo cover for UTI.

• Rate pneumonia severity using SMART COP or CORB and dose according to therapeutic guidelines (consider benzylpenicillin + doxycycline/ roxithromycin)

Common Ups

• Check sensitivites and choose a narrower spectrum antibiotic once known.

• Don’t give gentamicin/ other antibiotics for catheter changes.

• There is no evidence for using benpen plus fluclox to treat cellulitis.

• Bilateral cellulitits rarely exists.

• Don’t forget to dose adjust renally excreted drugs (check eTG)

Common Ups

• Investigate penicillin allergies before jumping to using moxifloxacin, vanc etc, around 10% of reported penicillin allergies are true.

• As a general rule remember to convert to oral therapy once afebrile for 48 hrs.

• For most surgical procedures a stat dose at time of induction is all the prophylaxis that is needed. Guidelines do not list any need for gentamicin prophylaxis in orthopaedic surgery.

An estimated 70 percent of all U.S. antibiotics are used nontherapeutically

in animal agriculture. (Image credit: Keep Antibiotics Working Coalition)

Remember M icrobiology guides therapy wherever possible

I ndications should be evidence based

N arrowest spectrum required

D osage appropriate to the site and type of infection

M inimise duration of therapy

E nsure monotherapy in most cases