Transcript ANTIBIOTICS2010 ppt

ANTIMICROBIAL AGENTS AND
PRINCIPLES OF THERAPY
Prof T Rogers
Clinical Microbiology TCD
SOME GENERAL PRINCIPLES
• Antibiotics can be naturally produced,
semi-synthetic, or synthetic substances
• Designed to have as much selective
toxicity on the bacteria as possible
• This is more likely to be achieved
compared to antimicrobials acting against
eukaryotic cells (fungi, protozoa)
EXAMPLES OF SELECTIVE
ACTION
• Penicillin on bacterial cell wall (organisms
without cell wall won’t be inhibited eg
Mycoplasma pneumoniae)
• Sulphonamides prevent bacteria
synthesising folic acid whereas humans
can use preformed folate
• Generally drugs acting on cell membranes
or protein synthesis are more toxic to
humans
The Penicillin Molecule
ANTIBIOTICS ACTING ON
CELL WALL OF BACTERIA
• BETA LACTAMS:
• Penicillins, cephalosporins, carbapenems,
• GLYCOPEPTIDES:
• Vancomycin, teicoplanin
THE IDEAL
ANTIBIOTIC?:PENICILLIN
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Narrow spectrum
Bactericidal
Very selective mode of action
Doesn’t disturb gut flora
Low serum protein binding
Widely distributed in body esp. CNS
Excreted by the kidneys
BENZYLPENICILLIN: MAIN
INDICATIONS
 Strep pyogenes sepsis (from sore throat to
fasciitis)
 Pneumococcal pneumonia, meningitis
 Meningococcal meningitis, sepsis
 Infective endocarditis (strep)
 Strep group B sepsis
 Diphtheria
 Syphilis, leptospirosis
THE DEVELOPMENT OF THE
BETA LACTAMS
• Benzylpenicillin and early cephalosporins mainly
active against gram positive bacteria
(strep and staph)
• Cloxacillin: stable to penicillinase
• Then “broad spectrum” penicillins appeared:
ampicillin, ureidopenicillins and cephalosporins:
cefuroxime, cefotaxime
• Carbapenems and latest generation of
cephalosporins, eg ceftazidime more active
against gram negatives
• Monobactam: aztreonam
CLOXACILLIN (METICILLIN)
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Narrow spectrum: Staph aureus (MSSA)
Stable to TEM1 beta lactamase
Similar antibiotics are meticillin, nafcillin
Similar safety profile to benzylpenicillin
MRSA emerged in the early 1970’s (MecA
gene encoding additional pbp)
BROADER SPECTRUM
PENICILLINS
• Ampicillin, amoxycillin cover most
organisms hit by penicillin but also Esch
coli, some Proteus (cause UTI’s)
• Augmentin stable to TEM1 beta lactamase
because of the clavulanic acid therefore
more active than ampicillin
• Tazocin: broader coverage than
augmentin against gram negatives
including Pseudomonas
PENICILLIN IS GENERALLY
VERY SAFE BUT….
• Allergic reactions not uncommon-rashes
• Most severe reaction being anaphylaxis
• A history of anaphylaxis, urticaria, or rash immediately
after penicillin indicates risk of immediate
hypersensitivity after a further dose of any penicillin or
cephalosporin (therefore these must be avoided)
• Allergy is not dependent on the dose given ie, a small
dose could cause anaphylaxis
• Very high doses of penicillin can cause neurotoxicity
• Never give penicillin intrathecally
What antibiotics can be used in
penicillin allergy?
• Macrolides: erythromycin, clarithromycin
• (mainly gram positive cover)
• Quinolones: ciprofloxacin, levofloxacin
(mainly gram positive cover)
• Glycopeptides (serious infections)
• Fusidic acid, rifampicin, clindamycin
(mainly gram positive)
REMEMBER WHAT THE OTHER
BETA LACTAMS ARE:
• All penicillins: ampicillin, augmentin,
piperacillin, cloxacillin
• Cephalosporins: cefuroxime, cefotaxime,
ceftriaxone, ceftazidime (5-10% cross
sensitivity)
• Monobactam: aztreonam (low cross
sensitivity)
• Carbapenems: imipenem, meropenem
CEPHALOSPORINS: MAIN USES
• Cefuroxime: surgical prophylaxis
• Cefotaxime/ceftriaxone: meningitis
nosocomial infections excluding
Pseudomonal,
• Ceftazidime: nosocomial infections
including those caused by Pseudomonas
Problems with antibiotic resistance:
how does it happen?
• Some bacteria are naturally resistant to
particular antibiotics (Pseudomonas has
permeability barrier to many antibiotics)
• Some typically susceptible species have minority
populations which are resistant by virtue of
mutational resistance (pneumococcus)
• Other species acquire resistance via plasmids
(“infectious resistance”) eg Neisseria
gonorrhoeae, many gram negatives
PENICILLIN RESISTANCE:
Organisms producing TEM1beta lactamase
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Haemophilus influenzae
Neisseria gonorrhoeae
Bacteroides fragilis
Staph aureus
Esch coli
What are ESBL’s???
• Enzymes which have a broad spectrum of
activity against third generation cephalosporins
eg cefotaxime
• Can be carried on extrachromosomal plasmids
which additionally encode resistance to eg,
fluoroquinolones, aminoglycosides
• Can be spread between different enterobacteria
by conjugation
• As big a threat as MRSA
CARBAPENEMS
• Imipenem, meropenem: have a very broad
spectrum activity against gram-negative
bacteria, anaerobes, streps
• Now used to treat gram negative infections
due to so called ESBL producing
organisms eg, E coli, Klebsiella
• Ertapenem is a new member of the group
but its not active against Pseudomonas
A new threat posed by antibiotic
resistance: NDM-1
• Confer resistance to carbapenems which
are among our most efffective antibiotics
• Pose a new threat
• Often linked to travel to India but now
reported around the World
Community
Healthcare ass’d
Hospital
More resistance
Less resistance
Current major antibiotic resistance
problems: community infections
• Respiratory tract: penicillin resistance in
pneumococcus (5-10%)
• Gastrointestinal: quinolone resistance in
Campylobacter
• Sexually transmitted: penicillin, quinolone
resistance in gonococcus
• Urinary tract: beta lactam resistance in Esch coli
• Tropical: multidrug resistance in Salmonella
typhi, Shigella spp
Current major resistance problems:
hospital infections
• MRSA: current strains are often multiplyantibiotic resistant
• VISA/GISA: intermediate resistance to
glycopeptides (thickened cell wall)
• VRSA/GRSA: highly resistant (transferable on
plasmids) from enterococci
• VRE: enterococci (multiply resistant)
• Broad spectrum beta lactam resistant (ESBL)
and quinolone resistant Esch coli, Klebsiella
• Multiply antibiotic resistant enterobacteria:
Acinetobacter, Stenotrophomonas, Serratia
© July Issue of Epi-Insight, Vol 6, Issue 7,
Health Protection Surveillance Centre, Ireland
S. aureus BSI 2006
HOSPITAL
HA ACQ’D
Antibiotic name
Erythromycin
Oxacillin
Cloxacillin
Linezolid
Vancomycin
Number
78
78
78
78
%R
56.4
65.4
0
0
HCA
Number
%R
24
54.2
24
50
24
0
24
0
COMMUNITY
NHCA
Number
18
18
18
18
%R
33.3
27.8
0
0
M
R
S
A
E. coli - distribution of fluoroquinolone
(CIP/OFX) resistance in EARSS countries in
2005
EARSS in Ireland – E. coli trends
1800
21
27
40
42
42
25%
1600
Number of isolates
1200
15%
1000
800
10%
600
400
5%
200
0
0%
2002
2003
2004
2005
2006
Time period
Total E.coli
%3GC-R
%CIP/OFX-R
Changes in the numbers of participating laboratories are indicated above the bars
%GEN-R
% Resistance
20%
1400
TUBERCULOSIS
The Threat of Multi-Drug Resistant
(MDR) T.B.
o HIV patients
o Erratic or incomplete treatment
o Non-compliance
o Persistent symptoms despite treatment
o Resident in area of high prevalence eg,
Former Soviet countries
Other major antibiotic groups:
aminoglycosides
• Gentamicin, amikacin (tobramycin,
streptomycin)
• Mainly active against gram negative
bacteria
• Mainly used to treat nosocomial infections:
pneumonia in ITU, septicaemia
• Limiting factors are nephrotoxicity (and
ototoxicity) and resistance
• Also used in combination
How we give aminoglycosides
• For serious nosocomial infections:
“extended interval” or once daily dosing
• 5 or 7mg/kg/day for gentamicin (Hartford
nomogram)
• Rationale based on concentrationdependent killing and post-antibiotic effect
• Reduced risk of nephrotoxicity
• In infective endocarditis use lower doses
to give synergy with penicillin
Some other antibiotics occasionally
used
• Co-trimoxazole (Stenotrophomonas)
• Chloramphenicol (typhoid fever,
meningitis)
• Colistin (resistant Pseudomonas) topical
• Neomycin: gut decontamination, topical
Some indications and limitations
of particular antibiotics
COMMUNITY ACQUIRED PNEUMONIA:
WHAT’S CAUSING IT?
TYPICAL GRAM APPEARANCE OF
Strep pneumoniae IN SPUTUM
GRAM POSITIVE CHAINS
DIPLOCOCCI
Community acquired pneumonia
• Pneumococcus (and H influenzae) are most
likely: therefore ampicillin, amoxycillin or
augmentin
• Severe pneumonia: cefotaxime
• Severe atypical pneumonia (Legionella):
macrolide or quinolone
• Resistant pneumococcus: vancomycin or
linezolid (new antibiotic!)
• A new quinolone moxifloxacin covers most of
these pathogens (likely to be used more in
community)
S. pneumoniae
Antibiotic name
Cefotaxime
Erythromycin
Penicillin G
*MIC 0.12 -1.0 mg/l
**MIC >= 2mg/l
Num.
60
222
221
%R
0
17.6
2.7**
%I
16.7
1.4
22.2*
%S
83.3
81.1
75.1
Lower Respiratory Tract Infection
Antibiotic Guidelines
Infection
Common Pathogens
Recommended antibiotics
(i) Community Acquired
Pneumonia
S. pneumoniae, H.
influenzae, Mycoplasma,
Legionella
Co-amoxiclav ,Clarithromycin
(ii) Exacerbation of
Chronic Obstructive
Pulmonary Disease
S. pneumoniae, H.
influenzae
Moraxella sp.
Co-amoxiclav , Moxifloxacin
(iii) During influenza epidemic
Consider S. aureus
Fluclox, Vancomycin
(iv) Hospital/institutional
acquired pneumonia
Aerobic Gram-negatives
Legionella, S. aureus
PipTaz, Cipro gentamicin
(v) Aspiration pneumonia
a) Community Acquired
Aerobic & anaerobic strep
b) Nosocomial
Aerobic Gram-negatives
Community acquired
urinary tract infections
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Ampicillin, amoxycillin, augmentin
Oral cephalosporin: cephradine
Trimethroprim
Nalidixic acid
Nitrofurantoin
Ciprofloxacin
Mecillinam
Top Five
URINARY isolates SJH 2006
HA
n = 1432
E. coli
HCA
n = 562
605(42%)
E. coli
NHCA
n = 870
306(54%)
E. coli
608(70%)
Enterococcus sp 230(16%)
Enterococcus sp 87(16%)
Enterococcus sp 67(8%)
Klebsiella sp.
Klebsiella sp.
50(9%)
Klebsiella sp.
40(5%)
P. mirabilis
30(5%)
P. mirabilis
28(3%)
P. aeruginosa
14(3%)
Coag neg Staph 25(3%)
P. mirabilis
S. aureus
162(11.3%)
100(7%)
31(2%)
One isolate per patient included
E. coli from Urine
HA
Antibiotic name
Number
Amoxicillin/Clavulanic 604
acid
Ampicillin
603
Ciprofloxacin
603
Gentamicin
278
Meropenem
277
Nitrofurantoin
604
Piperacillin/Tazobactam
278
Trimethoprim
604
%R
13.1
68
33.3
16.2
0
4.5
5
45
HCA
Number
303
303
305
114
115
305
115
303
%R
7.9
63
24.3
14
0
2.3
0.9
39.3
NHCA
Number
%R
606
3.8
604
55.5
606
7.3
85
7.1
85
0
605
2.8
85
3.5
605
34.2
Genitourinary infections
Antibiotic Guidelines
Infection
Urinary Tract Infection
1. simple cystitis: non- catheter
related, non-pregnant women, no
prior treatment in community
Common Pathogens
E. coli
Other Gram-negative
rods
Less commonly:
Enterococci
Staph. saprophyticus
2. recent treatment or hospitalised
Recommended antibiotics
Trimethoprim
Nitrofurantoin
Ciprofloxacin
Ciprofloxacin
3. Catheter-related
Pyelonephritis
or
Complicated UTI
E. coli
Ciprofloxacin
Co-amoxiclav
Ceftriaxone IV
Gentamicin
HA Cipro Resistant E.coli
410 patients with HA Cipro resistant E. coli from 2003 – 2006
29% were Care of the Elderly patients (speciality)
62% were from urine with and w/o catheter
Cipro resistance and usage
30
12000
25
10000
20
8000
15
6000
10
4000
5
2000
0
0
Q3
Q4
2003
Q1
Q2
Q3
2004
Q4
Q1
Q2
Q3
2005
Q4
Q1
Q2
2006
DDD ciprofloxacin in SJH
% resistance of E. coli to
ciprofloxacin
Ciprofloxacin Resistance in E. coli
Skin and soft tissue infections
• Cellulitis ? Streptococcal: penicillin or
augmentin
• Infected eczema ? Staphylococccal/mixed:
penicillin+flucloxacillin or augmentin
• Necrotising fasciitis: penicillin+clindamycin
• Septic arthritis: fluclox+fusidic acid
• Gangrene: metronidazole
Where there is deep-seated
infection: bone, abscess
• Need an antibiotic with good tissue and
phagocyte penetration
• Examples are rifampicin, clindamycin,
fusidic acid, ciprofloxacin, metronidazole
• So for treatment of Staph aureus
osteomyelitis: flucloxacillin+ fusidic acid
Why do we use combination
therapy?
• When treating serious infection empirically
we want to cover a broad spectrum
(severe pneumonia:cefotaxime+erythromycin)
• To prevent the emergence of drug
resistance: tuberculosis regimens
• For synergy: infective endocarditis
(aminoglycoside)
• For mixed infections eg, abdominal sepsis
(tazocin+metronidazole)
Are we moving to the Postantibiotic era?
o Judicious use of current antibiotics both
in Hospital and Community
o New antibiotics
o Improve Infection control practice
o Better management of hospitalised
patients
New antibiotics
• Daptomycin: lipopeptide active against strains of
Staph aureus (incl MRSA) and VRE
(bactericidal)
• Mode of action: disrupts bacterial cell membrane
• Given intravenously
• Indicated for skin and soft tissue infections and
R sided endocarditis, bacteraemia due to S
aureus
• Can cause myopathy (monitor CPK weekly)
Tigecycline
• A new glycylcycline antibiotic of
tetracycline class
• Broad spectrum of activity
• Mode of action: bact. ribosomal synthesis
• Indicated for skin and soft tissue, and
intraabdominal infections
• Has activity against MRSA, VRE, ESBL
producing enterobacteria
• Monitor liver function
Linezolid
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An oxazolidinone antibiotic
Inhibit bacterial protein synthesis
Bacteristatic
Active against gram positive bacteria incl
MRSA and VRE
• Can be used in pneumonia, skin and soft
tissue infections
• Thrombocytopenia and interactions with
SSRI’s 9serotonin release
http://www.ndsc.ie/A-Z/MicrobiologyAntimicrobialResistance/EuropeanSurveillanceofAntimicrobialConsumptionESAC/
Self assessment: Which one of the following is
often resistant to penicillin because of TEM1
encoded penicillinase production:
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Streptococcus pneumoniae
Neisseria meningitidis
Streptococcus pyogenes
Mycobacterium tuberculosis
Neisseria gonorrhoeae
Self assessment: which one of the following is not available
for oral administration in a case of systemic infection
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Augmentin
Ciprofloxacin
Gentamicin
Erythromycin
Rifampicin
Self assessment:Which of the
following is a beta lactam antibiotic
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Clarithromycin
Augmentin
Nitrofurantoin
Nalidixic acid
Fusidic acid
Self assessment:In a patient with a history of
anaphylaxis when previously given penicillin which
one of the following should be a safe alternative
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Clarithromycin
Cefuroxime
Augmentin
Flucloxacillin
meropenem