Antibiotics Cefa 1st

1
??? ??? ??

• 2009.4.20
• ????? ????
• ???? ???

2
2008? ???? ??? ???

Antibiotics Cefa 1st2nd C 3rd C
AMG Imipenem Quinolone
3
Start with the questionIs an antibiotic needed
in this patient?

• Avoid antibiotics in patients only
• - with Fever
• - with only URI
• Sx 1 week, should not be started immediately
• - Get sufficient information including cultures

4
Start with the questionIs an antibiotic needed
in this patient?

• Urgent probable infections
• Meningitis
• Febrile neutropenia
• Definite evidence of localized infections
• Pneumonia
• Cellulitis
• UTI

5
Three players in Antimicrobial therapy
6
Microbiologic factor

• Causative pathogen
• - Guessing ? Empirical therapy
• - Identifying ? Targeted therapy
• Antimicrobial susceptibility
• Inoculum (???)
• Growth phase
• Virulence factors (toxin, enzymes, metabolites)

7
Guessing

• Using Bacteriologic Statistics
• Site of infection
• Age
• Severity of disease
• Epidemiological factors
• Previous culture results
• Antimicrobial susceptibility pattern of the
  community
• ? Best-guess antibiotic therapy

8
Site of infection Common pathogen
Pneumonia S. pneumoniae, H. influenzae, M. pneumoniae, C. pneumoniae
Skin and soft tissue S.aureus, S.pyogenes
Intraabdominal infection Enterobacteriacae, Anaerobes
Meningitis
lt55yr S.pneumoniae, N.meningitidis
gt55yrs or alcoholics GNB, L.monocytogenes, S.pneumoniae
Febrile neutropenia P.aeruginosa, GNB
UTI E.coli TMP/SMX R 70
9
Identifying

• Gram staining
• Culture sensitivity testing
• BEFORE starting/changing antibiotics
• Serology
• PCR
• Ag detection

10
Host factors

• Site of infection
• Drug allergy, Genetic factor
• Renal, Hepatic function
• Age children, elderly
• Pregnancy, Breast feeding
• Underlying disease DM, Hematologic malignancy,
  Transplantation recipient
• Immunity Immunosuppressant, Immune-deficiency

11
Site of infection

• Determines class, dose, route of antibiotics
• Blood tissue barrier
• CNS - 3rd cepha, Penicillin O
• 1st, 2nd cepha, AMG X
• Prostate Quinolone O
• b-lactam, AMG X
• Foreign bodies, Vegetation, bone, devitalized
  tissue
• Low penetration of antibiotics
• Biofilms impair phagocytosis,? antibiotics
  penetration
• Abscess
• Pus, anaerobic, low PH condition ? AMG X
• Drainage is important!

12
Antimicrobial factors

• Antimicrobial spectrum
• Efficacy
• PK, PD
• Safety and toxicity
• Cost-effectiveness
• Drug interactions

13
Classification of antibiotics
Class Class Class Mechanism of action
Beta-lactams Beta-lactams Cell wall synthesis
Penicillin Penicillin Penicillin
Cephalosporin Cephalosporin Cephalosporin
Beta-lactamase inhibitor Beta-lactamase inhibitor Beta-lactamase inhibitor
Carbapenem Carbapenem Carbapenem
Monobactam Monobactam Monobactam
Fluoroquinolone Fluoroquinolone Fluoroquinolone DNA synthesis
Aminoglycoside Aminoglycoside Aminoglycoside Protein synthesis
Glycopeptide Glycopeptide Glycopeptide Cell wall synthesis
Macrolides Macrolides Macrolides Protein synthesis
Lincosamide Lincosamide Lincosamide Protein synthesis
Tetracycline Tetracycline Tetracycline Protein synthesis
Metronidazole Metronidazole Metronidazole Nucleic acid synthesis
Sulfonamides Sulfonamides Sulfonamides Cell metabolism
Oxazolidinone Oxazolidinone Oxazolidinone Protein synthesis
Polymyxin Polymyxin Polymyxin Cell membrane
14
Penicillin
G () G (-) Anaerobes Anaerobes
Natural Pn Penicillin G (non b-lactamase producing) Neisseria Neisseria
Penicillinase resistant Pn Nafcillin Staphylococcus - - -
AminoPn Ampicillin/ Amoxicillin (non b-lactamase producing)
Anti-Pseudomonal Pn Piperacillin (non b-lactamase producing)
15
Cephalosporin
Generation Examples G() S.pneumoniae G(-)
1st Cefazolin Cefazedone (????) Ceftezole(????)
2nd Cefuroxime (????) Cefotiam (????, ???)
Cepha-mycin Cefoxitin (????) Cefotetan (????) Cefmetazole (???) Cefbuperazone (????)
3rd Cefotaxime(????) Ceftriaxone (????) Ceftizoxime (????)
Cefoperazone (???) Ceftazidime Pseudomonas
4th Cefepime Pseudomonas
Anaerobes
16
(No Transcript)
17
B-lactam B-lactamase combination
G() G(-) Anaerobes
Ampicillin/Sulbactam (???)
Amoxicillin/Clavulanic acid (????)
Piperacillin/Tazobactam (????) Pseudomonas
Cefoperazone/Sulbactam (???) Pseudomonas
18
Carbapenem
IMI/CL MER ERT
G()
G(-)
Enterobacteriaceae
P. aeruginosa
Anaerobes
19
Quinolones
Generation Fluoroquinolones Antibacterial activity
1st Nalidixic acid, oxolinic acid, cinoxacin Enterobacteriaceae
2nd Ciprofloxacin, pefloxacin, Norfloxacin, Ofloxacin, Lomefloxacin Mainly G(-), Limited G()
3rd Levofloxacin, sparfloxacin, temafloxacin Both G() and G(-)
4th Moxifloxacin, gatifloxacin, gemifloxacin Both G() and G(-) Anaerobes
20
Other Antibiotics
G() G(-) Note
Aminoglycoside GentamicinTobramicinAmikacinIsepamicinMicronomicin MSSA ()Should not be used alone
Glycopeptide VancomycinTeicoplanin - MRSA
Macrolides ClarithromycinErythromycin Atypical pathogen
Lincosamide Clindamycin - Anaerobes
Tetracycline Doxycycline Rickettsia
Metronidazole - - Anaerobes
Sulfonamides TMP-SMX
Oxazolidinone Linezolid - VRE
Polymyxin Colistin -
21
Broad-spectrum, 3rd line antibiotics

• Piperacillin/Tazobactam (????)
• Imipenem, Meropenem
• Vancomycin, Teicoplanin
• Moxifloxacin (????)
• Linezolid, Colistin

• Do not waste them!
• ?More colonization with resistant organisms
• ?Superinfection with resistant organism
• ?Higher morbidity and mortality

22
Multidrug resistant organisms (So called
Superbacteria)
MDRO Current TOC New options
MRSA VancomycinTeicoplanin Linezolid DaptomycinTigecyclineTelavancin..Ceftobiprole
VRE Linezolid DaptomycinTigecyclineTelavancin..
ESBL GNB ImipenemMeropenem
MDR Pseudo/Acineto Colistin
23
Combination therapy?

• Indication
• Mixed infection
• Intra-abdominal infection, pelvic infection
• Initial therapy
• Febrile neutropenic patient
• Severely septic patient with presumed infection
• Prevent emergence of resistance
• Anti-Tb tx, H.pylori tx
• Synergism
• Entercococci penicillin AG
• S. aureus nafcillin GM
• P. aeruginosa piperacillin AG

24
Disadvantages of combination

• Antagonism
• Pneumococcal meningitis
• Mortality penicillin 21 vs PCNtetracycline 79
• Enterobacter, Serratia, Pseudomonas
• Beta lactam beta lactam beta lactamase
  induction
• Higher costs
• Toxicity
• Superinfection (???)
• Emergence of resistant organism

25
Pharmacokinetics/Pharmacodynamics(PK/PD)
26

GI tract (po)
Vessel, Muscle (parenteral)


27
Route of administration

• Severity of infection
• Site of infection
• Oral bioavailability
• Vancomycin, AMG, amphotericin B PO?IV
• Linezolid POIV
• Quinolone PO IV
• Function of GI tract
• Severely ill patient
• Antacid, antihistamine?FQ absorption

28
GI absorption rate of antibiotics
poor fair good
excellent 0 40 70
gt90
Vancomycin Aminoglycosides
Penicillin V Ampicillin Cefuroxime Cefixime (????)
Cefpodoxime (??) Azithromycin Clarithromycin Norf
loxacin
Amoxicillin Amox/clav Tetracycline Ciprofloxacin M
etronidazole
Cefadroxil, Cefaclor (????, ????) Cefprozil
(???) Doxycycline Ofloxacin Levofloxacin Clindamyc
in TMP/SMZ
29
Drug interactions inhibiting GI absorption
Antibiotics Ass.drug Results
Fluoroquinolones Antacids, Sucralfate, Didanosine (ddI), Ferrous sulfate, Zinc ? concentration d/t chelation
Tetracyclines Antacids, Bismuth, subsalicylate, Didanosine (ddI), Ferrous sulfate ? concentration d/t chelation
Clindamycin Kaolin-pectin ? absorption
30
Appropriate dose

• Check textbook!!
• Higher dose ? Toxicity
• Exception
• - CNS infection d/t blood-brain barrier
• - Decreased host immunity neutropenic fever
• Lower dose ? Resistance
• Drug level monitoring
• - Drugs low therapeutic/toxic ratio (AMG, Vanco)
• - Indications renal dysfunction, elderly

31
Pharmacodynamic parameters of antibiotics
Concentration dependent
Time dependent
32
??? ??? ? ????!
33
Streamline, sequence and monitor the
antimicrobial therapy
34
1st Empirical or Deferred Stage (1st 24 hours)

1. Best-guess antibiotic therapy 2. Consider
Host factors 3. Consider Antimicrobial
factors 4. Hold antibiotic therapy for about 24
hours for patients with less possibility of
bacterial infection and immune-competent state
35
2nd Re-evaluation, Definitive, or Continuous
Stage (3rd-5th days)

• 1. Evaluate the efficacy
• - Consider delayed response among compromised
  hosts
• 2. Definitive therapy
• - Identify the cultured microorganisms and
  choose susceptible antibiotics
• 3. Continuous therapy
• - No growth of microorganisms and good clinical
  response
• 4. Re-evaluate
• - If no clinical response, re-evaluate the
  clinical situation

36
Modification with culture data is essential!!

• Check culture results
• (Reported within 3-5 days)
• Switch antibiotics according to culture results
• Possible narrow spectrum antibiotics
• MSSA vancomycin?nafcillin or 1st cefa
• S E.coli ? 2nd cefa, ampicillin,
  TMP-SMX
• Less toxicity
• GNB AMG ?beta lactam (ampicillin, cefa)
• Cheap
• AMG Gentamicin (\870) vs Isepamicin
  (\2,754)

37
3rd Step-down or Discontinuous Stage (5th 14th
days)

• 1. Stop
• - No clinical and microbiological signs of
  infection and minimun duration satisfied
• 2. Step down
• - Oral switch if criteria fullfilled
• 3. Adjust
• - Superinfection, infection w resistant
  pathogen, opportunistic infections

38
Monitoring response

• Clinical assessment most important
• - Fever Sensitive indicator
• Defeverescence within 3-5 d
  usually
• - Local Sx. cough, sputum, diarrhea, abd. pain,
  headache
• - Physical Fx. rales, discharge, erythema,
  pain, swelling
• Laboratory parameters
• - Routine Lab WBC count, shift to left, CRP,
  ESR
• - Microbiology f/u cultures (blood, urine)
• Imaging studies
• - X-ray, Ultrasonography, CT scan, MRI

39
Suggested Duration of Antibiotic Therapy
Site Clinical Dx. Clinical Dx. Clinical Dx. Duration of Tx.
Bacteremia Bacteremia with removable focus Bacteremia with removable focus Bacteremia with removable focus 10-14
Bone Osteomyelitis, adult acute Osteomyelitis, adult acute Osteomyelitis, adult acute 42
adult chronic Until ESR normal
Endocardium Infective endocarditis, native valve Infective endocarditis, native valve Infective endocarditis, native valve
Viridans strep. Viridans strep. 14 or 28
Enterococci Enterococci 28 or 42
Staph. aureus Staph. aureus 14(Rt. Only) or 28
GI Shigellosis/travellers diarrhea Shigellosis/travellers diarrhea Shigellosis/travellers diarrhea 3
Typhoid fever Typhoid fever Typhoid fever FQ (10) or ceftriaxone (5)
Kidney Cystitis Cystitis 3
Pyelonephritis Pyelonephritis Pyelonephritis 14
Lung Pneumonia, pneumococcal Pneumonia, pneumococcal Pneumonia, pneumococcal Until afebrile 3-5 d (min. 5d)
Lung abscess Lung abscess Lung abscess 28-42
Meninges H. influenzae, N. meningitidis H. influenzae, N. meningitidis H. influenzae, N. meningitidis 7
S. pneumoniae S. pneumoniae S. pneumoniae 10-14
Listeria, Gr. B strep., coliforms Listeria, Gr. B strep., coliforms Listeria, Gr. B strep., coliforms 14-21
Sinuses Acute sinusitis Acute sinusitis Acute sinusitis 10-14
40
Optimal duration

• Adequate period, not unnecessarily prolonged
• To avoid colonization by resistant organisms
• Pneumonia X-ray improves slowly
• Recommended duration textbook
• Type of infection, pathogens, host immunity
• Follow recent data for shorter treatment
• Acute cystitis 7d ? 3d
• Scrub typhus 7d ? 3d

41

• Surgical prophylaxis

42
If the patient is improving and organisms
resistant to current antibiotics is isolated on
F/U cultures
Ignore it!
43
Reasons for treatment failure

• Delay in diagnosis or therapy
• Wrong or incomplete diagnosis
• No infection
• Nonbacterial infection
• Inadequate concentration of antibiotic at the
  site of infection
• Improper dose
• Decreased absorption from food or drug
  interaction
• Increased elimination of agent
• Poor delivery (eg, vascular disease)

44

• Other factors at the site of infection
• Collection requiring drainage
• Necrotic tissue
• Foreign body
• Decreased activity at the site
• Chemotactic factor (pH and others)
• Antibiotic antagonism
• Other host factors
• Impaired immune defenses
• Errors in antimicrobial susceptibility testing
• Development of resistance to antimicrobial agents
• Superinfection

45
Take home message

• Perform cultures
• Confirm correct doses
• Combination is not needed most of the time
• Check culture results
• Hold as soon as possible

46
Antibiotics
Undesirable effect Toxicity Resistance
Desirable effects

• Anti-anxiety drug???

47
???, ??? ??? ??
???? ? ??? ? ??? ?? ?

• ??? ??
• ?? ? ???
• ??, ??,
• PK, PD

?? ?? ??? ?? ????
48
(No Transcript)