Chap 51: Clinical use of antimicrobial agents

Empirical therapy
- presumptive therapy
- justification: early intervation = better outcome

Approach to empirical therapy
- get clinical dx
- specimen for lab exam
- formulate microbiologic dx
- is empirical therapy necessary?
- start treatment
- monitoring of treatment

Choice of antimicrobial agents
- host factor

• PMHx - liver, renal, AIDS
• drug allergy
• age
• pregnancy status

- pharmacologic factor

• pharmacokinetics
• delivery of drugs to site of action
• SE
• drug interaction

ABX OF KNOWN INFECTIOUS AGENTS
Interpretation of culture results
Reasons for -ve results

1. wrong sample - give abx first, contaminated
2. wrong request - bacterial vs viral culture
3. non-cultivable organism/slow growing stuff - H. capsulatum, bartonella
4. non knowing special needs of culture medium

Susceptibility testing
- measures MIC - minimum drug concentration to INHIBIT organism growth
- or MBC - minimal bacteriocidal concentration
- usually MIC is measured
- only in severe cases where MBC is measured - meningitis, endocarditis, neutropaenic sepsis

Specialised assay methods
- B lactamase assay
- synergy studies

Monitoring therapeutic response - duration of therapy
- 2 methods

1. microbiology - cultures/specimens should become sterile
2. clinically - symptoms, inflammatory markers, radiology

- duration depends on pathogen, site of infection, host factor

• generally determined empirically
• serious infection: 7-10 days after pt is afebrile
• recurrent infections: longer

Clinical failures
- check culture
- check host
- check abx

Bacteriostatic vs bacteriostatic activity
- generally, cell wall agents are bactericidal

• aminoglycosides
• B-lactams abx
• isoniazid
• metronidazole
• pyrazinamide
• quinolones
• rifampicin
• vancomycin

- protein synthesis inhibitors are bacteriostatic

• chloramphenicol
• clindamycin
• ehtambutol
• macrolides
• nitrofurantoin
• oxazolidinones
• sulfonamides
• tetracyclines
• trimethoprim

- which to choose?

• immunocompetent - doesnt matter it's the same
• immunocompromised - bactericidal
• severe infection like meningitis/endocarditis/neutropaenic - bactericidal

- bactericidal agents divided into 2 groups

• concentration dependent killing - aminoglycosides, quinolones
• time dependent killing - B-lactams, vancomycin; bactericidal activity continues as long as serum concentration > MBC

Postantibiotic effect
- persistant suppression of bac growth after limited exposure
- reason:

1. reversible non-lethal damage to cell structures --> needs time to recover
2. drug still at binding site within periplasmic space
3. then need to synthesize new enzymes before growth will resume

Route of administration
- many have similar pharmacokinetic properties po vs iv

• tetracycline
• trimethoprim-sulfamethoxazole
• quinolones
• chloramphenicol
• metronidazole
• clindamycin
• rifampicin
• fluconazole

- IV are for:

1. critically ill pt
2. bacterial meningitis/endocarditis
3. cannot swallow
4. abx that are poorly absorbed orally

Management of antimicrobial drug toxicity
- usually able to switch
- some no alternatives - eg neurosyphilis has anaphylaxis to penicillin - needs desensatisation
- penicillin + cephalosporin <10%>

- penicillin + imipenem cross reaction - >50%



ANTIMICROBIAL DRUG COMBINATION
Rationale
- seriously ill
- polymicrobial infections - intra-abdominal abscess
- reduce resistance (eg TB)
- reduce dose-related toxicity with single agent
- enhanced inhibition/killing



Synergism and antagonism
- 2 drugs together - MIC/MBC using 1/4th of the dosage compared to using single agent
- see text how to calculate synergism and antagonism

• FIC (fractional inhibition concentration) index <=0.5 = synergism
• FIC index >=4 = antagonism

- 3 mechanisms of synergism

1. Blockade of multiple steps in metabolic sequences - eg in bactrim as folic acid p/way - against PCP
2. Inhibit enzymatic inactivation - amoxyl-clavulanic acid, timentin, tazocin
3. Enhancement of antimicrobials uptake - cell wall agents (penicillin) increases aminoglycoside uptake by bacteria - eg Staph, enterococci, Pseudomonas, strep

- 2 mechanisms of antagonism

1. Inhibition of cidal agents by static agents - cell wall agents need dividing cells to act upon - if stopping cell division = cannot work; eg: tetracycline + chloramphenicol inhibit cell wall agents
2. Induction of enzymatic inactivation - g-ve (enterobacter, pseudomonas, serratia, citrobacter) if given imipenem, cefoxitin, ampicillin - can induce B-lactamase secretion --> hence B-lactams will lose activity

Antimicrobial prophylaxis
Surgical vs non surgical

• Surgical - needs to cover common pathogen - typically cefazolin/cefalothin
• Non-surgical - for suspected exposure or immunocompromised - depends on situation

National Research Council Wound classification
- clean

• infection rate <2%
• elective
• primarily closed procedure - respiratory, gastrointestinal, biliary, genitourinary, or
  oropharyngeal tract not entered
• no acute inflammation and no break in technique

- clean contaminated

• infection rate 10%
• emergency of an otherwise elective as above
• minimal spillage/minimal break

- contaminated

• Infection rate 20%
• Acute nonpurulent inflammation
• major technique break or major spill from hollow organ
• penetrating trauma <>
• chronic open wounds to be grafted or covered

- dirty

• Infection rate 40%
• Purulence or abscess present
• preoperative perforation of respiratory, gastrointestinal, biliary, or oropharyngeal tract
• penetrating trauma > 4 hrs old