1. Community Acquired Bacterial Infections: Principles of antibiotic therapy for common outpatient conditions
Dr K Outhoff

2. The scope Goals of Antibacterial therapy Tonsillitis / pharyngitis
Acute otitis media and sinusitis
Community acquired pneumonia in adults
Urinary tract infections
Summary

4. Antimicrobial activity against a specific pathogen is reliant on:
The agent penetrating to an appropriate binding site
Attaching itself to that site in adequate concentrations
Remaining there for a sufficiently long period to inhibit bacteria from carrying out its normal life functions

5. Pharmacokinetic Parameters used for antimicrobials
Time
Concentration of drug in plasma
Cmax (peak plasma concentration)
AUC (24 hour area under the concentration / time curve = total exposure to drug)
Trough levels (aminoglycoside monitoring)

7. Pharmacodynamics
The specific mechanism by which antibiotics cause cell death is different for each of the antimicrobial classes

8. Pharmacodynamics mechanism of action
Cell wall synthesis
Β-lactams (penicillins, cephalosporins, carbapenems, monobactams)
Vancomycin and teicoplanin
DNA
Quinolones
Rifampicin
Folate
Sulphonamides
Trimethoprim
Fungal Plasma membranes
Polymixins (colistin)
Nystatin
Amphotericin
Ribosomal Protein synthesis
Fucidic Acid
Macrolides (Erythromycin, Clarithromycin, Azithromycin)
Ketolides (Telithromycin)
Lincosamides (Clindamycin)
Oxazolidonones (Linezolid,)
Streptogramins (Quinupristin, Dalfopristin)
Tetracyclines (tetracycline, oxytetracycline, doxycycline, minocycline)
Chloramphenicol
Aminoglycosides (Gentamycin, Streptomycin, Amikacin, Tobramycin, Neomycin)

9. Pharmacodynamic parameters used in microbiology and microbiologic surrogate markers
Bacteriostatic
Bactericidal
Post antibiotic effect
MIC
MBC
Concentration dependent killing
Time dependent killing

10. Bacteriostatic antimicrobial agents
Bacteriostatic agents reliant on:
Host immune function
Post antibiotic effect
Macrolides
Clindamycin
Tetracyclines

11. Post antibiotic effect (PAE)
subnormal replication after exposure to antibiotic
allows for longer intervals between dosing

12. MIC Minimum Inhibitory Concentration
A value that is determined in the laboratory (in-vitro)
Use three concentrations of the drug known to inhibit wild type (parent) strains
Minimum concentration (μg/ml) of antibiotic required to inhibit more than 99% of the cultured bacteria (test strain)
Suggestive of what may actually happen in vivo
To determine susceptibility or resistance to antibiotic

13. Concentration dependent killing
Higher the antibiotic concentration, the greater the bactericidal activity
Aminoglycosides
Quinolones

14. Pharmacokinetic and pharmacodynamic considerations
To ensure efficacy and to prevent resistance, choice of antibiotic requires integration of:
Pharmacokinetics
Area under concentration curve (AUC)
Peak concentration (Cmax)
Drug half-life
Pharmacodynamic data
MIC (minimal inhibitory concentration)
Integration:
AUC/MIC ratio (quinolones)
Cmax/MIC ratio (aminoglycosides)
T>MIC (Time the concentration is above MIC) (beta lactams)
AUC = total exposure to the drug

15. Integration of kinetics and dynamics Aminoglycosides
Aminoglycosides exhibit concentration dependent bactericidal effects
To maximise peak Cmax/MIC ratio (> 10): given as high dose, once daily (instead of the traditional divided doses)
Aminoglycosides possess a post antibiotic effect (PAE) (persistent suppression of organism after concentrations fall below MIC
Advantage taken of this effect by giving once daily dose

16. Integration of kinetics and dynamics Fluoroquinolones AUC/MIC ratio
Exhibit concentration dependent killing
Optimal killing characterised by the AUC/MIC ratio:
> : effective for gram negatives (Pseudomonas)
>30-40: effective for gram positives (S pneumoniae)

17. Time and Duration dependent killing
As long as minimal inhibitory concentration (MIC) is reached, the destruction relies on keeping the levels above this concentration for as long as possible. (> 40-50% dosing interval)
T>MIC
Β-lactams
Vancomycin

18. Integration of kinetics and dynamics Beta-lactams and Vancomycin
Time-dependent bactericidal effects
Killing activity is only marginally enhanced if drug concentration exceeds MIC
Therefore duration drug exceeds MIC important: T>MIC
Effective dosing regimes require serum drug concentrations to exceed MIC for at least 40-50% dosing interval
Frequent small doses or continuous infusions of beta-lactams therefore associated with good outcome

19. Antibiotic Selection Factors I: Bug
Severity and acuity of disease
Infecting organism
Place of infection
Community acquired
Hospital acquired (nosocomial)
Travel

20. Antibiotic Selection Factors II: Host
Age
Drug allergies
Pregnancy
Genetic or metabolic abnormalities
Renal and hepatic impairment
Site of infection
Concomitant drug therapy
Underlying disease states

21. Antibiotic Selection Factors III: Drug
Pharmacokinetics / dynamics
Tissue penetration
Toxicity
Cost
Necessity for multiple agents
Local antimicrobial susceptibility data
Antibiogram is an annual summary of susceptibility for organisms cultured from patients in a given institution
Number of isolates
Percentage susceptible to antibiotic tested

22. Genetic and Biochemical Resistance

23. Indications for Combination Therapy
Serious, life-threatening illness
Polymicrobial infections eg STDs, intra-abdominal abscess
To prevent emergence of resistant strains eg TB
To decrease dose related toxicity by reducing doses of drugs used eg Flucytosine + Amphotericin B
Specific infections where organisms are unreachable
Empiric or ‘blind’ antibiotic therapy in very ill patients
In immuno-compromised patients

24. Upper and Lower Respiratory Tract Infections
Tonsillitis / pharyngitis
Bacterial sinusitis/ otitis media
Community acquired pneumonia

25. Acute tonsillitis / pharyngitis

26. Acute tonsillitis / pharyngitis
Updated guideline for the management of URTIs in South Africa: 2008: SA Fam Pract 2009;51(2):
Acute tonsillitis / pharyngitis
Viral 80%
Bacterial 20%
EBV
Cytomegalovirus
Adenoviruses
Measles
Streptococcus pyogenes (GABHS)
Tonsillitis
Acute glomerulonephritis
Rheumatic Fever
Rx aimed at preventing above complications
Pen VK given 30 minutes before food, twice daily X 10/7
Amoxicillin (rash if EBV present), no food restrictions, once or twice daily X 10/7
Clindamycin if allergy
(Macrolide if allergy)
Clindamycin better than erythromycin in pen. Allergy.
Clarithromycin, azithromucin alternatives
Short course (3-5 days) possible with co-amoxiclav, azithro, clarithro, cefpodoxime, cefuroxime
Short course (3-5 days) possible with co-amoxiclav, azithro, clarithro, cefpodoxime, cefuroxime

27. Points in favour of empiric antimicrobial treatment
Acute onset
Temperature > 38⁰C
Tender anterior cervical nodes
Tonsillar erythema / exudates
Age 3-15 years
Previous Rheumatic -fever or -heart disease

28. Indications for referral
Local complications:
Peritonsillar sepsis (quinsy, cellulitis, trismus)
Recurrent infections (> 4 / year)
Non-response to initial therapy
Systemic complications:
Acute rheumatic fever
Severe systemic illness

30. Sinuses

31. Acute bacterial sinusitis / otitis media
Aetiology:
S. pneumoniae
H. Influenzae
Moraxella catarrhalis (consider if no rapid clinical response)

32. Antibiotic options for ABS
Beta lactams:
Amoxicillin
Amoxicillin-clavulanate
Cefuroxime*
Cefpodoxime*
Macrolides:
Erythromycin
Azithromycin
Clarithromycin
Respiratory fluoroquinolones:
Moxifloxacin
Gemifloxacin
Levofloxacin
SP Oliver. Antimicrobial agents for common outpatient conditions. Mims Disease Review 2009/2010 Updated guidelines for the management of URTI in SA 2008 SA Fam Prac 2009
*SP Oliver. Antimicrobial agents for common outpatient conditions. Mims Disease Review 2009/2010
Updated guidelines for the management of URTI in SA 2008 SA Fam Prac 2009

33. Rx: acute bacterial sinusitis
Analgesia
Antibiotics:
Amoxicillin 10 days (first choice) or
Co-amoxiclav 10 days if failed therapy
Penicilin allergy:
Macrolide
Respiratory fluoroquinolone

34. Acute bacterial sinusitis and otitis media*
Bugs
First line
Second line -
No rapid response
Pen. allergy
S. Pneumoniae
H. influenzae
Amoxicillin
Co-Amoxiclav
Moxifloxacin
(Gemifloxacin)
(Levofloxacin)
(Cefpodoxime)
(Cefuroxime)
(Moxifloxacin)
Macrolide:
Erythromycin
Azithromycin
Clarithromycin
M. catarrhalis
Doxycycline
Chronic
Multiple bacteria +
anaerobes
Moxifloxacin or
Macrolide
Add Metronidazole
*SP Oliver. Antimicrobial agents for common outpatient conditions. Mims Disease Review 2009/2010
Updated guidelines for the management of URTI in SA 2008 SA Fam Prac 2009

35. Indications for referral
Failure to respond after 72 hours
Peri-orbital swelling
Evidence of CNS extension (meningism, focal neuro signs, altered level of consciousness)
Severe systemic illness
Chronic sinusitis: symptomatic > 30 days

36. Community Acquired Pneumonia (CAP)

38. CAP Confirm diagnosis CXR, other imaging devices
Establish aetiological diagnosis when identification of specific pathogens will significantly alter standard (empirical) management decisions. (not routine for OPD):
Sputum, microscopy, blood culture, sensitivity
Urinary antigen tests for Legionella, pneumococcus in severely ill
Endotracheal aspirate in intubated patients
Antibiotic susceptibility patterns

39. CAP: site of care decisions
Outpatient vs Hospital
ICU (septic shock / requiring mechanical ventilation) vs general ward
Severity-of-illness scores help identify candidates for outpatient treatment:
CURB-65 criteria: confusion, ureamia, respiratory rate, low blood pressure, age 65 or greater
Prognostic scores:
Pneumonia severity index (PSI)
CID 2007:44 (suppl 2). Mandell et al
CURB-65 <2 can be treated as OPD provided able to take oral meds, adequate support etc

40. Community acquired pneumonia empiric Rx
Bugs
OPD
OPD: risk factors for DRSP
Inpatient treatment
ICU
TY PICAL (7-10 )
Macrolide:
Respiratory fluoroquinolone:
Respiratory fluoroquinolone
Fluoroquinolone + beta lactam
Streptococcus pneumoniae +++
Azithromycin
Moxifloxacin
Haemophilus influenzae
Clarithromycin
Levofloxacin
Klebsiella pneumoniae
Erythromycin
Gemifloxacin
Staph. aureus
ATYPICAL (14)
Doxycycline
Macrolide +
Beta-lactam :
Beta-lactam
Azithromycin+
Legionella pneumoniae
High dose amoxicillin
Ig tds
Ampicillin
Mycoplasma pneumoniae
Amoxicillin-clavulanate
2g bd
Ceftriaxone, Cefotaxime
Chlamydia pneumoniae
Ceftriaxone, cefuroxime, cefpodoxime
Ertapenem for some with risk factors for gram - other than Pseudomonas
Vaccination against Hib has reduced the incidence of haemophilus influenzae pneumonia
HCAP=health care associated pneumonia (nosocomial)
DRSP = drug resistant strep pneumoniae:
Treat for 7-10 days usually
14 days for atypicals
RSA: prefer amoxicillin in ODD, but evidence shows macrolides better
ICU: pen allery: fluoroquinolone+aztreonam
MRSA: add vancomycin or linezolid

41. Community acquired pneumonia: Macrolides
Addition of macrolide to beta-lactam therapy:
Appears superior to respiratory fluoroquinolone monotherapy:
Provides coverage for atypical pathogens
Macrolides may modulate the host’s inflammatory response, even when used as monotherapy
Editorial commentary , CID 2008: (15 May)

42. Community Acquired Respiratory Tract Infections (CARTI)
Bacterial rhinosinusitis
Acute exacerbations of chronic bronchitis (COPD)
Pneumonia
Increased resistance of Strep pneumoniae
(MIC > 2 mcg/ml = high level resistance) to:
Penicillins
Macrolides (previous use of long acting macrolides)
Fluoroquinolones
Morbidity and mortality greater with PNRSP than PSSP (18.5% vs 12.2%)
Level of penicillin resistance in S. Pneumoniae at present only precludes the use of penicillin in meningitis caused by these organisms in South Africa
PNRSP = penicillin resistant strep pneumoniae

43. Risk factors for Drug Resistant S. Pneumoniae (DRSP)
Chronic comorbidity:
heart, lung, liver, renal disease DM
Alcoholism
Malignancies
Asplenia
Immunosuppressant drugs
Use of antimicrobials within last 3 months (use dif. class)

46. Severe CAP: combination therapy required
Ps. Aeruginosa:
Piperacillin – tazobactin + fluoroquinolone
MRSA emerging as CAP pathogen:
Add Vancomycin or Linezolid
Alter empiric to pathogen-directed therapy once culture results known
Switch from iv to oral once haemodynamically stable
Discharge as soon as clinically stable.
Ertapenem acceptable alternative
Telithromycin not yet adequately assessed for CAP.
Imipenem
Meropenem alternatives to piperacillin
Treat for minimum 5 days, should be afebrile for 72 hrs

47. Urinary Tract Infections

48. Overview Types of UTIs Diagnosis Pathogens Goals of treatment
Antimicrobials
Resistant patterns

49. UTI
Presence of micro-organisms in the urinary tract that cannot be accounted for by contamination (> 10² /ml)
Range: asymptomatic bacteriuria to pyelonephritis with bacteraemia or sepsis
Lower Tract Infections: frequency, dysuria, suprapubic pain, haematuria
Cystitis
Urethritis
Prostatitis
Epididymitis
Upper tract Infection: flank pain, systemic illness (vomiting, fever, etc)
Pyelonephritis

50. Types of UTI UNCOMPLICATED COMPLICATED
No structural or functional abnormalities of urinary tract that interfere with normal flow of urine / voiding mechanisms
Females of childbearing age who are otherwise healthy
Lower urinary tract only
Predisposing lesion of the urinary tract
Congenital abnormality
Renal stone
Indwelling catheter
Prostatic hypertrophy
Obstruction
Neurological deficit
Upper and lower urinary tract
Males and females

51. UTI subtypes Recurrent UTI:
multiple symptomatic infections with asymptomatic intervening periods
Relapse
Re-infection by different organism (majority)
Asymptomatic bacteriuria:
> /ml with no symptoms
Usually in those above 65yrs
Significant bacteriuria:
> 10² coliforms in symptomatic female or catheterised patient
>10³ coliforms in symtomatic male
>10⁵ bacteria in asymptomatic person on 2 consecutive specimens
Any growth from suprapubic catheterisation

52. Bacteria enter the urinary tract
Bacteria enter the urinary tract. Factors determining development of infection:
Size of inoculum
Virulence of micro-organism
Natural host defence mechanisms

53. Aetiology: bowel flora of the host
UNCOMPLICATED UTI
COMPLICATED UTI
E-coli (50%)
Enterococci (esp nosocomial)
Pseudomonas
Klebsiella
Proteus
Staphylococci
More resistance
Sometimes multiple organisms
E-Coli (85%)
Staph. Saprophyticus (5-15%)
Klebsiella (<1%)
Proteus (<1%)
Enterococcus (<1%)
Pseudomonas (<1%)
E-Coli commonest in both complicated and uncomplicated. Staph saprophyticus is the other bug in uncomplicated UTI. The other bugs don’t really feature.
In complicated UTI, E-Coli, enterococci, enterobacter spp (KEP) and Pseudomonas all play big part
Staph Aureus from bacteraemia, causing metastatic abscesses in kidney
Candida common in critically ill, chronic catheterisation

55. Notes on the flora: E-Coli
Increasing resistance to antimicrobials
? 30% resistant to amoxicillin, ampicillin and cephalosporins
Oral beta lactams eliminated rapidly;
unable to reach high renal tissue concentrations compared to others
Less successful at eradicating uropathogens from vaginal and GIT reservoirs
Increasing resistance to sulphonamides
Current or recent antibiotic exposure most significant risk factor associated with E-Coli resistance

56. In SA, complete resistance to co-trimoxazole (TMP-SMX) therefore use alternatives

57. Notes on the flora: Enterococci
Extensive use of third generation cephalosporins which are not active against enterococci
Vancomycin resistant enterococci (VRE)
E. faecalis + S. faecium
Widespread
Patients after long term hospitalisation
Patients with underlying malignancies

58. Treatment of UTI Desired Outcome:
Treat or prevent systemic consequences of infection
Eradicate invading organism
Prevent recurrence of infection
‘The ability to eradicate bacteria from the urine is related directly to the sensitivity of the micro-organism and the achievable concentration of the antimicrobial agent in the urine.’

60. Rx of Acute Uncomplicated UTI
Cost effective approach to management
Urinalysis
Initiation of empiric therapy
No culture
Short course antibiotics
Increased compliance
Good efficacy
Fewer side effects
Lower cost
Less potential for development of resistance
E-Coli , Staph saprophyticus ++, Klebsiella, Proteus

61. UTI antimicrobial options
Community acquired
Quinolones
Fosfomycin
Nitrofurantoin
Co-amoxiclav
Cephalosporins
Co-trimoxazole
Severe or Hospital acquired
Aminoglycosides
Piperacillin-tazobactam
Imipenem-cilastin

62. Rx UTI: cystitis Uncomplicated cystitis in non- pregnant women
Asymptomatic bacteriuria
Fluoroquinolone
(cipro-, levo-, norfloxacin)
Ciprofloxacin 250mg stat
Fluoroquinolone
(cipro, levo, norfloxacin)
Ciprofloxacin 250mg stat or
Ciprofloxacin 250mg bd for 3 days
Avoid in pregnancy

63. Rx UTI: Complicated cystitis
Fluoroquinolone: Ciprofloxacin for 3 days
Co-amoxiclav for 7 days
Nitrofurantoin for 7 days
2nd generation cephalosporin: cephalexin, cefuroxime for 7 days

64. Rx UTI: pyelonephritis
Uncomplicated pyelonephritis
Culture
Outpatient
14 day course of oral
Fluoroquinolone - ciprofloxacin

65. Rx UTI: pyelonephritis
Complicated pyelonephritis (Culture, admit. )
14 days: start intravenous, switch to oral when afebrile
Fluoroquinolone
Extended spectrum penicillin + aminoglycoside
Hospital acquired, catheter, nursing home: Pseudomonas
Antipseudomonas penicillin + aminoglycoside

66. UTI Types Bugs Drug Uncomplicated cystitis in non-pregnant women
coliforms
Ciprofloxacin one dose stat
Complicated cystitis
Ciprofloxacin x 3/7
Co-amoxiclav x 7/7
Nitrofurantoin x 7/7
2nd G cephalosporin x 7/7
Uncomplicated pyelonephritis
Ciprofloxacin x 14/7
Complicated pyelonephritis
IV fluoroquinolones or
Ampicillin + aminoglycoside
Hospital acquired
Pseudomonas
Piperacillin + aminoglycoside
UTI in pregnancy
Nitrofurantoin
Avoid fluoroquinolones

68. Overall summary – outpatient treatment
Infection
Bugs
Ist line
Alternatives
Pharyngitis/
Tonsillitis
Viral 80%
S. Pyogenes (GABHS)
Pen VK
Amoxicillin
Clindamycin (allergy) or
Macrolide(allergy)
Sinusitis
Acute otitis media
Strep. pneumoniae
H. Influenzae
Moraxella catarrhalis
Co-amoxiclav if chronic
Erythromycin (allergy)
Moxifloxacin (allergy)
Doxycycline (Moraxella)
Pneumonia (CAP)
Atypicals: Legionella, Chlamydia, Mycoplasma
Macrolide
Doxycycline
Respiratory quinolone (Moxiflox) if risk factors
Add beta lactam to macrolide if risk factors
Cystitis
uncomplicated
E-Coli
Other coliforms
Ciprofloxacin stat
(non-pregnant; uncomplicated)
Ciprofloxacin 3/7
Co-amoxiclav 7/7
Nitrofurantoin (pregnant)
Recommend amoxicillin in SA for CAP first line; however, evidence that macrolides superior
Second generation cephalosporins: cephalexin, cefuroxime also for UTI

69. The End