Antibiotic Update

Contents

 Emerging and reemerging infectious

diseases, antibiotic resistance, novel
agents and their clinical uses
 Reducing bacterial resistance with
IMPACT
 Antibiotic Stewardship Program (ASP)
Conventional antibiotics
 Penicillins  Nitrofurantoin,
 Cephalosporins metronidazole,
clindamycin,
 Carbapenems
vancomycin,
 Quinolones teicoplanin,
 Aminoglycosides cotrimoxazole,
 Macrolides fusidic acid, etc
 Tetracyclines  Isoniazid,
pyrazinamide,
ethambutol, rifampin,
cycloserine, etc
Penicillins
 Penicillin G
 Still useful for a number of diseases (e.g. meningitis, syphilis)
 Cloxacillin
 For MSSA infections
 Ampicillin, amoxicillin
 Active vs. Gram-positive (not MSSA), Gram-negative
organisms
 Augmentin, Unasyn
 Broad spectrum, covers Gram-positive, Gram-negative and
anaerobes
 Piperacillin, Tazocin, Timentin
 Are active vs. Pseudomonas
Cephalosporins
 Cefazolin, cephalexin
 Active vs. Gram-positive organisms including
MSSA
 Cefuroxime, Cefaclor
 Covers some Gram-negative organisms
 Cefotaxime, Ceftriaxone
 Broad spectrum, enhanced activity towards Gram-
negative organisms
 Ceftazidime, Cefepime, Sulperazon
 Additive Pseudomonas coverage
Carbapenems
 Imipenem
 Broad spectrum, covers Gram-positive, Gram-
negative (including ESBL-producing strains),
Pseudomonas and anaerobes
 Meropenem
 Less seizure-inducing potential, can be used to
treat CNS infections
 Ertapenem
 Lacks activity vs. Acinetobacter and Pseudomonas
 Has limited activity against penicillin-resistant
pneumococci
Quinolones
 Ciprofloxacin
 Active vs. MSSA, Gram-negative and
Pseudomonas
 Levofloxacin
 Has activity vs. Streptococcus pneumoniae, but
slightly less active towards Pseudomonas
compared to ciprofloxacin
 Moxifloxacin
 Has activity vs. anaerobes but less active towards
Pseudomonas
Aminoglycosides
 Active vs. some Gram-positive and Gram-negative
organisms
 Gentamicin
 Active vs. Pseudomonas
 Tobramycin
 More active vs. Pseudomonas than gentamicin
 Shows less activity against certain other Gram-negative bacteria
 Amikacin
 More stable to enzymes, used in severe infections by
gentamicin-resistant organisms
 Streptomycin
 Used for tuberculosis
Macrolides
 Erythromycin
 Active vs. Gram-positive organisms, atypicals
 GI side effects
 Clarithromycin
 Slightly greater activity than erythromycin
 Azithromycin
 Slightly less active than erythromycin vs. Gram-
positive but enhanced activity vs. some Gram-
negative organisms
Tetracyclines
 Drug of choice in infections caused by
Chlamydia, Rickettsia, Brucella and Lyme
disease
 Value has decreased due to increasing bacterial
resistance
 Tetracycline
 Role in Helicobacter pylori eradication (less frequently
used than other antibiotics)
 Doxycycline
 Once daily
 Minocycline
 Broader spectrum
Other antibiotics
 Clindamycin
 Vs. Gram-positive cocci and anaerobes
 Metronidazole
 Vs. anaerobes
 Preferred therapy in antibiotic associated diarrhoea
(Clostridium difficile) than oral vancomycin,
although unlicenced
 Vancomycin, teicoplanin
 For Gram-positive organisms (including MRSA)
Other antibiotics
 Cotrimoxazole
 Role in uncomplicated UTI, UTI prophylaxis, acute
exacerbations of chronic bronchitis
 Pneumocystis carinii (now jiroveci) infections
 Nitrofurantoin
 For UTI, prophylaxis vs. UTI
 Fusidic acid, rifampin
 For penicillin-resistant staphylococci
 Not for monotherapy due to risk of emergence of
resistance
Good news vs. bad news
 Good news
 A few novel antibiotics have shown promising results / are
undergoing clinical studies

 Bad news
 As immunosuppressive diseases and use of
immunosuppressive agents become more prevalent,
opportunistic infections becomes more common, esp. by
organisms rarely encountered previously
 Diseases: e.g. HIV, leukemia
 Drugs: e.g. in solid organ transplants, bone marrow transplants,
rheumatoid disorders
 Development of bacterial resistance to antibiotics is much
faster than research and development of new antibiotics
Emerging and reemerging infectious diseases
Antibiotic resistance
Novel agents and their clinical uses

Part 1
Gram-positive superbugs
Gram-positive superbugs
Resistant Gram-positive bacteria terminology
PRSP Penicillin resistant Streptococcus pneumoniae

MDRSP Multidrug resistant Streptococcus pneumoniae

MRSA Methicillin resistant Staphylococcus aureus

VRSA Vancomycin resistant Staphylococcus aureus
VISA (GISA) Vancomycin (Glycopeptide) intermediate
Staphylococcus aureus
VRE (GRE) Vancomycin (Glycopeptide) resistant Enterococcus
Case 1
 F/74, DM on oral hypoglycemic drugs
 Presented with fever and malaise, cough with sputum,
tachypnea; chest X-ray revealed bilateral infiltrates
 Travel history, occupation, contact and clustering non-
remarkable
 Received a course of amoxicillin for urinary tract
infection 10 weeks ago
 Diagnosis: Community-acquired pneumonia

 Question
 What is the empirical treatment for CAP?
Community-acquired pneumonia
(CAP)
 Microbiology
 “Typical” organisms
 Streptococcus pneumoniae
 Haemophilus influenzae
 Moraxella catarrhalis
 “Atypical” organisms
 Chlamydia pneumoniae
 Mycoplasma pneumoniae
 Legionella pneumophilia
 Empirical therapy
 Beta-lactams to cover typical organisms
 Doxycycline / macrolides to cover atypical organisms
 Respiratory fluoroquinolones (levo, moxi) for beta-lactam
allergy
Community-acquired pneumonia
(CAP)
 Empirical therapy (as per IMPACT)
 CAP, out-patient
 Augmentin/Unasyn PO ± macrolide PO
 Amoxicillin PO + clarithromycin / azithromycin PO
 CAP, hospitalized in general ward
 Augmentin / Unasyn IV/PO ± macrolide
 Cefotaxime / ceftriaxone IV ± macrolide
 CAP, hospitalized in ICU for serious disease
 Add cover to Gram-negative enterics
 Tazocin / cefotaxime / ceftriaxone IV + macrolide
 Cefepime IV + macrolide
Community-acquired pneumonia
(CAP)
 Empirical therapy
 Modifying factors
 Allergy to beta-lactams
 Fluoroquinolone (levofloxacin / moxifloxacin)
 Aspiration likely: anaerobes should be covered
 Augmentin / Unasyn / Tazocin already provide coverage
 Cephalosporins (except Sulperazon) is inactive
 Moxifloxacin
 Bronchiectasis: Pseudomonas cover essential
 Tazocin / Timentin / cefepime + macrolide
 Fluoroquinolone + aminoglycoside
Case 1
 Patient was started on Augmentin +
clarithromycin empirically
 3 days later, fever persisted, chest X-ray
showed progressive pneumonia
 Endotracheal aspirate (WBC +++, few
epithelial cells) grew heavy Streptococcus
pneumoniae, with penicillin MIC > 4mcg/ml

 Questions
 Risk factors for penicillin-resistant S. pneumoniae?
 Appropriate management in this case?
Penicillin resistant Streptococcus pneumoniae
(PRSP)

 Risk factors
 Age > 65 years
 Beta-lactam therapy in past 3 months

 Alcoholism

 Multiple medical comorbidities (e.g.

immunosuppressive illness or medications)
 Exposure to a child in a day care centre
Penicillin resistant Streptococcus pneumoniae
(PRSP)

 If susceptible, penicillin group is the drug of

choice for Streptococcus pneumoniae
 Check susceptibility and MIC if resistant to
penicillin

 Penicillin susceptible (MIC  0.1 mcg/ml)

 Penicillin G, amoxicillin
 Penicillin resistant (0.1< MIC 1.0 mcg/ml)
 High dose penicillin G or ampicillin, cefotaxime /
ceftriaxone
Penicillin resistant Streptococcus pneumoniae
(PRSP)

 Penicillin resistant (MIC > 2.0 mcg/ml)

 Vancomycin  rifampin
 High dose cefotaxime tried in meningitis
 Non-meningeal infection: cefotaxime / ceftriaxone,
high dose ampicillin, carbapenems, or
fluoroquinolone (levofloxacin, moxifloxacin)
 Multidrug resistant (MDRSP, resistant to any 2
of the following: penicillins, erythromycin,
tetracycline, macrolides, cotrimoxazole)
 Vancomycin  rifampin
 Clindamycin, levofloxacin, moxifloxacin could be
tried
Penicillin resistant Streptococcus pneumoniae
(PRSP)

 Any alternative for PRSP / MDRSP in

respiratory tract infection?

 Newer agents
 Telithromycin (Ketek®)
 Linezolid (Zyvox®)
Telithromycin (Ketek®)
 A ketolide (structurally related to macrolides)
 Spectrum of activity
 Group A, B, C and G Streptococci, Streptococcus
pneumoniae (including multidrug resistant strains),
MSSA
 Listeria monocytogenes, Neisseria meningitidis,
Moraxella catarrhalis, Haemophilus influenzae
 Legionella, Chlamydia, Mycoplasma
 No activity vs. MRSA, GRE, or any enteric gram-
negative bacteria
 Indications
 Mild to moderate community acquired pneumonia
Linezolid (Zyvox®)
 An oxazolidinedione
 Spectrum of activity and indications
 Vancomycin-Resistant Enterococcus faecium infections,
including cases with concurrent bacteremia
 Nosocomial pneumonia caused by MSSA or MRSA or Strep
pneumoniae (including MDRSP)
 Complicated skin and skin structure infections, including
diabetic foot infections, without concomitant osteomyelitis,
caused by MSSA or MRSA, Strep pyogenes, or Strep
agalactiae
 Uncomplicated skin and skin structure infections caused by
MSSA or Strep pyogenes.
 Community-acquired pneumonia caused by Strep
pneumoniae (including MDRSP), including cases with
concurrent bacteremia, or MSSA
Case 2

 M/56
 Presented with skin redness, warmth,
swelling, tenderness on his right lower
limb, a pocket of fluid palpated
 Diagnosis: cellulitis with pus formation

 Question
 Empirical treatment?
Skin and soft tissue infection

 Cellulitis
 Microbiology
 Staphylococcus, Streptococci
 Streptococci more likely when cellulitis is
well demarcated and there are no pockets
of pus or evidence of vein thrombosis
Staphylococcus aureus
 If susceptible, penicillinase-resistant penicillins are the
drugs of choice for methicillin-susceptible
Staphylococcus aureus (MSSA)

 Drug of choice
 Cloxacillin, flucloxacillin
 Cefazolin, cephalexin (penicillin allergic but tolerate cephs)
 With beta-lactamase inhibitor
 As two-agent combination in Augmentin, Unasyn
 Erythromycin, clindamycin (if penicillin allergic)
 The above antibiotics also have good activity vs.
Streptococci
Case 2
 Skin tenderness and redness did not appear to
improve despite Augmentin has been given
 Pus grew MRSA after 2 days
 R to methicillin, cephalothin, erythromycin
 S to clindamycin, vancomycin, gentamicin,
cotrimoxazole
 Patient is clinically stable

 Questions
 What is the drug of choice in MRSA infection?
 Can clindamycin be used in this case?
Methicillin resistant Staphylococcus aureus
(MRSA)

 Healthcare-associated  Community-associated
 Endemic in hospitals, old
age homes
 Risk factors
 Hospitalization in
previous 1 year
 Recent surgery
 Old age home residence
 Renal dialysis
 Exposure to invasive
devices
 Employment in a
healthcare institute
 Do not have usual risk
factors associated with
HA-MRSA
 More common in the
following in overseas
countries
 Children with chronic
skin condition
 Prisoners
 Military personnel
 Aboriginals
 Injection drug users
 The homeless
 Contact sports athletes
Methicillin resistant Staphylococcus aureus
(MRSA)

 Healthcare-associated  Community-associated
 Multiresistant to  Often remains
 Clindamycin susceptible to
 Aminoglycosides  Clindamycin
 Tetracyclines  Aminoglycosides
 Fluoroquinolones  Tetracyclines
 Fluoroquinolones
 More associated with
skin/soft tissue
infections and severe
necrotizing pneumonia
Methicillin resistant Staphylococcus aureus
(MRSA)

 Obtain culture for susceptibility testing right

before empirical antibiotics!
 Treatment (as per Sanford Guide 37th ed)
 Community-associated
 Mild to moderate infections
 Abscess, afebrile, immunocompetent, outpatient

Cotrimoxazole / doxycycline / minocycline  rifampin

Clindamycin (do not use if R to erythromycin due to
inducible resistance)
 Abscess with fever, outpatient

Cotrimoxazole-DS + rifampin or linezolid
Methicillin resistant Staphylococcus aureus
(MRSA)

 Clinical guideline for management of

suspected CA-MRSA infections (15 March
2007)
 Most CA-MRSA isolates in HKSAR are susceptible
to:
 Cotrimoxazole
 Doxycycline, minocycline
 Clindamycin
 Moxifloxacin
 Out-patient oral therapy available for uncomplicated
CA-MRSA skin and soft tissue infection
Methicillin resistant Staphylococcus aureus
(MRSA)

Antimicrobials for outpatient therapy of uncomplicated skin and soft tissue

infections (Clinical guideline for management of suspected CA-MRSA
infections,15 March 2007)
Agent Potential Precautions Usual adult dose
advantage (oral)
Cotrimoxazole Oral Not for patient with 960mg bd
sulfa allergy / G6PD
Doxycycline High skin Not for children <12 yo 200mg once,
concentration or pregnant women then 100mg bd
Minocycline As above As above 100mg bd
Clindamycin Inhibit toxin Inducible resistance if 300-450mg tds
production erythromycin resistant
Moxifloxacin Oral Resistance may 400mg qd
develop during therapy
Methicillin resistant Staphylococcus aureus
(MRSA)

 Appropriate treatment in uncomplicated

skin and soft tissue infection
 Cotrimoxazole, doxycycline, minocycline or
moxifloxacin
 Clindamycin is not reliable in this case
 Inducible clindamycin resistance due to
erythromycin resistance
Case 2

 What to do if
 the organism is resistant to agents listed
above and vancomycin, and
 Infection is complicated (unstable patient,
extensive involvement, severe sepsis, etc)?
VISA and VRSA
 VISA: vancomycin-intermediate Staph aureus
 VRSA: vancomycin-resistant Staph aureus
 Classified based on minimum inhibitory
concentration (MIC)
 (CDC definition)
 VISA: vancomycin MIC is 4-8 µg/ml
 VRSA: vancomycin MIC is >16 µg/ml
 (HA Central Committee on Infectious Diseases)
 Susceptible: vancomycin MIC is ≤ 4µg/ml
 VISA: vancomycin MIC is 8-16 µg/ml
 VRSA: vancomycin MIC is >32 µg/ml
VISA and VRSA
 More likely to develop among patients with
 Underlying conditions (including renal failure) which
predispose the patient to MRSA colonization;
 Indwelling medical devices; and/or
 MRSA infection requiring treatment with
vancomycin for a prolonged period
 Usually isolated during vancomycin (or
teicoplanin) therapy for MRSA infections which
fail to respond
VISA and VRSA

 Linezolid (Zyvox®)
 (discussed in PRSP session)
 Quinupristin/dalfopristin (Synercid®)
 Dalbavancin (Zeven®)
 Still under investigation
 Daptomycin (Cubicin®)
 Tigecycline (Tygacil®)
Linezolid (Zyvox®)

 Demonstrate bacteriostatic action vs.

VISA and VRSA
 Indications
 Complicated skin and skin structure infections,
including diabetic foot infections, without
concomitant osteomyelitis, caused by MSSA or
MRSA, Strep pyogenes, or Strep agalactiae
 Uncomplicated skin and skin structure infections
caused by MSSA or Strep pyogenes
Quinupristin/dalfopristin (Synercid®)
 Intravenous streptogramins (combination results in synergy)
 In vitro activity has been demonstrated against VISA and VRSA
 Spectrum of activity
 Vancomycin-resistant Enterococcus faecium
 Penicillin-resistant Streptococcus pneumoniae
 Methicillin-resistant Staphylococci
 Vancomycin-resistant Enterococcus faecalis is relatively resistant to
quinopristin/dalfopristin
 Anaerobes and some gram-negative pathogens (e.g., Haemophilus
influenzae) have also been susceptible
 Indications
 Bacteremia - Vancomycin-resistant Enterococcus faecium infection
 Infection of skin and/or subcutaneous tissue, Complicated, caused
by Staphylococcus aureus and Streptococcus pyogenes
Dalbavancin (Zeven®)
 Second generation glycopeptide
 First generation: vancomycin, teicoplanin
 Spectrum of activity
 Staphylococci and Streptococci, including resistant
isolates
 Clostridium spp., Peptostreptococcus spp.,
Actiniomyces spp., Corynebacterium spp. and
Bacillus subtilis
 No activity vs. most gram-negative bacteria
 No activity vs. vancomycin-resistant enterococci
with Van A gene
Dalbavancin (Zeven®)
 Demonstrated favorable in vitro activity against MSSA,
MRSA,VISA, VRSA, and linezolid-resistant S. aureus
 Also, methicillin-susceptible, methicillin-resistant, and
vancomycin-intermediate Coagulase negative
Staphylococci strains have had favorable in vitro
results
 Place of therapy (no FDA approved indication at the
moment)
 Currently in phase III trials for treatment of resistant gram-
positive organisms
 Published efficacy and safety data from 2 clinical trials are
available for treatment of skin and soft-tissue infections and
catheter-related bloodstream infections
Daptomycin (Cubicin®)
 Cyclic lipoglycopeptide
 Spectrum of activity
 MSSA, MRSA, Streptococcus pyogenes, Streptococcus
agalactiae, Streptococcus dysgalactiae subsp. equisimilis,
and
 Enterococcus faecalis (vancomycin-susceptible isolates only)
 Indications
 Complicated skin and skin structure infections caused by
susceptible Gram-positive microorganisms
 Staphylococcus aureus bloodstream infections including
those with right-sided infective endocarditis (methicillin-
susceptible and methicillin-resistant) (native valve)
Tigecycline (Tygacil®)
 A glycylcycline
 Derived from minocycline
 A very broad spectrum antibiotic
 Covers many resistant strains of Gram-positive,
Gram-negative, and anaerobic organisms
 Note active vs. Pseudomonas
 Both in vitro and in vivo activities have been
demonstrated against MSSA, MRSA, and
VISA
Tigecycline (Tygacil®)
 Indications
 Complicated skin and skin
structure infections by
 Escherichia coli
 Enterococcus faecalis
(vancomycin-susceptible
isolates only)
 Staphylococcus aureus
(Methi-S or Methi-R)
 Streptococcus agalactiae
 Streptococcus anginosus
grp.
 Streptococcus pyogenes
 Bacteroides fragilis
 Complicated intra-
abdominal infections by
 Citrobacter freundii
 Enterobacter cloacae
 E. coli, K. oxytoca, K.
pneumoniae
 Enterococcus faecalis
(Vanco-S isolates only)
 Staphylococcus aureus
(Methi-S or Methi-R)
 Streptococcus anginosus
group
 Bacteriodes fragilis
 Clostridium perfringens
 Peptostreptococcus
micros
Emerging and reemerging infectious diseases
Antibiotic resistance
Novel agents and their clinical uses

Part 2
Gram-negative superbugs
Gram-negative superbugs
Resistant Gram-negative bacteria terminology
ESBL-producing Extended spectrum beta-lactamases
Enterobacteriaceae producing Enterobacteriaceae, e.g.
Escherichia coli, Klebsiella pneumoniae

MRPA (MDR-PA) Multidrug resistant Pseudomonas aeruginosa

MRAB (MDR-AB) Multidrug resistant Acinetobacter baumannii

Pan-resistant Pseudomonas aeruginosa /

Acinetobacter baumannii
Case 3
 M/59
 Presented with 2-day history of right upper quadrant
pain, fever, jaundice
 Emesis x 2 past 24 hours, dark color urine
 Elevated LFT
 Radiologic finding: dilated common bile duct, no
increase in gallbladder size
 Diagnosis: acute cholangitis

 Question
 What is the empirical therapy?
Acute cholangitis/cholecystitis

 Microbiology
 Gram negative enterics
 E. coli, Klebsiella spp., Proteus spp.
 Anerobes
 Bacteriodes fragilis, Clostridium spp.
 Enterococcus
Acute cholangitis/cholecystitis

 Adequate drainage is essential

 Empirical treatment complementary to
drainage
 Augmentin/Unasyn ± aminoglycoside
 Timentin

 Cefuroxime + metronidazole

 Ciprofloxacin (if beta-lactam allergic)

Case 3
 Biliary drainage performed with cefuroxime +
metronidazole pre- and post-operation
 Became septic (with high fever, tachycardia,
WBC > 12 x 109/L) 2 days post-op
 Blood culture grew E. coli (ESBL-producing),
moderately sensitive to Augmentin, sensitive
to Sulperazon and imipenem

 Question
 What is the appropriate treatment?
 Can Augmentin or Sulperazon be used?
Enterobacteriaceae

 Susceptible strains of E. coli and

Klebsiella are sensitive to
 Augmentin/Unasyn
 Cefuroxime (if resistant to above)

 Other anti gram-negative penicillins/cephs

also work
 Fluoroquinolones (if allergic to beta-
lactams)
ESBL-producing
Enterobacteriaceae
 Extended-spectrum beta-lactamases
 Any bacterial enzymes that are capable of
inactivating third generation cephalosporins
 Generally regarded as resistant to penicillins and
cephalosporins
 Drug of choice
 Urinary tract infection
 Cotrimoxazole, Augmentin, nitrofurantoin, levofloxacin /
ciprofloxain
 Other serious infections
 Carbapenems: imipenem, meropenem, ertapenem (reliable
activity vs. ESBL-producing Enterobacteriaceae)
 Fluoroquinolone + aminoglycoside
Case 3
 Augmentin and Sulperazon are not
appropriate
 Patient is clinically septic (likely due to the ESBL-
producing strain of E. coli)
 The strain is only apparently susceptible to the
above agents
 Appropriate agent
 Ertapenem (no activity vs. Pseudomonas)
 Imipenem (when activity vs. Pseudomonas
required)
Case 4
 M/33
 Victim of road traffic accident
 Experienced severe burns during accident
 Early excision and repair performed; silver
sulfadiazine cream topically
 High fever on day 5, blood culture grew
Pseudomonas aeruginosa on day 7

 Question
 Appropriate known pathogen therapy?
Pseudomonas aeruginosa
 Gram-negative bacilli
 Frequently present in small numbers in the
normal intestinal flora and on the skin of
humans and is the major pathogen
 Causes diseases in patients with abnormal
host defenses, e.g.
 When mucous membranes and skin are disrupted
 When intravenous or urinary catheters are used
 When neutropenia is present (as in chemotherapy)
 Intrinsically resistant to many antibiotics
Pseudomonas aeruginosa
 Drug of choice
 Antipseudomonal penicillins/cephalosporins
 Piperacillin, piperacillin/tazobactam (Tazocin),
ticarcillin/clavulanate (Timentin)
 Ceftazidime, cefoperazone, cefepime
 Carbapenems
 Imipenem, meropenem (NOT ertapenem)
 Aminoglycosides
 Gentamicin, tobramycin, amikacin
 Fluoroquinolones
 Ciprofloxacin, levofloxacin (less activity than cipro)
 Often a two-drug combination is employed except in
uncomplicated UTI
Case 4
 Tazocin (Piperacillin/tazobactam) plus
gentamicin were prescribed
 Microbiologist suggested using piperacillin
plus gentamicin is sufficient for this patient

 Question
 What is the difference in activities (and hence uses)
between Tazocin and piperacillin?
Piperacillin vs. Tazocin

 Tazobactam in Tazocin®
 Tazobactam is a beta-lactamase inhibitor
 Renders the combination of Tazocin® more
active against
 Gram positive: MSSA
 Gram negative: Haemophilus influenzae and

others
 Anaerobe: Bacteroides fragilis
Piperacillin vs. Tazocin

 Tazobactam in Tazocin®
 For Pseudomonas aeruginosa susceptible
to piperacillin, Tazocin 4.5g Q8H IV and
Piperacillin 4g Q8H IV are equivalent
 At common usual dose (HA Corp drug price
as of May 2007)
 Piperacillin 4g/vial: $56
 Tazocin® 4.5g/vial: $108
Multidrug resistant
Gram-negative organisms
 Any treatment options for
 ESBL-producing Enterobacteriaceae, or
 Pseudomonas aeruginosa,

that are pan-resistant?

Colistin (Colomycin®)
 Indeed an old, toxic drug!
 a.k.a. Polymyxin E, colistimethate sodium
 Now being used with increasing frequency due to necessity
(multidrug resistant Gram-negatives)
 Risk of neurotoxicity and nephrotoxicity
 Spectrum of activity (check susceptibility!)
 Pseudomonas aeruginosa, Acinetobacter spp.
 E. coli and Klebsiella (incl. ESBL-producing strains),
Enterobacter spp.
 Citrobacter spp, Hemophilus spp.
 Indications
 Disease due to Gram-negative bacteria, acute or chronic due
to sensitive strains of certain gram-negative bacilli
Case 5
 F/67
 Admitted due to subarachnoid hemorrhage
 Desaturated on day 21, given oxygen,
admitted to HDU
 Chest X-ray showed consolidation of right
middle and lower lobe
 Bronchoalveolar lavage grew heavy
Acinetobacter baumannii

 Question
 Appropriate known pathogen therapy?
Acinetobacter baumannii
 Common cause of nosocomial infection
especially in ICU setting
 Drug of choice
 Ampicillin/sulbactam or cefoperazone/sulbactam
(sulbactam highly active vs. Acinetobacter) or
fluoroquinolone (ciprofloxacin, levofloxacin)
 Gentamicin added to prevent resistance and for
synergy
 Imipenem, meropenem can be used
Case 5

 Patient was given Unasyn + gentamicin

for her hospital acquired pneumonia

 Question
 Any treatment options for pan-resistant
strains?
Acinetobacter baumannii

 Acinetobacter strains are often resistant

to antimicrobial agents
 Other agents with in vitro activity vs.
Acinetobacter baumannii
 Minocycline / doxycycline
 Tigecycline

 Colistin
Case 6
 M/40 y/o, good past health
 Referred by GP
 Presented with fever, chills and night sweats; cough
initially nonproductive but became productive over
past 2 months
 Did not recognize weight loss
 A sputum smear revealed acid-fast bacilli, further
culture and sensitivity results pending
 Diagnosis: Pulmonary TB

 Question
 What is the drug(s) of choice in tuberculosis?
Mycobacterium tuberculosis
 Acid-fast bacilli, replicates very slowly (once
every 24 hours vs. 20-40 mins in other
organisms)
 Contagious and spreads through the air
 Disease of poverty; affecting mostly young
adults in their most productive years
 Leading killer among HIV-infected people with
weakened immune systems
 8.8 million new TB cases in 2005, and 1.6
million people died from TB worldwide
 A curable disease with appropriate treatment
Mycobacterium tuberculosis
 Requires combination therapy
 The usual course of drug treatment for
pulmonary TB lasts 6 months:
 4 drugs in the first 2 months: isoniazid, rifampin,
pyrazinamide, ethambutol/streptomycin
 2 drugs in the subsequent 4 months: isoniazid,
rifampin
 Can be given daily or three times a week
 Given under DOT (directly observed treatment) by
healthcare staff
Case 6
 Patient was started on isoniazid, rifampin,
pyrazinamide and ethambutol
 Culture of sputum grew Mycobacterium
tuberculosis
 Resistant to isoniazid and rifampin

 Question
 Is this a case of multidrug resistant TB?
 What agents are available?
Multidrug Resistant TB
 MDR-TB (Multidrug Resistant TB )
 Resistant to isoniazid and rifampin
 Isoniazid and rifampin are “backbone” in first-
line TB treatment
 Isoniazid exhibits very low MIC vs. the organism
 Rifampin allows short-course treatment (6-9
months)
 Treatment generally extends to at least 18 months without
rifampin
 Resistance to rifampin is frequently associated with
resistance to isoniazid
Multidrug Resistant TB
Multidrug Resistant TB

 Management
 Microbiologist consultation!
 Check susceptibility to other agents!
Multidrug Resistant TB
Tuberculosis
 Modify treatment plan according to
 Weight
 Hepatic function
 Hepatotoxic: isoniazid, rifampin
 Renal function
 Nephrotoxic: aminoglycosides
 Dose adjustment: fluoroquinolones (except moxifloxacin)
 Pregnancy: Isoniazid, rifampin, ethambutol theoretically relatively
safe, insufficient safety data for pyrazinamide
 Penetration (e.g. in TB meningitis)
 Drug interactions (e.g. with anti-HIV drugs)
 Duration
 May require longer treatment in specific drug combinations,
extensive diseases / extrapulmonary diseases
Case 6
 Patient was alarmed that the organism was
resistant to isoniazid and rifampin (i.e. MDR-
TB)
 He heard of the term XDR-TB from newspaper
some months ago and was very worried

 Question
 Difference(s) between MDR-TB and XDR-TB?
Extensive Drug Resistant TB
 MDR-TB (Multidrug Resistant TB)
 Resistant to isoniazid and rifampin
 XDR-TB (Extensive Drug Resistant TB)
 In addition to resistance vs. isoniazid and rifampin,
 Resistant to any fluoroquinolones, and
 At least one of three injectable second-line drugs
(capreomycin, kanamycin and amikacin)
 Revised definition agreed by the WHO Global Task Force
on XDR-TB in October 2006
Extensive Drug Resistant TB

 Situation worldwide
 XDR-TB found in
 USA: 4% of MDR-TB
 Latvia: 19% of MDR-TB

 S. Korea: 15% of MDR-TB

 May 2007: Italy reports first cases of TB

resistant to all anti-TB drugs
 2 cases R to all drugs and 11 XDR from 2888
culture-confirmed TB cases
Extensive Drug Resistant TB
 The facts
 Grave public health threat especially in populations with high
HIV rates
 Occurs as a result of poorly-managed TB control programs
 If identified early, can be treated and cured in some cases
under proper TB control conditions, based on the experiences
in a few successful programs where HIV prevalence was low
 Underlines the need for investment in the development of new
TB diagnostics, treatments and vaccines
 XDR-TB strains have been found in all regions of the world,
although still thought to be uncommon
 Infection control measures must be strengthened everywhere,
and especially where HIV prevalence is high, to protect the
vulnerable and those at risk of XDR-TB
Extensive Drug Resistant TB
Extensive Drug Resistant TB
Reducing bacterial resistance
 IMPACT (Interhospital Multi-disciplinary
Programme on Antimicrobial ChemoTherapy)
 Available for download at:
 HKU Centre of Infection
http://www.hku.hk/hkucoi/impact.pdf
 DH Centre for Health Protection

http://www.chp.gov.hk/files/pdf/reducing_bacterial_resista
nce_with_impact.pdf
 HA intranet
http://ha.home/ho/ps/impact.pdf
 Most updated: third version 2005 (version 3.0)
IMPACT guideline

 Contents of IMPACT guideline

 Local antibiotic resistance
 Guidelines for selected antimicrobial use,
e.g.
 Vancomycin
 Ceftazidime

 Imipenem/meropenem/ertapenem

 Once daily aminoglycosides

 Selected antifungal agents

IMPACT guideline

 Contents of IMPACT guideline

 Recommendations for empirical therapy of
common infections
 Guidelines for known pathogen therapy

 Guidelines for surgical prophylaxis

 Cost and recommended dosage of

commonly used antimicrobial agents
Antibiotic Stewardship Program
 Optimal selection, dosage, and duration of
antimicrobial treatment that
 Results in the best clinical outcome for the
treatment or prevention of infection
 With minimal toxicity to the patient and
 With minimal impact on subsequent resistance
Antibiotic Stewardship Program

 Involves
 Prescribing antimicrobial therapy only when
it is beneficial to the patient
 Targeting therapy to the desired pathogens

 Using the appropriate drug, dose, and

duration
Antibiotic Stewardship Program

 Should not be viewed simply as reduced

use or a strategy for cost containment
 A strategy to enhance patient safety by
 Minimizing exposure to drugs
 Performing dose adjustments

 Reducing redundant therapy

 Targeting therapy to the likely pathogens

ASP in Hospital Authority

 Annual plan target of year 2005/06

 Objectives
 Control the emergence and spread of
antibiotic resistance
 Optimize selection and use of antibiotics

 Cost containment
ASP in Hospital Authority
 Multidisciplinary, programmatic, prospective,
interventional approach to optimizing the use
of antimicrobial agents
 The multidisciplinary team typically includes
 Clinical microbiologists
 Infectious diseases specialists
 Clinical pharmacists
 Infection control practitioners
ASP in Hospital Authority
 Overall strategies
 Build an antibiotic usage database in terms of usage
density i.e. DDD/1000 patient-days (recommend
consistent DDD definition throughout all HA units to
maximize data utility)
 Develop a HA-wide an antibiotic resistance database of
selected organisms
 Formation of multidisciplinary Antimicrobial Stewardship
Teams (AST) in each hospital/cluster
 Audit use of antimicrobials based on established
guidelines, e.g. IMPACT guideline
 Education and consensus-building
 Outcome measurement and user feedback
ASP in Hospital Authority

 Procedures for Antibiotic Stewardship

Program using the AOF + ICF model:
 Obtain consensus with targeted specialties
for the introduction of an Antibiotic Order
Form (AOF) to monitor antibiotic usage
 Targeted antibiotics
 Big guns antibiotics
 IV-PO switch
ASP in Hospital Authority
 Logistics
 Daily review all AOFs and follow up targeted cases
by assigned personnel
 Provide immediate concurrent feedback on
prescribing to prescribers based on guidelines
 Monitor feedback acceptance
 Provide education and liaison based on guideline
(e.g. educational note or face-to-face intervention)
 Collate and analyze data, with user feedback of the
findings via educational activities
ASP in Hospital Authority
 Big gun audit
 Tienam, Meropenem
 Ceftazidime, Cefepime
 Tazocin, Sulperazon
 Vancomycin and Teicoplanin
 IV to oral switch
 Ciprofloxacin, levofloxacin,
 Clarithromycin, azithromycin
 Amoxicillin/clavulanate (Augmentin®) and
fluconazole
Big gun audit

 Big gun audit

 Targets 2 types of antibiotics
 Broad-spectrum antibiotics
 Tienam, Meropenem, Ceftazidime, Cefepime, Tazocin,
Sulperazon
 All these agents have good Gram-negative as well as
Pseudomonas coverage
 Anti Gram-positive antibiotics
 Vancomycin and teicoplanin
 Active vs. methicillin-resistant Staphylococcus aureus
 To be used as second-line agents
Big gun audit

 Big gun audit

 Data collection form completed and faxed
with MAR on first order of big gun
 Encourage physicians to prescribe big guns
only when clinically indicated
Big gun audit
Big gun audit
IV-PO switch
 IV-PO switch
 IV antimicrobials are always required in serious
infections or initial stages of infection to ensure
tissue levels
 PO antimicrobials are useful to complete a full
course of antimicrobial therapy
 Convenience in out-patient setting
 Cost effectiveness (cost of drugs + hospitalization)
 Decreased risk of IV-catheter related problems
 Except those infections of which PO antibiotics are
unreliable / inappropriate
IV-PO switch
 IV-PO switch
 Targets IV antibiotics which
 Have their oral counterparts (ease of switch)
 Exhibit good oral bioavailability

 Examples
 Penicillins
 Cefuroxime

 Macrolides

 Quinolones

 Fluconazole
IV-PO switch
 IV-PO switch
 IV antimicrobials are indicated in
 Meningitis
 Intracranial abscess
 Infective endocarditis
 Mediastinitis
 Severe infections during chemotherapy-related
neutropenia
 Inadequately drained abscess and empyema
 Severe soft tissue infections
 S. aureus or P. aeruginosa bacteremia
IV-PO switch

 IV-PO switch
 Criteria (as per IMPACT)
 1. No indication for IV therapy
 2. Patient is afebrile for ≥ 8 hours

 3. WBC count is normalizing

 Falling towards or < 10 x 109/L
 4. Signs and symptoms related to infection are
improving
 5. Patient is not neutropenic
 Neutrophil count > 2 x 109/L
IV-PO switch
 IV-PO switch
 Criteria (as per IMPACT)
 6. Able to take drugs by mouth (non-NPO)
 7. No continuous nasogastric suctioning

 8. No severe nausea or vomiting, diarrhea,

gastrointestinal obstruction, motility disorder
 9. No malabsorption syndrome
 E.g. small bowel syndrome due to resection
 10. No pancreatitis or active gastrointestinal
bleeding or other conditions that contraindicated
to the use of oral medications
IV-PO switch

 IV-PO switch
 Points to note
 Prescribe dose based on creatinine clearance
when antimicrobials require renal dosage
adjustment
 Augmentin®, Unasyn®, clarithromycin, ciprofloxacin,
levofloxacin
 Drug interactions
 Oral ciprofloxacin and levofloxacin with antacid,
sucralfate, didanosine, dairy products and enteral
feeds
Useful guides to antimicrobial
therapy
 Sanford Guide
 Covers a broad range of infectious diseases
 IMPACT
 With commonly prescribed empirical
therapy and useful local resistance
information
 Local antibiogram
 Bacterial resistance specific to an institution
or a cluster of institutions
Conclusion
 New antibiotics intended to treat complicated
diseases are under investigation
 Need to protect our antibiotic arsenal
 Justified use of antimicrobials not only treats
infections, but also improves patient outcomes
and reduces the risk of development of
bacterial resistance
 Adherence to clinical guidelines, antimicrobial
stewardship program and education helps to
promote appropriate antimicrobial use
Conclusion
 Last but not least…
 Infection control is of utmost importance in
reducing risk of infection, use of antibiotics
and hence emergence of bacterial
resistance
 Hand hygiene
 Appropriate isolation / contact restriction

 Prompt reporting of certain infectious diseases

(e.g. MRSA infections)
 Many more!
End

Questions and Answers