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 Cephalosporins Carbapenems Quinolones Aminoglycosides Macrolides Tetracyclines

Nitrofurantoin, metronidazole, clindamycin, vancomycin, teicoplanin, cotrimoxazole, fusidic acid, etc Isoniazid, pyrazinamide, ethambutol, rifampin, cycloserine, etc

Penicillins

Penicillin G

Still useful for a number of diseases (e.g. meningitis, syphilis)

For MSSA infections

Cloxacillin

Ampicillin, amoxicillin

Active vs. Gram-positive (not MSSA), Gram-negative organisms

Broad spectrum, covers Gram-positive, Gram-negative and anaerobes Are active vs. Pseudomonas

Augmentin, Unasyn

Piperacillin, Tazocin, Timentin

Cephalosporins

Cefazolin, cephalexin

Active vs. Gram-positive organisms including MSSA

Covers some Gram-negative organisms Broad spectrum, enhanced activity towards Gramnegative organisms Additive Pseudomonas coverage

Cefuroxime, Cefaclor

Cefotaxime, Ceftriaxone

Ceftazidime, Cefepime, Sulperazon

Carbapenems

Imipenem

Broad spectrum, covers Gram-positive, Gramnegative (including ESBL-producing strains), Pseudomonas and anaerobes Less seizure-inducing potential, can be used to treat CNS infections
Lacks activity vs. Acinetobacter and Pseudomonas Has limited activity against penicillin-resistant pneumococci

Meropenem

Ertapenem

Quinolones

Ciprofloxacin

Active vs. MSSA, Gram-negative and Pseudomonas Has activity vs. Streptococcus pneumoniae, but slightly less active towards Pseudomonas compared to ciprofloxacin
Has activity vs. anaerobes but less active towards Pseudomonas

Levofloxacin

Moxifloxacin

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
More stable to enzymes, used in severe infections by gentamicin-resistant organisms Used for tuberculosis

Amikacin

Streptomycin

Macrolides

Erythromycin

Active vs. Gram-positive organisms, atypicals GI side effects Slightly greater activity than erythromycin
Slightly less active than erythromycin vs. Grampositive but enhanced activity vs. some Gramnegative organisms

Clarithromycin

Azithromycin

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
Broader spectrum

Minocycline

Other antibiotics

Clindamycin

Vs. Gram-positive cocci and anaerobes

Vs. anaerobes Preferred therapy in antibiotic associated diarrhoea (Clostridium difficile) than oral vancomycin, although unlicenced For Gram-positive organisms (including MRSA)

Metronidazole

Vancomycin, teicoplanin

Other antibiotics

Cotrimoxazole

Role in uncomplicated UTI, UTI prophylaxis, acute exacerbations of chronic bronchitis Pneumocystis carinii (now jiroveci) infections
For UTI, prophylaxis vs. UTI For penicillin-resistant staphylococci Not for monotherapy due to risk of emergence of resistance

Nitrofurantoin

Fusidic acid, rifampin

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 MDRSP MRSA Penicillin resistant Streptococcus pneumoniae Multidrug resistant Streptococcus pneumoniae Methicillin resistant Staphylococcus aureus

VRSA
VISA (GISA) VRE (GRE)

Vancomycin resistant Staphylococcus aureus

Vancomycin (Glycopeptide) intermediate Staphylococcus aureus 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 nonremarkable 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 Chlamydia pneumoniae Mycoplasma pneumoniae Legionella pneumophilia

Atypical organisms

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 Augmentin / Unasyn IV/PO macrolide Cefotaxime / ceftriaxone IV macrolide Add cover to Gram-negative enterics Tazocin / cefotaxime / ceftriaxone IV + macrolide Cefepime IV + macrolide

CAP, hospitalized in general ward

CAP, hospitalized in ICU for serious disease

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 Tazocin / Timentin / cefepime + macrolide Fluoroquinolone + aminoglycoside

Bronchiectasis: Pseudomonas cover essential

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 High dose penicillin G or ampicillin, cefotaxime / ceftriaxone

Penicillin resistant (0.1< MIC 1.0 mcg/ml)

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 gramnegative bacteria Mild to moderate community acquired pneumonia

Indications

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 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

Community-associated 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

Clindamycin Aminoglycosides Tetracyclines Fluoroquinolones

Often remains susceptible to

Clindamycin Aminoglycosides 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 advantage Precautions Not for patient with sulfa allergy / G6PD Not for children <12 yo or pregnant women As above Inducible resistance if erythromycin resistant Resistance may develop during therapy Usual adult dose (oral) 960mg bd 200mg once, then 100mg bd 100mg bd 300-450mg tds 400mg qd

Cotrimoxazole Oral Doxycycline Minocycline Clindamycin Moxifloxacin High skin concentration As above Inhibit toxin production Oral

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 g/ml VRSA: vancomycin MIC is >16 g/ml Susceptible: vancomycin MIC is 4g/ml VISA: vancomycin MIC is 8-16 g/ml VRSA: vancomycin MIC is >32 g/ml

(HA Central Committee on Infectious Diseases)

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 Bacteremia - Vancomycin-resistant Enterococcus faecium infection Infection of skin and/or subcutaneous tissue, Complicated, caused by Staphylococcus aureus and Streptococcus pyogenes

Indications

Dalbavancin (Zeven)

Second generation glycopeptide

First generation: vancomycin, teicoplanin

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

Spectrum of activity

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 grampositive 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) Complicated skin and skin structure infections caused by susceptible Gram-positive microorganisms Staphylococcus aureus bloodstream infections including those with right-sided infective endocarditis (methicillinsusceptible and methicillin-resistant) (native valve)

Indications

Tigecycline (Tygacil)

A glycylcycline

Derived from minocycline

Covers many resistant strains of Gram-positive, Gram-negative, and anaerobic organisms Note active vs. Pseudomonas

A very broad spectrum antibiotic

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

Complicated intraabdominal 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

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 Enterobacteriaceae Extended spectrum beta-lactamases producing Enterobacteriaceae, e.g. Escherichia coli, Klebsiella pneumoniae Multidrug resistant Pseudomonas aeruginosa

MRPA (MDR-PA)

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. Bacteriodes fragilis, Clostridium spp.

Anerobes

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 Carbapenems: imipenem, meropenem, ertapenem (reliable activity vs. ESBL-producing Enterobacteriaceae) Fluoroquinolone + aminoglycoside

Other serious infections

Case 3

Augmentin and Sulperazon are not appropriate

Patient is clinically septic (likely due to the ESBLproducing strain of E. coli) The strain is only apparently susceptible to the above agents Ertapenem (no activity vs. Pseudomonas) Imipenem (when activity vs. Pseudomonas required)

Appropriate agent

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)

Gentamicin, tobramycin, amikacin Ciprofloxacin, levofloxacin (less activity than cipro)

Aminoglycosides

Fluoroquinolones

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
Pseudomonas aeruginosa, Acinetobacter spp. E. coli and Klebsiella (incl. ESBL-producing strains), Enterobacter spp. Citrobacter spp, Hemophilus spp. Disease due to Gram-negative bacteria, acute or chronic due to sensitive strains of certain gram-negative bacilli

Spectrum of activity (check susceptibility!)

Indications

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 firstline 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 Nephrotoxic: aminoglycosides Dose adjustment: fluoroquinolones (except moxifloxacin) Pregnancy: Isoniazid, rifampin, ethambutol theoretically relatively safe, insufficient safety data for pyrazinamide

Renal function

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. MDRTB) 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

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)

XDR-TB (Extensive Drug Resistant TB)

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

Ciprofloxacin, levofloxacin, Clarithromycin, azithromycin Amoxicillin/clavulanate (Augmentin) and fluconazole

IV to oral switch

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

With commonly prescribed empirical therapy and useful local resistance information

IMPACT

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