Principles of chemotherapy

Chemotherapy

• bacteria produce antibiotics naturally as a way to compete with other microbes for resources

• resistance mechanisms are already present - antimicrobial use leads to the selection of resistant micro-organisms

• use of it has fuelled an increase of drug resistant organisms

• highly resistant gram neg - hard to treat

• spread in medical care across countries

antibiotic resistance

• using when unlikely to have bacterial infection

• using antibiotics over unnecessarily prolonged periods

• mutiple agents or broad spectrum agents

• used in agriculture to stimulate growth and prevent infection in livestock

antibiotic misuse

• broad specturm antiobiotics are not ideal as less effcacious, more toxic, more expensive

• infections causes by antibiotic resistant species - due to increases costs, morbidity, mortality

• most new antibiotics are similar to older drugs and must maintain the effectiveness of these drugs

antimicrobial resistance

• organisms present major global threats due to their high burden, & ability to resist treatment & spread resistance to other bacteria.

criticial priority organisms

• salmonella and shigella - high burden in low and middle income countries

• aeruginosa and aureus - significant challenges in healthcare settings

• gonorrhoeae and faecium - present unique public health challenges, persistance infections and resistance to multiple antibiotics

high priority pathogens

• group A/B streptococci - high burden cases

medium priority pathogens

• First- & second-choice antibiotics (narrow-spectrum, highly effective for common infections, ave a lower potential to develop resistance).

• up to 70% of selection

access classification

Broad-spectrum antibiotics (recommended for specific, limited indications).

Higher risk of resistance; primary targets for global stewardship programs.

watch classification

• Last-resort" antibiotics (severe, life-threatening infections caused by MDR bacteria).

• Highly monitored; restricted

reserve classification

Microbiological test results

Patient (host) factors

Patient preference

Hypersensitivity

Recent antimicrobial use

Pregnant/ BF

Altered P

\Site of infection & tissue penetration of antimicrobial

Adverse effects

Antimicrobial shortages

Antimicrobial stewardship principles

selecting an antimicrobial

• Decide whether antimicrobial therapy is needed

• Most viral & self-limiting bacterial infections do not benefit from

  antibiotics

• collect samples for microbiological testing before

  antibiotics started

• document treatment and do it for shortest possible duration

• using clinical judgement - symptoms , history

prescribing antimicrobial

• meets therapeutic guidelines

• local protocols based on antibiograms

• advice from infectious disease specialists

• microbiological tests

• identifying & characterizing microorganism

• Simple & rapid lab techniques are available

selected antimicrobial

overview of how susceptible specific microorganisms are to different antimicrobials
for Bacteria Fungi Viruses

antibiograms

• the lowest concentration of an antibiotic that prevents visible growth of an organism on agar or in broth cultured in the lab

• used to determine whether the bacteria can be inhibited by drug concentrations that are achievable & safe in the blood stream

• larger the MIC, the lower the susceptibility of the organism

• peak serum concentration of an antimicrobial drug should be several times > than the MIC of the pathogenic mo for the drug to eliminate the organism

• peak serum concentration of a drug should be 4 – 10x greater than the MIC

• based on susceptibility, intermediate sensitivity, resistance

minimum inhibitory concentration

• highest plasma concentration of the drug that can safely be achieved in the patient

• whether an organism is susceptible or resistant to the drug

breakpoint

• functional state of host defense mechanisms

• local factors at the site of infection

• Presence of a foreign body in an infected site ↓ the likelihood of successful antimicrobial therapy

• pacemakers, prosthetic joints

• Promotes the formation of a bacterial biofilm that impairs phagocytosis

patient factors

• Biofilm formation is a complex process during which bacteria adhere to a noninert or inert surfaces

• bacteria grow, they produce a film- like matrix to protect themselves from the host immune response and antimicrobial therapy.

biofilm

• Newborn - poorly developed liver & kidney eg Tc, chloramphenicol – gray

  baby syndrome

• Elderly - clear drugs eliminated by kidneys less well bec of decrease creatinine

  clearance eg May metabolise drugs less rapidly

other factors to take into consideration in selecting antimicrobial agent - age

• Risk to foetus/ infant eg aminoglycosides,

  tetracyclines

other factors to take into consideration in selecting antimicrobial agent - pregnant and bf

Glucose-6-phosphate dehydrogenase deficiency (G-6-PD)

May produce acute hemolysis eg

sulfonamides

other factors to take into consideration in selecting antimicrobial agent - drug allergy

• history of seizures predisposes patients on high doses of penicillin G

other factors to take into consideration in selecting antimicrobial agent - comorbidities

• oral bioavailability, peak serum

  concentration, distribution, elimination & half-

  life

pharmacokinetic properties in selecting microbial

Absence of IV catheter associated infection risk

Lower drug cost

Reduced hospital costs (staff, equipment)

Shorter length of stay in hospitals

advantages of oral antimicrobials

• More expensive

• Extra cost of equipment

• Greater risk of serious side effects

• Additional time & expertise needed to administer the drug

disadvantage of paraneternal antimicrobials

• GI absorption is a problem

• Not tolerated or not possible

• An oral antimicrobial with a suitable spectrum of activity is not available

• Urgent Tx is needed

• Patient likely to be noncompliant

• High doses are needed to achieve effective concerns at site of infection

when oral antimicrobials are not advantageous

• Oral absorption is reliable

• Appropriate for indication

• Adequate tissue penetration at site of infection

• Good bioavailability

oral therapy can be used if

• people that are obese, septic shock, severe burns, cystic fibrosis, pregnant people

• they have altered drug clearance and volume distribution

selecting for people with altered pharmcokinetiecs

• nebulised antimicrobials - eye drops

• topical antimicrobial - restricted to bacteial conjun

• not for systemic therapy

• applied to a wound or a surgical incision for surgical

  antibiotic prophylaxis is not recommended

• Potential for harm eg Hypersensitivity reactions, bacterial

  resistance

other antimicrobials

• antimicrobials can cause adverse effects - must consider benefit-

  harm profile

• Most adverse effects are minor/ self-limiting but sometimes can be

  serious/ life-threatening

• check if patient has a history of adverse drug reaction

• Non-immune pharmacologically predictable reactions (eg nausea,

  vomiting, diarrhoea)

• can eradicate normal flora and cause bacteria to overgrow - Clostridiodies difficle

• infection of drug resistant pathogen

• candida - due to broad spectrum antibiotics

adverse effects of antimicrobials

• appearance of bacteriological & clinical evidence of a new infection during the chemotherapy of a primary one

• Potentially very dangerous because the micro-organism is responsible for the new infection can be drug-resistant strains of:

  • Pseudomonas

  • Candida

  • Enterobacteriaceae

    • Large group of G-ve rods in intestinal tract

    • The family includes Escherichia, Shigella, Salmonella, Klebsiella, etc

superinfection

Spectrum of activity - daptomycin - no activity against Pseudomonas

aeruginosa

Site of infection & tissue penetration of antimicrobial - Benzylpenicillin

Drug interactions - Erythromycin + atorvastatin

Erythromycin may increase concentration of atorvastatin & risk of myopathy or rhabdomyolysis; stop atorvastatin for the duration of erythromycin Tx, choose an alternative antibacterial, or use an alternative statin (eg pravastatin).’

Formulation - For children unable to swallow tablets, the availability of a suitable drug formulation can affect antimicrobial choice

Antimicrobial shortages - May need alternative antimicrobial

other factors to consider for antimicrobials

advantages - ↓ risk of nosocomial pathogens (pathogen in healthcare settings)

Patients can continue routine activities eg work or schooling

Reduced health care cost

disadvantages - Medical complications Non-adherence to simple measures eg bed rest, Inappropriate AB selection eg based on dosing convenience

rather than appropriate prescribing principle

Outpatient intravenous antibiotic therapy

• due to improper selection of antimicrobial agent,

  dose, ROA or duration of Tx

• Non-compliance

• The nature of the original diagnosis may have been incorrect or may have been more complex than originally thought

• Failure of tx may be due to

  • Pus that needs to be drained.

  • Infections in joint prostheses and heart valves

  • The microbiological nature of the infection should be reassessed eg

    • For a mixed aerobic/ anaerobic intra-abdominal infection, there may be a resistant pathogen.

antibiotic failure

• Exert optimal bactericidal effect when drug concns are maintained above the MIC.

• Typically, concns are maintained at 2 – 4x the MIC throughout dosing interval

• Higher concns don't result in greater kill of mo

• beta lactam

time-dependent activity

• Achieve increasing kill with increasing

  level of drug

• aminoglycosides

concentration dependent activity

• the time it takes for an mo to

  recover from the effects of exposure to an

  antimicrobial & resume normal growth

• bactericidal action continues for a period of

  time after the antibiotic level falls below

  the MIC

post antibiotic effect

• used to treat an established infection when the causative organism has not been identified.

• Antimicrobial choice is based on:

  • Clinical presentation

  • Susceptibility of most likely pathogen

  • Tx must be started before culture results/ susceptibility testing is available

  • When infection not serious enough to warrant taking samples

  • If sample cannot be obtained

  • Tx must be started before culture results/ susceptibility testing is available

  • When infection not serious enough to warrant taking samples

  • If sample cannot be obtained

empiricial antimicrobial therapy

factors for choosing an antimicrobial agent for empirical

therapy

Allergic

 Age

 Pregnant

 Inpatient/ outpatient

 Site of infection?

 Other meds

 Other medical conditions?

• Used to treat an established infection when:

  • The pathogen has been identified, and

  • Antimicrobial with activity against the pathogen can be selected.

• Preliminary microbiology results (eg Gram stain) may allow targeting of antimicrobial therapy before definitive results are available

  • But ongoing therapy should be modified once the pathogen & susceptibility are known.

  • Organisms found to be present may not necessarily be responsible for the

    clinical condition

  • Laboratory data should be interpreted in the context of the overall clinical picture

  • Antimicrobial therapy directed at specific organisms should include:

    • The most effective

    • Least toxic

    • Narrowest spectrum

    • single drug should be used - unless combined therapy is required

    • less than 7 days

prolonged therapy for Endocarditis Osteomyelitis Staphylococcus aureus bacteraemia

direct antimicrobial therapy

• The use of 2 or more antimicrobials at the same timey for empiric therapy may be needed to broaden the spectrum of activity

  • eg for empiric therapy of Staphylococcus aureus bacteraemia

• But if possible

  • Use single-drug directed therapy based on microbiology results and clinical response.

• Inappropriate use of combination therapy

  • Contributes to antimicrobial resistance

  • May cause harm to patient.

• If combination therapy is needed

  • Ensure the benefit of combination therapy outweighs the increased risk of toxicity.

  • Consider risk of drug interactions between antimicrobials.

combination therapy

• the combined

  effect is less than the effect of

  either drug alone

antagonisitic

• the combined

  effect is equal to the sum of the

  independent effects

additive

• the combined

  effect is greater than sum of the

  independent effects

synergistic

• the combined

  effect is similar to the greatest

  effect produced by either drug

  alone 

indifferent

• hight cost

• Selection of multi drug resistant mo

• increase risk of toxicity from 2 or more agents

• Eradication of normal flora which can cause superinfection

disadvantage of combination therapy

• Achieve synergy that is known to improve outcomes

• Extend the spectrum

  • Empirical therapy of suspected mixed infections such as PID

• Prevent the emergence of resistant mo eg

  • The concomitant use of 2 or more agents greatly improves cure rates by preventing the development of resistance eg TB

combination therapy should only be used if

• Highly effective in some clinical settings

• accounts for some of the most blatant misuses of antimicrobials

• 1/3 – 1/2 of antibiotic use in hospitals is for surgical antibiotic prophylaxis

  • Inappropriate prescribing is high.

• Prophylactic therapy should be restricted to situations - In which it has been shown to be effective or

  • Where the consequences of infection are disastrous

    • Cardiac surgery

      • Valve replacement

      • Coronary artery bypass surgery

      • Heart transplant

    • Orthopaedic surgery - Large joint replacement

prophalytic therapy

•  parenteral

  & commence just before the procedure

• To achieve high plasma & tissue levels at the time the

  contamination is most likely during the procedure

• second dose or up to 24 hour Tx may be

  needed when procedures are delayed or

  prolonged

surgical prophalyxsis

used to protect a healthy

person from invasion by a mo to which

they were exposed eg

Prophylaxis against specific organisms

eg

 Malaria for travellers to endemic areas

 Frequent recurrent UTIs

 Selected contacts of active TB

 Prevention of recurrent rheumatic fever

non surgical prophalysis

Insertion of a prosthetic implant

 Abdominal surgery that involves the

breach of colonic mucosa or opening of

infected cavities eg colon resection

 Cardiac surgery

 Neurosurgical procedures

 Deep lacerations penetrating to joint

cavities

 Amputation of gangrenous limb

examples of surgical prophalysis

Taking the wrong antibiotic

 Tx of nonresponsive infections

 Therapy of fever of unknown origin

 Improper dose/ duration

 Inappropriate reliance on antimicrobial chemotherapy

alone

 Lack of adequate bacteriological information

antimicrobial misuse

• promotes optimal antimicrobial prescribing
  improve patient outcomes

   To reduce adverse consequences such as

   Resistance

   Toxicity

   Unnecessary costs.

antimicrobial stewardship

• encompasses all the activities that promote & monitor

appropriate prescribing of antimicrobials within an organisation.

• AMS program should be part of the organisation’s quality

improvement & patient safety governance structure.

• Dedicated staff are required to carry out AMS activities in a hospital.

• The Antimicrobial Stewardship Clinical Care Standard produced by the

ACSQHC includes 8 quality statements for effective AMS in hospitals

antimicrobial stewardship in hospitals

• Life-Threatening Infections: Start antimicrobials immediately—do not delay treatment while waiting for investigation results.

• Microbiological Sampling: Collect appropriate culture/diagnostic samples before starting therapy whenever clinically feasible.

• Guidelines & Formularies: Prescribe according to Therapeutic Guidelines: Antibiotic, evidence-based protocols, and local hospital formularies.

statements for antimicrobial stewardship in terms of initiation

• Adverse Reactions: Always document the active ingredient, date, nature, and severity of any reported reaction or allergy.

• Medical Record Documentation: Must explicitly record:

  • Indication

  • Active ingredient

  • Dose & frequency

  • Route of administration

  • Intended duration or review plan

statements for antimicrobial stewardship in terms of documenting and safety

• Patient Communication: Discuss the condition, treatment options, correct usage, potential adverse effects, when to stop, and the review plan with the patient.

statements for antimicrobial stewardship in terms of patient education and shared decision making

• Regular Review: Frequently reassess therapy (frequency based on illness severity) to de-escalate spectrum, optimize dose/route, or cease therapy as lab results return.

• Surgical Prophylaxis: Follow guidelines strictly for indication, drug selection, dose, route, timing, and total duration.

statements for antimicrobial stewardship in terms prophaylxsis

Community-based practitioners can use many strategies to

optimise antimicrobial prescribing.

 The ACSQHC is also developing AMS strategies for general

practice

 Examples of strategies for general practice:

 Primary Health Networks can:

 Promote Antibiotic Awareness Week

 Establish a local AMS advisory group

GP owners

 Promote ‘Antimicrobial Stewardship Clinical Care Standard’

 Provide staff with access to Therapeutic Guidelines: Antibiotic

 GPs

 Participate in online learning modules on AMS

 Prescribe according to Therapeutic Guidelines: Antibiotic

 Specify the duration of antimicrobial therapy on prescriptions

 General practice staff

 Display AMS information for consumers

ams in community setting

Older people (especially those in RACF) have increased susceptibility to

infection due to physiological changes that occur with aging.

There are high rates of antimicrobial use in RACF.

Rate of AMR is higher in residential aged-care facilities than in

hospitals

Patients in RACF often move in & out of hospital

This increases the risk of infection.

Antimicrobial use in RACF is often inappropriate

ams in resident facilities