Journal Club

Principles of Antibiotic Therapy

ByDr. Sayan Chakraborty

Final Year JR- MD Tropical MedicineSchool of Tropical Medicine, Kolkata

E-mail: dr.sayan@gmail.com

Authors & Journal

AJ Varley BSc MB BS MRCS FRCAJumoke Sule MB ChB MRCP FRCPath

AR Absalom MB ChB FRCA MD

doi:10.1093/bjaceaccp/mkp035Continuing Education in Anaesthesia, Critical Care & Pain |

Volume 9 Number 6 2009© The Author [2009]. Published by Oxford University Press on

behalf of the British Journal of Anaesthesia.

Historical perspectiveMicroscopy:• Magnifying glass: by Pliny in 1st century AD • Modern microscope: in 1590 by Dutch spectacle maker Zaccharias

Jannsen• 270x microscopes: by Antonie van Leeuwenhoek (1632–1723), first to

see & describe bacteriaBacteria:• Abu Ali ibn Sina: first to propose the presence of bacteria in 1020• Louis Pasteur: demonstrated that fermentation is due to

microorganisms• Robert Koch: proposed the ‘germ theory of disease’, received

nobel prize• Hans Christian Gram: in 1884, developed Gram’s staining

Historical perspective

• Ancient Chinese, Greeks and Egyptians used moulds and plants to treat infection Eg: Quinine for malaria• Ernest Duchesme, first described the antibacterial

properties of Penicillium spp. in 1897• Fleming developed penicillin in 1928• Paul Ehrlich: Discovered the first true antibiotic,

Salvarsan, treatment for Syphilis, after his work on arsenic and other metallic compounds in Germany, 1909.• Gerhard Domagsk, a pathologist, discovered the

sulphonamides in the Bayer laboratories in 1932.

Pharmacology of antibiotics

• Defined as pharmacological agents that selectively kill or inhibit the growth of bacterial cells, while having little or no effect on the mammalian host• Bacteriostatic antibiotics prevent replication of bacteria,

rely on an intact immune system to clear the infection• Bactericidal antibiotics kill the bacteria• Use of a bactericidal agent is mandatory when treating

infective endocarditis since the bacteria are protected from host immune functions within valve vegetations• Cidal activity can sometimes be achieved by a

combination of antibiotics

Pharmacokinetics & pharmacodynamics

• Pharmacokinetic (PK), pharmacodynamic (PD) and microbiological parameters are increasingly used to predict microbiological and clinical outcome

• PK refer to absorption, metabolism, distribution, and elimination• PD refer to the effects of the drug on the body or organism• After bolus, peak concn depends on the dose and the initial volume

of distribution• The rate of decline of drug concn depends on the rates of

redistribution, metabolism, or renal clearance. • Most antibiotics are eliminated via the kidneys— glomerular

filtration or tubular secretion• Exercise caution in impaired kidney function eg: Aminoglycosides

PK & PD parameters/IndicesParameters:• Peak concentration• Minimum inhibitory concentration (MIC),• Area under the concentration–time curve at steady state

over 24 h (AUC)• Protein binding• Post-antibiotic effect

Indices:• Peak/MIC, • Time/MIC,• AUC/MIC

Concentration dependent killing

Aminoglycosides and Fluoroquinolones• Peak concentration/MIC and AUC/MIC best correlate with

efficacy• Prolonged antibiotic effect after the serum level decreases

below the MIC• Higher doses result in efficacy and once-daily dosing for

aminoglycosides maximizes the peak concentration/MIC• Different ratios efficacious for different drug–bug combinations• Eg: for FQs, optimal AUC/MIC ratio for successful t/t of Strepto

pneumoniae is 25–35, whereas ratios >100 may be required for successful t/t of Gram-negative bacilli.

• Higher AUC/MIC ratios less likely to be associated with development of resistance

Time-dependent killing

• β-Lactams, erythromycin, clindamycin, linezolid• Time/MIC being the most important index for

efficacy• The proportion of time above MIC is the most

important parameter• AUC/MIC correlates best with efficacy for

azithromycin, tetracyclines, glycopeptides, and quinupristin–dalfopristin

Adverse reactions

Hepatic & Renal dysfunction:• Most commonly: rashes, diarrhoea, nausea & vomiting,

headache• Carbapenems associated with transient increase in

transaminases, which resolve after the cessation of therapy.• Aminoglycosides can cause permanent nephrotoxicity

(tubular damage, even at safe levels) and ototoxicity if intracellular accumulation occurs

• Aminoglycosides commonly used in patients with sepsis and renal hypoperfusion, both independent risk factors for renal dysfunction, so difficult to determine the 1° cause of toxicity.

• Once-daily dosing regimens proposed to reduce SE.

Adverse reactions

Allergic reactions• Most common with β-lactams• Allergic reactions in 1950-60s commonly caused by

contaminants, not present in modern formulations• True allergy rate was 33% if an allergy documented

in the medical notes, whereas it’s only 7% when based on self-reporting – One study• In penicillin allergic patients, the incidence of

cross-reactivity to other β-lactam agents (including cephalosporins and carbapenems) is 10%

Resistance• Sulphonamides in 1935 and Penicillin in 1941• In 1946, 14% Staph aureus cultures were resistant• By 1948 only 20% of Neisseria gonorrhoeae isolates were

sensitive to sulphonamides• Some bacteria may not be inhibited adequately by drug concn

that are safely achievable at the affected body site.• Eg: penicillin remains effective for the t/t of pneumonia, but

not meningitis, caused by pneumococci with intermediate susceptibility to penicillin

• Resistance -- intrinsic or acquired• Intrinsic resistance arises if the drug target is not present in

the bacterium’s metabolic pathways or drug impermeability, eg β-lactams have no effect against mycoplasma

Resistance

• Acquired -- by mutation or by transfer of genetic material from resistant to susceptible organisms• Mutations occur frequently with rifampicin and fusidic

acid• Transfer of genetic material occurs via plasmids and

transposons, bacteriophages or direct conjugation• Niederman defined 4 main factors driving microbial

resistanceexcess antibiotic usageincorrect use of broad spectrum agentsincorrect dosingnon-compliance

Principles of prescribing

Prophylaxis: • Three principles:High risk of infectionLikely infecting organisms and their susceptibilities

should be knownProphylaxis to be administered at the time of risk• Eg: Management of contacts of a case of meningococcal

meningitis, who should be offered chemoprophylaxis at the time of greatest risk of developing the infection (rifampicin or ciprofloxacin is commonly used)

Principles of prescribing

Surgical chemoprophylaxis:Depends on the type of procedure to be performed and are as follows:• (i) clean: those that do not open body cavities, not associated

with inflamed tissue• (ii) clean-contaminated: involve the opening of body cavities

like GIT or GU tract• (iii) contaminated: procedures involving acute inflammation or

visible wound contamination;• (iv) dirty: operations performed in the presence of pus,

previously perforated viscus or open injuries that are >4 hr old

Principles of prescribing

Surgical chemoprophylaxis recommendations:• Clean operations (thyroidectomy): prophylaxis is

generally not recommended. Maintaining strict asepsis and good surgical technique• Large bowel surgery associated with heavy levels of

bacterial contamination & post-op infection rates higher• Prophylaxis depends on faecal bacterial load by

mechanical means and the administration of systemic antibiotics active against aerobic and anaerobic organisms, administered at induction to ensure adequate antibiotic levels at the start of surgery

Principles of prescribingSurgical chemoprophylaxis recommendations contd:• Foreign materials implanted have a higher risk of infection, may

require chemoprophylaxis. In orthopaedic procedures, skin commensals mostly implicated in peri-prosthetic infections

• Procedures that cause a transient bacteraemia, usually cleared by RE system, may result in endocarditis in at-risk patients (with anatomical abnormalities, prosthetic valves, or sequelae of rheumatic fever)

• Prophylaxis is not recommended for dental procedures or procedures of the upper and lower GI, GU, respiratory tracts when there is no evidence of infection at the site of the procedure (NICE guidelines)

• Patients with repeated UTI, mainly due to anatomical abnormalities, can be given permanent courses of trimethoprim or nitrofurantoin

Treatment of existing infections

Choice of empirical therapy:• Clinical assessment and a reasonable estimate of etiology• Imp clinical factors include the severity of illness, immune

status, other co-morbidities, & infected prosthetic implants• Before commencing antibiotic therapy, it is vitally important to

obtain appropriate samples for culture except in meningitisBroad spectrum vs narrow spectrum:• Broad-spectrum antibiotics such as β-lactam/β-lactamase

inhibitor combinations, third generation cephalosporins, FQs, and carbapenems useful for initial empirical therapy in critically ill patients

• More targeted therapy once C/S reports available

Treatment of existing infections

Broad spectrum vs narrow spectrum:

• Broad-spectrum agents are more likely to lead to selection of resistant organisms, including fungi• Third-generation cephalosporins and FQs have the

propensity to cause antibiotic-associated diarrhoea• Narrow spectrum agents (e.g. penicillin, trimethoprim

and flucloxacillin) are preferred, where possible, less likely to develop resistance and less likely to be associated with Clostridium difficile

Route of administration• To be determined by the site and severity of the infection• Eg: Mild impetigo affecting a small area of skin can be treated

by short-term topical antibiotics• Choice of oral or IV therapy will depend on: drug levels required at the site of infectionpotential for absorption from the GI tractseverity of the disease process

• Eg: Ciprofloxacin has good bioavailability when taken enterally, and results in similar blood levels and AUC values compared with IV administration (absorption may be reduced by antacid use)

Duration of treatment• Continued until resolution of the infection is achieved.• This can be judged by means of a clinical assessment, for

example: improvements in gas exchangeresolving pyrexiaDecreasing secretionsresolution of infiltrates in CXR in VAP• This clinical information supplemented with lab data such as:decreasing white cell countsC-reactive protein assays• The duration of therapy required varies enormously between

different anatomical sites and organisms

Microscopy and culture• Early microbiological information of appropriate body fluid

samples eg. blood, urine or CSF• A count of white blood cells, red blood cells or epithelial cells

according to sample type allows an assessment of inflammation and sample quality

• Gram’s staining allows an assumption of the likely organism type, thus providing an early opportunity for the selection of empirical antibiotic therapy

• Bacterial culture is integral to microbiological practice, since it enables empirical treatments to be refined to agents that may be less toxic, cheaper, or more effective

• Non-culture techniques, including nucleic acid amplification tests, are now being performed to identify bacteria and their resistance genes

Susceptibility tests• Disc diffusion tests: Discs with known antibiotic concentrations

are applied to the agar plate and incubated in standard conditions for 18–24 h. Interpretation of susceptibility is determined by comparing the diameter of the zones of inhibition around the antibiotic disc with published data for susceptible and resistant organisms

• Broth and agar dilution methods: use a standardized amount of organism incubated in doubling dilutions of culture media in standard conditions for 18–24 h. The lowest concentration at which no growth occurs is referred to as the MIC• E-test: uses a pre-defined gradient of antibiotic within a plastic

strip; applied onto an agar plate inoculated with the test organism and incubated. This test gives an accurate MIC comparable with agar or broth dilution tests and is technically less demanding

Antibiotic assays• Antibiotic serum levels are performed for:to prevent the development of toxic levelsto ensure that levels are therapeuticto assess compliance with drug regimes ( predominantly TB

treatment courses)• Commonly performed during aminoglycoside therapy• Alternatively, they can be more complex ‘microbiological

assays’ or ‘back-assays’ in which samples of a patient’s plasma containing the administered antibiotics are combined with standardized concentration of the infecting organism; rarely performed because results are inconsistent and difficult to interpret

Conclusion

• Understanding of the role of PK and PD parameters allows for greater efficacy in the use of current antibiotics and may reduce the development of resistance• Reductions in the amount of overall antibiotic use,

greater use of narrow-spectrum agents, and ensuring compliance with therapy may also reduce the development of resistance• Use of routine chemoprophylaxis should be considered

carefully with reference to recognized guidelines• Appropriate use of the microbiology laboratory is central

to correct antibiotic usage and guides the use of correct agents and dosage to ensure efficacy and avoid toxicity