Principles of antibiotic therapy

Presentation is a review of an original article on principles to choosing an antibiotic in a specific scenario

1. Journal Club Principles of Antibiotic Therapy By Dr. Sayan Chakraborty Final Year JR- MD Tropical Medicine School of Tropical Medicine, Kolkata E-mail: [email protected]

2. Authors & Journal AJ Varley BSc MB BS MRCS FRCA Jumoke Sule MB ChB MRCP FRCPath AR Absalom MB ChB FRCA MD doi:10.1093/ bjaceaccp /mkp035 Continuing 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.

3. Historical perspective Microscopy : Magnifying glass : by Pliny in 1 st century AD M odern microscope : in 1590 by Dutch spectacle maker Zaccharias Jannsen 270x microscopes : by Antonie van Leeuwenhoek ( 1632–1723) , first to see & describe bacteria Bacteria : 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

4. Historical perspective A ncient 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 .

5. Pharmacology of antibiotics D efined 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 U se 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

6. Pharmacokinetics & pharmacodynamics P harmacokinetic (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

7. PK & PD parameters/Indices Parameters : 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

8. Concentration dependent killing A minoglycosides and Fluoroquinolones P eak concentration/MIC and AUC/MIC best correlate with efficacy P rolonged 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

9. T ime-dependent killing β -Lactams , erythromycin, clindamycin , linezolid T ime/MIC being the most important index for efficacy T he proportion of time above MIC is the most important parameter AUC/MIC correlates best with efficacy for azithromycin, tetracyclines , glycopeptides , and quinupristin – dalfopristin

10. 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. A minoglycosides 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.

11. Adverse reactions Allergic reactions M ost common with β -lactams A llergic reactions in 1950-60s commonly caused by contaminants, not present in modern formulations T rue 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%

12. Resistance Sulphonamides in 1935 and Penicillin in 1941 In 1946, 14% Staph aureus cultures were resistant B y 1948 only 20 % of Neisseria gonorrhoeae isolates were sensitive to sulphonamides S ome 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 R esistance -- 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

13. 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 resistance excess antibiotic usage incorrect use of broad spectrum agents incorrect dosing non-compliance

14. Principles of prescribing Prophylaxis: T hree principles: H igh risk of infection L ikely infecting organisms and their susceptibilities should be known P rophylaxis 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)

15. 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

16. Principles of prescribing Surgical chemoprophylaxis recommendations: C lean 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 P rophylaxis 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

17. Principles of prescribing Surgical chemoprophylaxis recommendations contd : F oreign 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

18. Treatment of existing infections Choice of empirical therapy: C linical 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 meningitis Broad 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 M ore targeted therapy once C/S reports available

19. Treatment of existing infections Broad spectrum vs narrow spectrum : Broad-spectrum agents are more likely to lead to selection of resistant organisms, including fungi T hird-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

20. 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 infection potential for absorption from the GI tract severity 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)

21. Duration of treatment C ontinued until resolution of the infection is achieved. This can be judged by means of a clinical assessment, for example: improvements in gas exchange resolving pyrexia Decreasing secretions resolution of infiltrates in CXR in VAP This clinical information supplemented with lab data such as: decreasing white cell counts C-reactive protein assays The duration of therapy required varies enormously between different anatomical sites and organisms

22. 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

23. 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

24. Antibiotic assays Antibiotic serum levels are performed for: to prevent the development of toxic levels to ensure that levels are therapeutic to assess compliance with drug regimes ( predominantly TB treatment courses ) C ommonly 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

25. Conclusion U nderstanding 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 U se 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