ACEM Primary
Antimicrobial Pharmacology
Principles of Action
Empirical therapy – used before pathogen is known, hope that early intervention improves outcome
- Approach:
- Determine clinical source of infection
- Obtain specimens for cultures/ PCR/serology
- Formulate microbiological diagnosis
- Determine need for empirical therapy
- Institute treatment
- Choice of agent:
- Depends on host factors such as concomitant disease states (AIDS, neutropenia in setting of chemotherapy, immunosuppression), prior AE, hepatic/renal function, age, pregnancy status, epidemiologic exposure
- Pharmacologic factors such as kinetics of absorption/distribution/elimination, ability of drug to be delivered to site of infection, potential toxicity of agent, interactions with other drugs
- Susceptibility of organism to therapy in hospital/ community setting
Definitive therapy – when pathogen is known, narrower coverage to target sensitivities
- Interpretation of culture results: Lack of diagnosis may be due to
- Sample error = obtaining cultures post Abx therapy, insufficient volume, contamination
- Non cultivatable or slow growing organisms (histoplasma, bartonella, brucella)
- Requesting bacterial cultures when infection is due to another organism
- Not recognizing need for special media or isolation techniques (charcoal yeast extract agar for Legionella, shell-vial tissue culture system for rapid isolation of CMV)
- Susceptibility testing:
- Measure minimal inhibitory concentration (MIC) – concentration of drug needed to inhibit growth of organism and minimal bactericidal concentration (MBC) – to kill organism
- Specialised assays:
- Beta lactamase assay
- Synergy studies
- Duration of therapy:
- Clinical improvement in patient
- Follow up cultures to detect superinfection or resistance
Antimicrobial Pharmacodynamics
Bacteriostatic versus bactericidal activity
- Bacteriostatic = in general, inhibit protein synthesis
- Macrolides, tetracyclines, trimethoprim
- Bactericidal = act against cell wall
- Should be used when host defences are impaired (endocarditis, meningitis, infections in neutropenic cancer patients)
- Two groups:
- Concentration dependent killing (aminoglycosides, quinolones)
- Rate and extent of killing increase with increasing drug concentration – can be optimised with drug dosing regime
- Eg. Once daily dosing of aminoglycosides
- Time dependent killing (beta lactams, vancomycin)
- Bactericidal activity continues if serum concentration is greater than MBC (minimal bactericidal concentration)
- Eg. Penicillins given QID or as infusion in critically unwell
- Concentration dependent killing (aminoglycosides, quinolones)
Post antibiotic effect (PAE)
- Persistent suppression of bacterial growth after limited exposure
- Reflects time required for bacteria to return to logarithmic growth
- PAE = T-C
- T = time required for viable count in the test culture to increase tenfold above the count observed immediately before drug removal
- C = time required for count in an untreated culture to increase tenfold above the count observed immediately after completion of same procedure used on test culture
- Mechanisms:
- Slow recovery after reversible non-lethal damage to cell structures
- Persistence of drug at binding site or within periplasmic space
- Need to synthesise new enzymes before growth can resume
- Antimicrobials
- PAE >1.5 hours against G +ve cocci (cephalosporins, aminoglycosides, carbapenems, penicillins, quinolones)
- Significant PAE against G-ve bacilli limited to carbapenems and agents that inhibit protein/DNA synthesis (aminoglycosides, quinolones, tetracyclines)
- In vivo PAE are usually longer than in vitro PAE due to post antibiotic leukocyte enhancement (PALE)
- Efficacy of once daily dosing is partially due to PAE
- Aminoglycosides/ quinolones have concentration dependent PAE = high doses result in enhanced bactericidal activity
Antimicrobial Pharmacokinetics
Route of administration
- Mostly have similar efficacy parenterally and orally
- IV preferred for critically ill patients, patients with bacterial meningitis or endocarditis, patients with nausea/vomiting/gastrectomy/ileus/diseases impairing oral absorption or when giving specific antimicrobials that are poorly absorbed PO route
Conditions that alter pharmacokinetics:
- Renal/ hepatic impairment = decreased elimination, dose adjustment required
- Contraindicated in renal impairment – nitrofurantoin, sulphonamides LA, tetracyclines
- Elderly, pregnancy, neonates
- Burns/ cystic fibrosis or trauma may have increased requirements
Drug concentrations in body fluids
- Mostly well distributed to body tissues, except CSF
- In meningeal inflammation, do penetrate BBB
- Eg. Ampicillin 2-3% CSF concentration if uninflamed meninges, increases to 2-100% CSF concentration in inflamed meninges
Monitoring serum concentrations
- Most agents, relation between dose and therapeutic outcome is well established and serum concentration monitoring is unnecessary
- To justify serum monitoring:
- Direct relationship exists between drug concentration and efficacy or toxicity
- Substantial interpatient variability exists in serum concentrations with standard doses
- Narrow therapeutic window
- Clinical efficacy/toxicity of drug is delayed or difficult to measure
- Accurate assay is available
- Routinely performed for aminoglycosides, vancomycin
Management of toxicity
- Possible to select alternative in case of allergy
- Cross reactivity of penicillins and cephalosporins is 10%
Antimicrobial drug combinations
- Provides broad spectrum empiric therapy in seriously ill patients
- Treats polymicrobial infections
- Decreases emergence of resistant strains
- Decrease dose related toxicity by using reduced doses of one or more components
- Obtain enhanced killing or inhibition
Synergism and Antagonism
- Synergism = inhibitory or killing effect enhanced
- Reduction of MIC or MBC of each drug when used in combination
- Mechanisms:
- Blockade of sequential steps in metabolic sequence
- Trimethoprim- sulfamethoxazole: folic acid pathway
- Inhibition of enzymatic inactivation
- Beta lactamase inhibitor with penicillin
- Enhancement of antimicrobial uptake
- Penicillin can increase uptake of aminoglycosides
- Blockade of sequential steps in metabolic sequence
- Antagonism = effect is less than when drugs are used individually
- Mechanisms:
- Inhibition of cidal activity by static agents
- Bacteriostatic agents such as tetracyclines and chloramphenicol can antagonise bactericidal cell wall agents, because the latter require bacteria to be actively dividing and growing
- Induction of enzymatic inactivation
- Some G-ve bacilli (P aeruginosa, serratia) possess inducible beta lactamases-> which can be activated by beta lactam antibiotics
- Inhibition of cidal activity by static agents
- Mechanisms:
Antimicrobial prophylaxis
Surgical prophylaxis: General principles of antibiotic use
1. Active against common surgical wound pathogens
2. Proven efficacy in trials
3. Achieve concentrations greater than MIC of suspected pathogens, present at time of incision
4. Shortest possible course
5. Newer broad spectrum antibiotics reserved for therapy of resistant infections
6. Least expensive agent
Cefazolin is agent of choice for head/neck, gastroduodenal, biliary tract, gynaecologic and clean procedures, administered 60 mins pre incision and repeated if procedure lasts 2-6 hours.
Beta Lactam Compounds
- Have 4 membered lactam ring
- Susceptible to hydrolysis by beta lactamases unless have paired inhibitor
Penicillins:
- MOA = bind PBP (penicillin binding protein)-> inhibits transpeptidation reaction-> halts proteoglycan synthesis-> disrupts cell wall building-> cell death
| Penicillins | Anti-staphylococcal penicillins | Extended spectrum penicillins |
| G+ve (streptococci including pneumococci, staphylococci, enterococci, clostridium, actinomyces)G-ve cocci (meningococci)Non beta lactamase producing anaerobesTreponema pallidum Reduced activity against G-ve rods | Resistant to staphylococcal beta lactamases Used against staph/ strep Not effective against enterococci, anaerobes or gram -ve cocci/rods | As Penicillins however improved activity against G-ve cocci Susceptible to beta lactamases unless paired with clavulanate/ tazobactam-> effective against beta lactamase producing strains of staph and gram negs. |
| Penicillin G and V Benzathine (IM)SyphilisProcainePneumococcalGonorrhoeaHigh resistanceBenzylpenicillin (IV)Pneumococcal pneumonia | Cloxacillin (PO) Dicloxacillin (PO) Nafcillin Oxacillin | Ampicillin (IV) Amoxicillin (PO) Piperacillin (IV) Ticarcillin |
- Resistance: 4 mechanisms
- Inactivation of antibiotic by beta lactamase
- Modification of target PBP
- Impaired drug access to PBP-> in Gram -ve due to outer membrane of cell wall
- Antibiotic efflux via pump
- Pharmacokinetics:
- Absorption impaired by food, take 1-2 hours pre or post meals
- Amoxicillin not affected
- Mostly renal excretion
- AE: hypersensitivity, anaphylaxis, GI upset, vaginal candidiasis
Aminoglycosides
MOA = bactericidal inhibitors of protein synthesis that interfere with ribosomal function
Useful against aerobic Gram-ve organisms
- Gentamicin, streptomycin, tobramycin
Properties:
- Structure: Hexose ring, water soluble, increased activity at alkaline pH
- MOA: Binds to 30s ribosomal unit, inhibits protein synthesis in 3 ways:
- Interference with initiation complex
- Misreading of mRNA-> non-functional protein
- Breakup polysomes to non-functional monosomes
- Resistance mechanisms:
- Presence of transferase enzyme inactivates antibiotic
- Impaired antibiotic entry into cell
- R protein on 30s subunit mutated
- Pharmacokinetics
- Poor oral absorption thus given IV 30-60 min infusion
- t1/2 2-3 hours, up to 24-48 hours if renal impairment
- Does not penetrate CNS or eye-> however if inflammation (meningitis) CSF level may be ~20% plasma level
- Daily dosing for two reasons:
- Concentration dependent killing (higher concentration in one go more effective)
- Post antibiotic effect (lasts for hours after measurable drug is present)
- When given with beta lactam = Synergistic
- Renally cleared: CrCl >60 mL/min, give 5-7 mg/kg gentamicin
- Goal: peak level 5-10mcg/mL at 30-60min post if >once daily dosing OR <1mcg/mL at 18-24 hours post
- Adverse effects
- Ototoxicity, nephrotoxicity (>5d therapy)
- Reversible neuromuscular block (calcium gluconate/ neostigmine as tx)
- Uses = aerobic gram-negative organisms
- With beta lactam to extend coverage to gram positive
- No activity against anaerobes
| Aminoglycoside | Clinical use |
| Streptomycin | Isolated from strain of streptomyces griseus Resistance emerged Limited role as single agent 0.5-1g/day IM or IV Mycobacterial infections (second line for TB) Plague, tularemia and brucellosis Enterococcal/ strep viridans endocarditis – if resistant to gentamicin |
| Gentamicin | Isolated from micromonospora purpurea Effective against gram positive and negatives aerobes Streptococci/ enterococci are resistant due to failure to penetrate cell-> when paired with vancomycin/penicillin however = enhanced uptake, bactericidalGenerally not used alone 5-6mg/kg/day IV Severe infections caused by gram negative bacteria (P aeruginosa, Enterobacter, Serratia, proteus, Acinetobacter and Klebsiella) Endocarditis caused by gram positive bacteria Not used for pneumonia as low pH and low oxygen tension contribute to poor activity Topical therapy for infected burns, skin lesions or ocular infections Intrathecal for meningitis caused by gram negative bacteria |
| Tobramycin | Similar to gentamicin Slightly more active against P aeruginosa Used in cystic fibrosis patients as inhaled therapy |
| Amikacin/ Netilmicin | Resistant to many enzymes that inactivate gentamicin/ tobramycin Used as alternative |
| Neomycin/ Kanamycin | Limited to topical use – too toxic for parenteral Can be used orally in preparation for bowel surgery |
| *Spectinomycin | Aminocyclitol antibiotic Structurally related to aminoglycosides Used as alternative treatment to drug resistant gonorrhoea |
Cephalosporins
- More stable against beta lactamases, thus broader spectrum
- MOA = inhibit cell wall synthesis
- Renally excreted, require dose adjustment at CrCl 50mL/min
- Except Ceftriaxone
- Increasing anaerobic and G-ve activity from Generation 1 to 4
- AE = allergy, local irritation
| 1ST GENERATION | 2ND GENERATION | 3RD GENERATION | 4TH GENERATION | |
| Drugs | Cephalexin (PO) Cefazolin (IV) | Cefoxitin (IV) Cefuroxime (IV) Cefaclor (PO) | Ceftriaxone (IV) Cefotaxime Ceftazidime | Cefepime” -more resistant to ex spec beta lactamases (made by Enterobacter) -penetrates CSF -t ½ 2 hours |
| Good activity | Gram +ve cocci Gram -ve rods = E Coli, K pneumoniae and Proteus | K pneumoniae G-ve cocci = H influenzae, Moraxella catarrhalis Anaerobic rod = Bacteroides fragilis strains | G-ve bacilli = Citrobacter, Providencia G-ve rod = Serratia marcescens Beta lactamase producing strains of Haemophilus and Neisseria Ceftazidime-> P aeruoginosa Cefotaxime-> B fragilis | P aeuroginosa Enterobacteriacea S aureus S pneumoniae Haemophilus Neisseria |
| Poor activity | P aeruginosa, Enterobacter and Citrobacter | G-ve rods = P aeruginosa, Enterobacter Enterococci = G+ve cocci | Enterobacter | |
| Clinical uses | UTI Cellulitis Surgical px | Sinusitis, otitis LRTI Peritonitis, diverticulitis, PID | Meningitis Empirical sepsis | Penetrate CSF |
Carbapenems
- Increased activity against G-ve rods, G+ve organisms and anaerobes including enterobacter and pseudomonas
- Meropenem (0.5-1g 8 hourly IV)
- Imipenem – degraded by renal dehydropeptidase, requires coadministration with inhibitor called cilastatin
- Resistant to beta lactamase
- Degraded by carbapenemases/ metallo b lactamases
- Nil activity against enterococci, MRSA, C diff or Burkholderia (G-ve rod)
- Penetrate CSF
- Renal excretion
- Uses: Mixed aerobic and anaerobic
- AE: allergy, vomiting
- Low cross reactivity with penicillins
Glycopeptides
| Vancomycin | Gram +ve only Effective against most beta lactamase producing staphylococci (MRSA) MOA = inhibits transglycosylase-> nil cross linking of peptidoglycans-> inhibits cell wall synthesis Resistance = modification of binding site Pharmacokinetics = Poor absorption from GI tract (used for C diff colitis)IV infusion (BSI, endocarditis, meningitis due to penicillin resistant pneumococcus) Elimination = renal, dose adjustment required Normal dose 30-60mg/kg/day ~ 1g 12 hourly AE = “Red man syndrome” |
| Teicoplanin | Long t ½ IM once daily dosing |
| Dalbavancin | Long t ½ 6-11 days IV weekly dosing |
| Telavancin | Dual MOA, improved against MRSA IV |
Monobactams: Aztreonam
- For aerobic, G-ve organisms (pseudomonas)
- Useful in setting of immediate hypersensitivity to penicillins
- IV 8 hourly
- Renally cleared, t ½ 1.5 hours
- Nil cross reactivity with penicillins
- No activity against G+ve or anaerobes
Lipopeptide: Daptomycin
- For G+ve organisms causing sepsis, endocarditis
- MOA = binds cell membrane-> depolarisation-> death
- IV dosing
- Renally cleared, t ½ 8 hours
- Inactivated by surfactant, thus not used in pneumonia
- AE = myopathy (check CK)
Other:
Fosfomycin – 3g PO for UTI
Bacitracin – topical therapy
Cycloserine – mycobacterium tuberculosis, resistant to 1st line agents
| Drug | ||
| Sulfonamides | MOA = inhibit dihydropteroate synthase enzyme and folate production-> bactericidal Active against gram +/- including Nocardia, Chlamydia trachomatis, E Coli, K pneumoniae, Salmonella, Shigella and Enterobacter Do not work against pseudomonas or anaerobes Organisms which can utilise exogenous folate are resistant Metabolised in liver, excreted by kidney AE = rash, fever, bone marrow suppression, hyperkalaemia, crystalluria | Sulfamethoxazole – UTI (t ½ 10-12 hr) Used in combination with trimethoprim (dihydrofolate reductase inhibitor) for UTI or PCP prophylaxis Sulfadiazine – Toxoplasmosis Sulfasalazine – UC |
| Quinolones | MOA = inhibit DNA gyrase + topoisomerase-> nil DNA replication, bactericidal Excellent for g-ve aerobes Active against enterobacter, pseudomonas, N meningitidis, Haemophilus, Campylobacter MSSA Mycoplasma, Chlamydiae Legionella Cleared renally AE = GI upset, neurotoxicity, tendonitis Not recommended for age <18 as affects cartilage growth Not safe in pregnancy | Ciprofloxacin – pseudomonas Ofloxacin – UTI, non gonococcal urethritis/ cervicitis Levofloxacin – “respiratory” against pneumococcus UTI, gastroenteritis, osteomyelitis, anthrax |
| Metronidazole | MOA = disruption of electron transport chain-> bactericidal Anaerobic infections Vaginitis C difficile colitis PO/IV Hepatic clearance t ½ 8 hours Disulfiram like reaction if given with ETOH AE – GI upset, metallic taste, neuropathy, seizures | Alternative – Tinidazole (once daily dosing, for trichomonas/ giardiasis and amebiasis) |
| Macrolides | MOA = prevent bacterial protein synthesis by binding to 50s ribosomal unit-> bacteriostatic/ bactericidal at high concentrations Active against: Pneumococci, streptococci, staphylococci Mycoplasma pneumoniae, chlamydia trachomatis/ pneumoniae, listeria Neisseria, bartonella CAP Pertussis Chlamydial infections Resistance mechanisms: Reduced permeability of cell membrane or active efflux Production of esterases that hydrolyse macrolidesModification of ribosomal binding unit | Erythromycin: PO/IV, t ½ 1.5 hr Cytochrome P450 inhibitor Enteric coating required Food interferes with absorption AE – GI upset, hepatotoxicity, QTc prolongation Clarithromycin: PO, longer half life 6 hours Increased activity against Mycobacterium avium complex, Mycobacterium leprae, Toxoplasmosis gondii and H influenzae Lower incidence GI upset Less frequent dosing Azithromycin: PO/IV, half life 68 hours Once daily dosing or 5 day course therapy for CAP Active against chlamydia spp Higher tissue concentrations than serum |
| Tetracyclines | MOA = prevent bacterial protein synthesis by binding to 30s ribosomal unit-> bacteriostatic Used for mycoplasma, chlamydiae, rickettsiae and some spirochetes Malaria (P falciparum) H Pylori Acne Divalent cations (Ca/Mg/Fe/Al, dairy products and antacids impair oral absorption AE – GI upset, hepatotoxicity, photosensitivity, deposition in bone and teeth Resistance mechanisms: Impaired influx or increased efflux by active transport protein pump Production of proteins-> prevent binding and protect ribosome Enzymatic inactivation | Doxycyline: PO/IV, half life 16-18 hours Non renal elimination Absorption minimally affected by divalent cations – 100% For CAP/ bronchitis exacerbations Minocycline: PO, half life 16-18 hours Tigecycline: IV, half life 36 hours Unaffected by common resistance mechanisms, broad spectrum of G +/-/ anaerobic activity |
| Lincosamide (Clindamycin) | MOA = prevent bacterial protein synthesis by binding to 50s ribosomal unit-> bacteriostatic Derivative of lincomycin Staph and strep – often active against MRSA for skin/ soft tissue Anaerobic infections by bacteroides In combination with aminoglycoside/ cephalosporin for penetrating wounds of abdomen, infections of female genital tract and lung abscess PO/IV Hepatic clearance t ½ 2.5 hours AE – GI upset, C diff colitis |
Last Updated on September 24, 2021 by Andrew Crofton
Andrew Crofton
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