Pharmacology of antibacterials

Bacterial classification

• Gram-positive cocci
  • Staphylococci (catalase +)
    • Staphylococcus aureus (Coagulase positive)
    • Staphylococcus epidermidis and Staphylococcus saprophyticus (Coagulase negative)
  • Streptococcus (Catalase -)
    • S. pyogenes (GAS), S. agalactiae (GBS) (beta-haemolytic)
    • Enterococcus faecalis, E. faecium (Gamma-haemolytic)
    • S. pneumoniae, Viridans group (S. mutans, S. sanguis) [alpha-haemolytic)

Bacterial classification

• Gram-positive rods (bacilli)
  • Corynebacterium
  • Clostridium difficle, C. tetani, C. botulinum
  • Listeria
  • Bacillus cereus

Bacterial classification

• Gram-negative
  • Coccobacilli
    • H. influenzae, B. pertussis, Brucella, Pasteurella, Legionella
  • Cocci
    • Neisseria meningitidis and Neisseria gonorrhoea
  • Bacilli (rods)
    • Lactose fermenters – Klebsiella, E. coli, Enterobacter, Citrobacter, Serratia
    • Non-lactose fermenters – Vibrio cholerae, Pseudomonas aeruginosa, Proteus, H. pylori, Yersinia, Campylobacter, Salmonella, Shigella, Bacteroides fragilis (strict anaerobe)

Bacterial classification

• Anaerobic bacteria
  • Gram-negative rods: Bacteroides, Prevotella, Porphyromonas, Fusobacterium, Bilophila
  • Gram-negative cocci: Veillonella
  • Gram-positive cocci: Peptostreptococcus
  • Gram-positive spore-forming: Clostridium
  • Gram-positive non-spore-forming bacilli: Actinomyces, Proprionibacterium, Lactobacillus

Introduction

• Bacteriostatic or bactericidal effects do not always clinically correlate depending on concentration to which bacteria are exposed
• Therefore, drug of choice is usually more dependent on reaching site of infection, spectrum of agent and safety/cost
• Mechanisms of action
  • Cell wall active agents e.g. penicillins, cephalosporins, vancomycin, teicoplanin, daptomycin
  • Protein synthesis inhibitors e.g. aminoglycosides, macrolides, linezolid, tetracyclines, clindamycin
  • Nucleic acid synthesis inhibitiors e.g. fluoroquinolones, rifampicin, nitrofurantoin
  • Enzyme inhibitors e.g. sulfonamides, trimethoprim

Beta-lactams

• Penicillins, cephalosporins and monobactams
• Studies on Gram-negative bacilli show bactericidal activity that is slow, time-dependent and maximal at relatively low concentrations
• Bacterial killing almost entirely dependent upon time above MIC
• Minimum time above MIC is 60% of dosing interval for effective use
• Lack significant post-antibiotic effect, particularly against Gram-negatives
• It is suggested that concentrations should be maintained at 4-5x MIC for long periods

Carbapenems

• Also time-dependent killing but have some post-antibiotic effect
• Prolonged infusions can increase time > MIC
• Low concentrations predispose to resistance

Aminoglycosides

• Concentration-dependent killing
• High peak concentration provides better, faster killing
• All exhibit significant post-antibiotic effect
• The higher the previous peak concentration, the longer the PAE
• PAE more pronounced with Gram-negatives
• Once-daily dosing improves bacterial killing, reduces nephrotoxicity, higher peak/MIC ratios, further prolongs the PAE and reduces administration costs

Quinolones

• Ciprofloxacin has combined time- and concentration-dependent killing
• Shows some post-antibiotic effect
• Most valuable parameter for monitoring is area under inhibitor curve (AUIC) i.e. AUC/MIC > 125
• Inappropriately low doses lead to resistance

Glycopeptides

• Vancomycin has PAE and post-antibiotic sub-MIC effect

Tissue penetration and Vd

• Aminoglycosides and glycopeptides distribute well into fluids but poorly into tissues
  • Therefore, should not be first-line or sole agents for solid organ infections e.g. lung, kidney, liver and in situations of high third-spacing, the Vd is significanty affected
• Quinolones have very high Vd suggesting good tissue penetration and are therefore good for solid organ infections
• Beta-lactams and carbapenems also have good tissue penetration

Cell wall active agents

• Beta-lactams and glycopeptide agents 
• Beta-lactams bind to penicillin-binding proteins leading to peptidoglycan cell wall component deterioration, cell wall weakening and cell lysis
• Glycopeptides bind to terminal ALA-ALA dipeptide in cell wall peptidoglycan and by steric hindrance prevent cross-linking
• Both bactericidal at usual doses
• Daptomycin insert lipophilic part of molecule into cell wall of gram-positives, depolarising the cell wall causing leakage of intracellular contents and bactericidal effect
• Resistance
  • Mutations in PBP (e.g. MRSA and penicillin-resistant S. pneumoniae)
  • Terminal dipeptide mutation to Lactate-Alanine (VRE)

Protein synthesis inhibitors

• 30S ribosomal subunit – Aminoglycosides and tetracyclines
• 50S ribosomal subunit – Macrolides and clindamycin
• Inhibit transfer RNA function, decreasing protein synthesis
• Must be able to enter cell wall and bind in adequate concentrations
• Resistance
  • Reduced cell wall permeability
  • Active efflux pump
  • Ribosomal-binding site mutations

Nucleic acid synthesis inhibition

• Fluoroquinolones
  • DNA gyrase inhibition, thus preventing DNA unwinding and replication
  • Resistance can be due to cell wall permeability reduction, active efflux or DNA gyrase mutations
• Rifampicin
  • Broad-spectrum agent against Gram-positive, Gram-negative and mycobacteria
  • Inhibits RNA synthesis by binding to DNA-dependent RNA polymerase
• Nitrofurantoin
  • Modified by bacterial enzymes to a compound that damages DNA
  • Resistance is very rare

Enzyme inhibitors

• Sulfonamides and trimethoprim
  • Block folic acid synthesis
  • Sulfonamides inhibit dihydropteroate synthase (converts p-aminobenzoic acid to dihydrofolic acid)
  • Trimethoprim inhibits dihydrofolate reductase (converts dihydrofolic acid to tetrahydrofolic acid)

Classification of agents

• Natural penicillins – Pen G and Pen V
• Aminopenicillins – Ampicillin/Amoxicillin
• Penicillinase-resistance penicillins – Flucloxacillin
• Anti-pseudomonal penicillins – Piperacillin/Ticarcillin
• Beta-lactamase inhibitor combination – Augmentin, Timentin, PipTaz
• Monobactems and carbapenems – Aztreonam, Ertapenem, Meropenem, Imipenem
• Aminoglycosides – Gentamicin, Amikacin, Streptomycin, Tobramycin
• Fluoroquinolones – Moxiflocacin, Ciprofloxacin, Levofloxacin

Classification of agents

• First-gen cephalosporins – Cephalexin, Cefazolin
• Second-gen cephalosporins – Cefaclor, Cefuroxime, Cefoxitin
• Third-Gen Cephalosporins – Ceftriaxone, Cefotaxime, Ceftazidime
• Fourth-Gen Cephalosporins – Cefepime
• Macrolides/tetracyclines – Doxycycline, Erythromycin, Azithromycin, Clarithromycin, Roxithromycin, Tetracycline, Minocycline
• Folate inhibitors – Trimethoprim, Bactrim
• Miscellaneous – Metronidazole, Nitrofurantoin, Linezolid, Daptomycin
• Glycopeptide – Vancomycin
• Lincosamides – Lincomycin, clindamycin

Spectrum of action

• Aminoglycosides
  • Gentamicin
    • Broad Gram-negative spectrum including Pseudomonas
    • 95% of aerobic Gram-negative isolates remain susceptible to gentamicin
  • Tobramycin
    • Marginally more active in vitro than gentamicin against Pseudomonas
  • Amikacin
    • Most resistant to enzymatic inactivation and restricted to use against agents resistant to other aminoglycosides

Spectrum of action

• Carbapenems
  • Imipenem, meropenem and doripenem
    • Wide activity against Gram-negative rods (ESBL, Klebsiella, E. coli, Pseudomonas aeruginosa, Acinetobacter baumanii)
    • Excellent activity against anaerobes including Bacteroides fragilis and many Gram-positives
    • Not active against Enterococcus faecium, MRSA, VRE, Mycoplasma, Chlamydia, Stenotrophomonas and some Pseudomonal species
    • Resistance is increasing worldwide due to carbapenemase enzymes, that also confer resistance to other antibiotics

Spectrum of action

• Cephalosporins
  • Moderate-spectrum (cephalexin, cephazolin)
    • Strep, Staph (including beta-lactamase-producing staphylococci), E. coli and most Klebsiella
    • Inactive against Gram-positive (Enterococci and Listeria), Gram-negative aerobes (Serratia, Enterobacter, Pseudomonas) and Gram-negative anaerobe (Bacteroides fragilis)
  • Moderate-spectrum with anti-Haemophilus activity (Cefuroxime and Cefaclor)
  • Moderate-spectrum with antianaerobic activity (Cefoxitin)

Spectrum of action

• Broad-spectrum cephalosporins (Cefotaxime and Ceftriaxone)
  • Cover majority of enteric Gram-negative rods
  • Less active against Staphylococcus than earlier generations cephalosporins
  • No useful activity against enterococci or MRSA
  • Effective in meningitis as better penetrate BBB and higher intrinsic activity in CSF (in the presence of inflammation)
  • ESCAPPM (Enterobacter, Serratia, Citrobacter, Hafnia, Aeromonas, Proteus, Providencia, Morganella morganii
    • Some organisms carry inducible chromosomal cephalosporinases
  • Plasmid-mediated extended- spectrum beta-lactamases (ESBLs) e.g. (E. coli, Klebsiella, Enterobacter)
  • Cefotaxime has better anti-staphylococcal activity than Ceftriaxone

Spectrum of action

• Broad-spectrum cephalosporins with antipseudomonal activity (Ceftazidime, cefepime)
  • Cover majority of enteric Gram-negative rods including Pseudomonas aeruginosa
  • Both drugs inactivated by ESBL
  • Ceftazidime may be inactivated by cephalosporinases
  • Cefepime is more active against Gram-positives than Ceftazidime
• Broad-spectrum cephalosporins with anti-MRSA activity
  • Ceftaroline has good activity against Gram-positive aerobes including MRSA and anaerobes. Variable gram-negative activity

Spectrum of action

• Monobactams
  • Aztreonam
    • Active against majority of aerobic Gram-negative bacteria including beta-lactamase producing H. influenzae, enteric Gram-negative rods and Pseudomonas
    • Inactive against Gram-negative anaerobes and all Gram-positives
    • Very sensitive to ESBLs but resistant to metallo-carbapenemase enzymes

Spectrum of action

• Penicillins
  • Narrow-spectrum penicillins
    • Mainly active against Gram-positive organisms but are inactivated by beta-lactamase
    • Benzylpenicillin (Pen G) treatment of choice for susceptible infections e.g. pneumococcal pneumonia
    • Procaine penicillin for rural where IV is not an option  so given IM
    • Phenoxymethylpenicillin (PenV) is intrinsically less active than benzypenicillin
  • Narrow-spectrum penicillins with anti-staphylococcal activity
    • Dicloxacillin produces less irreversible hepatotoxicity than flucloxacillin but more interstitial nephritis

Spectrum of action

• Penicillins
  • Moderate-spectrum penicillins
    • Amoxicillin and ampicillin have better activity than benzylpenicilin against Gram-negatives (e.g. E. coli, H. influenzae) but still inactivated by beta-lactamases
    • Drug of choice for enterococcal infection
  • Broad-spectrum penicillins (beta-lactamase inhibitor combinations)
    • Should be reserved for infections by organisms that produce beta-lactamase
    • Additional anaerobic cover is usually not required
  • Broad-spectrum penicillins with antipseudomonal activity
    • Piperacillin and ticarcillin

Spectrum of action

• Chloramphenicol
  • Broad-spectrum against Gram-positive and Gram-negative bacteria, Rickettsia and Chlamydia
  • Used topically
• Daptomycin
  • Gram-positive cover only with similar spectrum as glycopeptides
  • Inactivated by pulmonary surfactant
  • Causes myopathy

Spectrum of action

• Fidaxomicin
  • Novel antibiotic used for recurrent C. diff
  • Not systemically absorbed
• Folic acid antagonists
  • Bactrim (sulfamethoxazole + trimethoprim)
    • Should be limited to Pneumocystis jirovecii, CA-MRSA, melioidosis, Listeria monocytogenes and Nocardia
• Fosfomycin
  • Active against Gram-negative bacteria including ESBL’s (except Pseudomonas aeruginosa) and Enterococcus (including VRE)
• Glycopeptides (Teicoplanin and vancomycin)
  • Wide activity against Gram-positives but NOT gram-negatives
  • Prime indications are MRSA, MRSE or Enterococcus faecium
  • Vanco used orally for C. diff

Spectrum of action

• Lincosamides (Clindamycin, Lincomycin)
  • Active against most Gram-positive aerobic bacteria (not Enterococcus) and most anaerobes
  • Often used for CA-MRSA
  • Limited clinical evidence of effect against toxin production in necrotising skin and soft tissue infections
  • Commonly cause diarrhoea
• Linezolid
  • Active against Gra—positives including MRSA, coagulase-negative Staph, VRE and penicillin-resistant S. pneumoniae
  • Can cause bone marrow suppression and peripheral neuropathy after 14 days
  • Weak monoamine oxidase inhibitor

Spectrum of action

• Macrolides (azithromycin, roxithromycin, erythromycin, clarithromycin)
  • Broad-spectrum against Gram-positives, Legionella, Corynebacterium, Gram-negative cocci, Mycoplasma, Chlamydia and Gram-positive and Gram-negative anaerobes
  • Clarithromycin is active against non-tuberculous Mycobacteria including MAC and is used to eradicate H. pylori
  • Attain high intracellular concentrations which is theoretically beneficial for intracellular pathogens
  • Erythomycin and clarithromycin are potent CytP450 3A4 inhibitors
  • Prolong the QT
• Nitrofurantoin
  • Active against E. coli, Enterococcus
  • Excreted by kidneys and even in mild renal impairment, reduced tubular concentrations limit its effectiveness

Spectrum of action

• Nitroimidazoles
  • Metronidazole and tinidazole active against all Gram-negative anaerobes (e.g. Bacteroids), most Gram-positive anaerobes (C. difficile but NOT Proprionibacterium acnes), H. pylori and protozoa (Trichomomonas vaginalis, Giardia, Entamoeba histolytica)
  • Cause disulfiram-type reaction
• Polymyxins
  • Colistin bactericidal against many Gram-negs (including Pseudomonas and Acinetobacter baumanii)
  • Severe renal and neurotoxicity
  • Used for polyresistant Gram-negative infections

Spectrum of action

• Quinolones
  • Ciprofloxacin broadly active against Gram-negative bacteria including H. influenzae, enteric Gram-negative rods, P. aeruginosa, Gram-negative cocci, some Gram-positive cocci and intracellular agents including Listeria and Mycobacteria
  • Cipro/Norflox/Oxiflox have no activity against anaerobes and poor anti-streptococcal activity
  • Moxifloxacin is extended-spectrum against Gram-positives (including Staph and Strep) and many Gram-negative aerobes (but not Pseudomonas) and has anaerobic activity and most atypical pneumonia pathogens
  • Damage joints of children
  • Tendinitis is common, especially if older, concomitant steroid use, renal impairment or prolonged therapy
  • Can prolong QT

Spectrum of action

• Rifamycins
  • Rifampicin active against Gram-positive bacteria including Staph, Gram-negatives and mycobacteria
  • Must always be used in combination due to rapidly rising resistance
  • Can cause hepatitis, orange discolouration of body fluids
  • Massive interactions
• Tetracyclines
  • Broad-spectrum against Gram-positives, Gram-negative, Chlamydia, Rickettsia, Mycoplasma, spirochaetes, non-tuberculous mycobacteria and Plasmodia
  • Some practitioners avoid use up to age 12 due to dentine discolouration and enamel dysplasia, however, for some infections still used despite risk e.g. Q fever, Rickettsial infection

Empirical antibiotics

• Community-acquired sepsis, source not apparent
  • Gentamicin continues to be part of empirical guidelines in severe illness due to low resistance and rapid bactericidal activity with balance of benefit
  • Need Gentamicin 7mg/kg in severe sepsis to achieve target AUC due to increased Vd and enhanced renal clearance and ensures pathogens with high MIC will achieve adequate concentrations
  • Use lower dose range if >80yo or renal impairment CrCl 40-60 (5mg/kg) or <40 (4mg/kg)
  • Gentamicin 4-7mg/kg IV + Flucloxacillin 2g q4h IV
  • Use vanc 25-30mg/kg if penicillin allergic instead of flucloxacillin or any increased risk of MRSA
  • Replace all with meropenem 1g IV q8h if at risk of MDR Gram-negative or in tropical regions to cover Burkholderia pseudomallei
  • If meningitis is suspected, treat as for meningococcal sepsis
  • MDR Gram-negatives
    • Mostly E. coli, Klebsiella, Acinetobacter baumaniin and Pseudomonas aeruginosa
    • ESBL increasing and confers resistance to penicillins, cephalosporins + often show co-resistance to aminoglycosides and quinolones
    • Risk factors: Recent international travel to area of high-prevalence in last 6 months, prolonged hospitalisation, residence in long-term care facility or previous colonisation or infection with MDR Gram-negative

Empirical antibiotics

• Hospital-acquired sepsis, source not apparent (adults or children)
  • Increased risk of HA-MRSA, MDR Enterobacteriaceae, Pseudomonas and Candida sepsis
  • PipTaz 4.5g q6h or if risk factors for MDR Gram-negative, consider meropenem
  • Addition of aminoglycoside confers increased risk without benefit (unless known microbiome with significant portion of Gram-negatives remaining aminoglycoside susceptible)
  • Add vancomycin if high rates of nosocomial MRSA infection or line sepsis is likely
  • Consider antifungals if risk of Candidaemia

Empirical antibiotics

• Community-acquired sepsis in children, source not apparent, <2 months
  • Meningitis not excluded – Cefotaxime 50mg/kg IV q6h + Ampicillin 50mg/kg IV q6h +- Acyclovir
  • Meningitis excluded – Gentamicin 7.5mg/kg IV + Ampicillin 50mg/kg IV q6h
• >2 months
  • Sepsis but not critically ill
    • Cefotaxime 50mg/kg (up to 2g) q6h or Ceftriaxone 50mg/kg (up to 2g) BD
    • + Consider adding vancomycin 25-30mg/kg IV if risk of CA-MRSA
    • If penicillin allergic – Cipro + Vanc
    • Remember dexamethasone 0.15mg/kg (up to 10mg) IV if meningitis +- Acyclovir
  • Critically ill
    • Cefotaxime 50mg/kg q6h or Ceftriaxone 50mg/kg BD + Gentamicin 7.5mg/kg IV + Vancomycin 30mg/kg IV

Antibiotics in the critically ill

• Cefotaxime – 50mg/kg q6-8h
• Ceftriaxone – 50mg/kg BD
• Cephazolin – q6h for adults
• Flucloxacillin – q4h
• Gentamicin – 7mg/kg
• PipTaz – 4.5g q6h and consider giving as infusion over 3-4 hours to increase percentage time above MIC
• Vancomycin– 25-30mg/kg 

Intravascular device source

• Consider S. aureus, S. epidermidis, Candida and Gram-negative rods (Klebsiella, E. coli, Citrobacter, Serratia, Pseudomonas)
• Remove peripheral IVC’s immediately if suspected source of infection and send tip + 2 sets of BC from other sites
• Differential time to positivity (DTP)
  • If catheter sample positive 2 hours prior to peripheral culture, 85% sensitive and 91% specific for catheter-related infection
• Central catheters should usually be removed after consultation with treating team
  • Must be removed if septic shock, tunnel infection, DIC, thromboembolism or if Candida/S. aureus identified
  • Salvage can rarely be attempted with IV antibiotics via infected lumens or antibiotic/ethanol lock
• Empirical therapy
  • Gentamicin 4-7mg/kg + Vancomycin 30mg/kg IV
• Sepsis may resolve rapidly if low-virulence organism (e.g. S. epidermidis) and antibiotics may be able to be ceased
• Conversely, sepsis can be prolonged with deep-seated infection (e.g. endocarditis, osteomyelitis) in the case of high virulence infective agents (e.g. S. aureus, Candida)

Patterns of kill

• Concentration-dependent killing
  • Determined by Cmax = Peak concentration
  • The higher the Cmax, the greater the rate and extent of microbial killing
  • Gentamicin should have Cmax/MIC ratio of 8-10 to prevent resistance
• Time-dependent killing
  • Time above MIC
  • Seen with beta-lactams, clindamycin, erythromycin and linezolid
  • Should have time above MIC of 70% of dosing interval
• AUC above MIC
  • 24hr AUC above MIC is predictor of efficacy
    Seen with fluoroquinolones
    • For Gram-negative bacteria – optimal 24hr AUC/MIC is 125
    • For Gram-positive bacteria – optimal 24hr AUC/MIC is 40

Directed therapy for sepsis

• Staphylococcus aureus
  • Uncomplicated bacteraemia need total 14 days IV
    • Negative BC 48-72 hours after starting antibiotics
    • Rapid resolution of fever
    • Normal valves and no evidence of IE
    • Identifiable source of infection has been removed
    • No evidence of metastatic focus e.g. vertebral osteomyelitis, IE
    • No intravascular prosthetics
    • No immunocompromise
  • Otherwise = complicated and need minimum 4 weeks
  • TTE vs. TOE
    • TTE preferred as first-line
    • TOE indicated if abnormal/prosthetic valve, poor visualisation on TTE, high clinical suspicion or complicated bacteraemia (See above)
    • Children do not need echo unless known intra-cardiac pathology, prolonged fever or persistently positive BC

Directed therapy for sepsis

• Gram-negative enteric bacteria
  • E. coli, Klebsiella, Proteus
  • Gentamicin OR Ceftriazone OR Cefotaxime
  • If ESBL considered likely or at high-risk of MDR Gram-negative use meropenem 1g q8h
  • Carbapenem-resistant organisms are rare but need expert advice if considered possible
• Pseudomonas aeruginosa
  • Gentamicin + (Ceftazidime 2g q8h OR PipTaz 4.5g q6h)
• Candida
  • Anidulfungin OR Caspofungin
  • Fluconazole is an alternative if haemodynamically stable, not neutropaenic, no recent exposure to azoles and are likely to be infected with C. albicans
  • All patients need ophthalmological examination to rule out endophthalmitis

Outpatient parenteral antimicrobials

• Returns patients home sooner, patient satisfaction improved, reduced HAI, cost-saving
• Patients should at all times receive care equal to or better than hospitalisation
• Models of care
  • Visiting nurse
  • Self-administration or carer after training
  • Infusion centre
• Medical responsibility lies with treating doctor (must be clearly identified)

Outpatient parental antimicrobials

• Patient selection
  • Infection must require IV therapy
  • Appropriate drug must be amenable to dosing in outpatient setting
  • Patient must be medically stable
  • Patient must be willing and be able to return to hospital if necessary
  • Patient compliant
  • Home environment suitable e.g. running water, light, heat, refrigeration, working phone and safe for visiting staff

Outpatient parenteral antimicrobials

• Indications
  • Clinical diagnosis must be clearly established before discharge from hospital
    • Common misdiagnoses are PE thought to be pneumonia and DVT/venous insufficiency diagnosed as cellulitis
  • Pyelo and pneumonia are usually amenable to initial IV then change to oral rather than OPAT
    • May be suitable if no oral regime is available due to resistance pattern/GI pathology
  • Infections not suitable due to potential for rapid progression are:
    • Severe cellulitis including necrotising fasciitis
    • Hand space infections
    • Eye infections including periorbital cellulitis
  • Infections suitable
    • Skin and soft tissue infection
    • Infective exacerbations of cystic fibrosis or bronchiectasis
    • Endocarditis
    • Osteomyelitis
    • Septic arthritis
    • Bacteraemias requiring weeks of therapy
    • Tertiary syphilis

Antimicrobial drug concentration monitoring

• Blood samples usually taken once steady state achieved (after at least 5 half-lives of drug if loading dose not given)
• Beta-lactams
  • Usually not necessary unless prolonged IV therapy (>2 weeks) or altered pharmacokinetics e.g. critically ill or severe renal impairment)
  • 15-50% of critically ill have suboptimal concentrations, especially if augmented creatinine clearance (can be 2x normal, especially if neutropaenic, burns, pancreatitis, major trauma)

Principles of aminoglycoside use

• Advantages
  • Rapid bactericidal activity
  • Low rates of resistance including community and hospital-acquired infections
  • Post-antibiotic effect where bacterial killing continues hours after plasma concentration is undetectable
  • Synergistic killing with cell wall active drugs for Enterococcus and Strepcoccus
  • Low hypersensitivity rate
  • Low rates of C. diff
  • Low cost
• Disadvantages
  • Nephrotoxicity – Usually reversible and associated with prolonged treatment courses and pre-existing renal impairment
  • Vestibular and auditory – Usually irreversible and seen with prolonged courses
  • Some resistance in Enterobacteriaceae strains (Klebsiella, E. coli, Proteus)

Principles of aminoglycoside use

• Patients that have altered pharmacokinetics that need increased monitoring
  • Critically ill
  • RRT
  • Severe burns
  • Cystic fibrosis
  • Pregnant women
  • Ascites
  • Morbidly obese
• Contraindications to aminoglycosides
  • History of aminoglycoside-induced vestibular/auditory complications
  • Previous hypersensitivity reaction
  • Myaesthenia gravis
  • Relatively CI if pre-existing auditory/vestibular impairment, FHx of auditory/vestibular toxicity due to aminoglycoside, chronic renal impairment (CrCl <40) or rapidly deteriorating renal function or age >80
    • Sudden idiosyncratic deafness can occur and has a genetic basis (hence the FHx question)

Estimating glomerular filtration rate

• Options include estimated CrCl using Cockcroft-Gault; eGFR using MDRD or CKD-EPI formulas
• The Cockcroft-Gault estimated CrCl has not been revalidated for standard Creatinine assays used in Australia
  • Although estimated CrCl has been the historical basis for drug dosage adjustment 
  • Lean body weight is used as creatinine is a muscle breakdown product
  • If overweight, ideal body weight is used for simplicity
• MDRD and CKD-EPI formulas have been validated with assays in Australia and provide more accurate eGFR
  • The GFR estimates produced are often used for dosage adjustment, though the equations have not been validated for this purpose unlike estimated CrCl
  • If eGFR is used for dose alterations, patients at extremes of body weight should have values adjusted by multiplying eGFR by body surface area and dividing by 1.73m2
• For patients with unstable renal function, a measured (urinary) creatinine clearance is advised

Gent toxicity

• Nephrotoxicity
  • Due to ATN
  • 5-10% of dose gets taken up in proximal tubular cells  where concentration vastly exceeds serum levels
  • Binds to proximal tubule membrane anion binding sites as a cation and then enters cell
  • Single daily dose has less toxicity than multiple daily doses showing dose frequency may well be contributory
  • Results in intracellular protein sorting and mitochondrial toxicity
  • Prevention
    • Correct hypoK and hypoMg prior to administration (the more cations around, the less likely the aminoglycoside will bind to anion phospholipids as a cation)
    • Avoid in reduced effective arterial volume
    • Adjust dose for renal fx
    • Limit duration to 48 hours unless specifically treating resistant organism
    • Minimise other nephrotoxic agents
    • Trough level monitoring
    • Once daily dosing

Gent toxicity

• Ototoxicity
  • Cochlear and vestibular toxicity
  • Sustained or excessive peak concentrations are thought to increase risk
  • Unclear pathogenesis
  • Prevention
    • Same as nephrotoxicity
    • Seen even if trough levels below target and once daily dosing
    • NAC may be protective (single study of 53 haemodialysis patients)

ESCAPPM

• Gram-negative with inducible chromosomal AmpC cephalosporinase/beta-lactamase.Includes:
  • Enterobacter
  • Serratia
  • Citrobacter
  • Acinetobacter
  • Aeromonas
  • Proteus
  • Providencia
  • Morganella
• Confers resistance to cephalothin, cefazolin, cefoxitin, most penicillins and beta-lactamase inhibitor/beta-lactam combinations
• Variable sensitivity to Tazobactam but NOT inhibited by clavulanic acid
• Meropenem is first-line

ESBL

• Extended-spectrum beta-lactamase producers
• Plasmid, non-inducible 
• Confer resistance to penicillins, cephalosporins and monobactams
• Most commonly E. coli and Klebsiella
• Cystitis may be managed with fluoroquinolones, bactrim or nitrofurantoin
• Non-cystitis requires empirical meropenem

Enterococcus

• E. faecalis is more common and causes less severe illnessE. faecalis is susceptible to BenPen and Ampicillin and resistant to carbapenems
• E. faecium is susceptible to Quinupristin-dalfopristin and resistant to vancomycin and carbapenems
• Enterococci are intrinsically resistant to penicillins due to low affinity PBP
  • E. faecalis is frequently susceptible to ampicillin though
  • Ticarcillin and cephalosporins are essentially useless

VRE

• VanA
  • Teicoplanin resistant, vancomycin resistant
• VanB
  • Teicoplanin sensitive, moderate vancomycin-resistant
• Consequences
  • Need for isolation
  • Potential for clinically significant VRE infection
  • Potential for transmission of vancomycin-resistance to Staphylococcus aureus
• Empirical treatment for clinically significant infection
  • Linezolid

MRSA

• Multiresistant MRSA (mrMRSA)
  • = Methicillin + 3 or more classes of non-beta-lactam antibiotic
• nmMRSA
  • Methicillin + <3 classes of non-beta-lactam antibiotic

MRSA

• Multi-resistant MRSA has become established in tertiary care hospitals in Australia
  • Aus-2/3 clone was the original variant but is reducing
    • Resistant to penicillin, macrolides, lincosamides, tetracyclines, trimethoprim, Bactrim, gentamicin +- ciprofloxacin and rifampicin
  • EMRSA-15 is increasing and most common now
    • Consistently resistant to penicillins and ciprofloxacin and often macrolides/lincosamides 
    • Usually susceptible to other agents
    • Seen in hospital and community-acquired MRSA
    • Likely reservoir is frequently hospitalized patients, nursing-home residents and healthcare workers

MRSA

• Community-acquired MRSA occurs Australia-wide now
  • Usually only resistant to beta-lactams
  • Some clones possess Panton-Valentine Leucocidin (PVL) toxin
  • 50% of infections are hospital-onset
  • WA-1 is a common clone
    • Usually susceptible to non-beta-lactams
    • 50% harbor resistance to macrolides/lincosamides or fusidic acid
    • Only 10% produce PVL
  • SWP clone (South-west Pacific)
    • Only 10%  show resistance to non-beta-lactams
    • Produces PVL
  • Qld Clone is most common in Australia
    • Similar to SWP it usually is susceptible to non-beta-lactams and produces PVL

MRSA

• Mechanism of resistance to methicillin is not penicillinase (beta-lactamase) but is due to production of pbp-2a (mecA gene) with much lower affinity for penicillins, cephalosporins and carbapenems
  • Means beta-lactamase inhibitors are ineffective
• Panton-Valentine leucocidin (PVL)
  • Associated with excessive purulence, recurrent boils, multifocal osteomyelitis and necrotizing pneumonia
  • Less likely to cause bacteraemia
  • Not more life-threatening but cause more morbidity, hospitalization and surgical intervention

Pseudomonas DTR-P

• Intermediate or resistant to all tested first-line agents including fluoroquinolones, carbapenems and extended-spectrum cephalosporins
• May require novel new antibiotics, colistin or amikacin

Last Updated on November 18, 2020 by Andrew Crofton