antibiotics

empiric therapy

antibiotics that are chosen that have activity against the predicted or most likely pathogen causing the patient’s infection

directed or targeted therapy

antibiotics that are used to treat an established infection. selection is based upon the susceptibility result of the identified organism

beta lactam antibiotics mechanism of action 

interferes with bacterial cell wall synthesis during active multiplication, causing cell wall death and resultant bactericidal activity against susceptible bacteria 

what kind of killing do beta lactams display against bacteria?

time dependent killing

natural penicillin drugs

• penicillin

• cephalosporins

• carbapenems

• monobactam

penicillin G formulation 

IV

penicillin VK formulations

oral

penicillin benzathine/procaine formulation

intramuscular

main uses of penicillins

• good activity against most Streptococcus infections (groups a, b, c, f, and g). acute pharyngitis “strep throat”

• good activity against mouth anaerobes (peptostreptococcus, prevotella, fusobacterium)

  • good for dental procedures

  • drug of choice for syphilis (Treponema pallidum)

avoid uses of penicillins 

• Streptococcus pneumoniae - when resistant, not the best empiric choice 

• unreliable against enterococcus 

pharmacokinetics of penicillins

• renally eliminated

• distribution: widely distributed to the kidneys, liver, skin, tonsils, and into synovial (joint), pleural (lungs), and pericardial tissue

adverse reactions with penicillins

• rash

• anaphylaxis

• fever

• seizures: usually secondary to accumulation with poor clearance of the drug

• GI upset

Aminopenicillins 

• ampicillin (IV/PO)

• amoxicillin (PO)

main uses of aminopenicillins

• similar gram-positive activity to the natural penicillins. (Strep activity/mouth anaerobes/ADDS enterococcus)

• Streptococcus pneumoniae (less resistance than penicillin)

• gram negative: H.influenzae, E.coli, Proteus, Salmonella, and Shigella)

avoid uses of aminopenicilins

pharmacokinetics of aminopenicillins

• both ampicillin and amoxicillin are renally eliminated (both need to be renally adjusted and are good for UTIs) 

• good tissue penetration-useful for: sinusitis, lung infections, and ear infections 

adverse effects of aminopenicillins

• rash/allergic reaction

• fever

• seizures-secondary to accumulation due to renal insufficiency

clinical pearls of aminopenicillins

• drug of choice for Listeria infections

• drug of choice for susceptible Enterococcus infections (usually not empiric)

• amoxicillin is the better oral agent-more reliably absorbed

aminopenicillin + Beta Lactamase Inhibitor combos 

• ampicillin + Sulfbactam (IV) 

• amoxicillin + clavulanate (PO)

aminopenicillin + Beta lactamase inhibitor main uses

• Gram-positive: similar activity to the natural penicillins, but adds MSSA activity

• gram-negative: more reliable against PEK(proteus, E.coli, and Klebsiella [NOT Klebsiella aerogenes])

• sulfbactam has activity against Acinetobacter species

• gut anaerobes: adds Bacteroides fragilis activity

pharmacokinetics of aminopenicillins + B-lactamase inhibitors

• both amipicillin and amoxicillin are renally eliminated

• good tissue penetration-useful for:

  • sinusitis, lung infections, and ear infections

adverse effects of aminopenicillins + B-lactamase inhibitor combos

• rash/allergic reaction

• fever

• seizures

• extended-spectrum = increased incidence of GI side effects including diarrhea (amoxicillin/clavulanate combo is the worst)

clinical pearls of aminopenicillin + B-lactamase inhibitor combos

• often used to treat infections caused by animal bites

• combos can be used for the same purposes as the parent compound

• more stable against gram negative bacteria that exert resistance via beta-lactamase production

anti-pseudomonal penicillins + Beta-lactamase inhibitor combos

piperacillin + tazobactam (IV): Zosyn is brand name

zosyn main uses

• gram positive: continues activity against Streptococcus. Piperacilin has activity against Enterococcus

• gram negative: more stable activity against SPACE bugs (serratis, Pseudomonas, Acinetobacter, Citrobacter, and Enterobacter)

• gut anaerobe: adds Bacteroides fragilis activity

pharmacokinetics of Zosyn 

piperacillin is renally eliminated 

adverse effects of Zosyn

• rash (potential for Stevens-Johnson syndrome)/allergic reaction

• Clostridioides difficle associated diarrhea(CDAD)

• formulations contain large amounts of sodium, so fluids may need to be adjusted

• interstitial nephritis- check renal function periodically

clinical pearls of Zosyn

• often used as empiric therapy for hospital or healthcare associated infections where multi-drug resistant (MDR) gram negative organisms are suspected

anti-staphylococcal penicillins 

• nafcillin (IV, IM) 

• oxacillin (IV) 

• Dicloxacillin (PO) 

main uses of anti-staphylococcal penicillins

• useful against Methicillin-Susceptible Staphylococcus Aureus (MSSA)

• group A streptococcus

avoid use of anti-staphylococcal penicillins

any infection not caused by MSSA or group A streptococcus

pharmacokinetics of anti-staphylococcal penicillins 

• nafcillin: hepatically eliminated 

• oxacillin: adjusted at CrCl < 10ml/min

adverse effects of anti-staphylococcal penicillins

• rash/allergic reactions

• fever

• interstitial nephritis- check renal function periodically

clinical pearls of anti-staphylococcal penicillins

• dicloxacillin generally limited to skin infections

• nafcillin/oxacillin preferred for systemic infections

  • bacteremia/endocarditis/osteomyelitis

  • nafcillin can be used for CNS infections

main uses of pivmecillinam (PO) 

ONLY approved for use in uncomplicated UTIs caused by susceptible isolates of E.coli, Proteus, Staph saprophyticus 

avoid use of Pivmecillinam

Non-UTI infections

adverse effects of pivmecillinam

• rash/allergic reactions

• fever

clinical pearls of pivmecillinam

• oral absorption similar to ampicillin (bioavailability = 25-35%)

• has activity against Extended Spectrum Beta Lactamase (ESBL) producing organisms

• may also protect against the formation of ESBL organisms

cephalosporins mechanism of action

interferes with bacterial cell wall synthesis during active multiplication, causing cell wall death and resultant bactericidal activity against susceptible bacteria

1st generation cephalosporins

• cephalexin (oral)

• Cefazolin (IV)

• Cefadroxil (oral)

main uses of 1st generation cephalosporins 

• good activity against Streptococcus groups A, B, C, F, and G 

• unreliable activity against Streptococcus pneumoniae 

• excellent activity against MSSA 

• some gram-negative activity: Proteus, E.coli, Klebsiella (PEK) 

avoid use of 1st generation cephalosporins

• listeria spp, atypical organisms, MRSA, and Enterococcus (LAME)

• anaerobes

pharmacokinetics of 1st gen cephalosporins

• widely distributed into most body tissues and fluids including gallbladder, liver, kidneys, bone, sputum, bile, pleural and synovial: CSF penetration is poor

• mainly excreted in the urine- good for UTIs and renally adjusted

adverse effects of 1st gen cephalosporins 

• rash/allergic reactions 

• fever

• seizures- due to accumulation due to renal insufficiency 

• overall pretty well tolerated 

clinical pearls of 1st gen cephalosporins

• excellent for skin and skin structure infections (MSSA, Strep Groups A-G)

• cefazolin can treat bacteremia and osteomyelitis

• cefazolin often used prior to non-GI tract surgeries to prevent infection

• treats the most common causes of UTI

2nd gen cephalosporins

• cefaclor(oral)

• cefuroxime (IV, oral)

• Cefprozil (oral)

• Cefoxitin (IV)

main uses of 2nd gen cephalosporins 

• continues to have good activity against Streptococcus groups A-G(better than 1st gen) 

• continues gram negative activity against Proteus, E.coli, Klebsiella (B. fragilis

avoid use of 2nd gen cephalosporins

• MSSA (not reliable)

• Listeria spp, Atypical organisms, MRSA, Enterococcus (LAME)

adverse effects of 2nd gen cephalosporins

• generally well tolerated

• cefuroxime/cefoxitin: diarrhea

• rash/allergic reaction

• fever

• cefoxitin can cause decreased Vitamin K dependent clotting factor activity in the liver

clinical pearls of 2nd gen cephalosporins

• less commonly used for skin and skin structure infections than 1st gen

• oral 2nd gen can be used to treat Upper Respiratory Infections (URIs): sinusitis, bronchitis, otitis, and pneumonia due to activity against Streptococcus pneumoniae

• cefoxitin has gut anaerobe activity: can be used to prevent infection during GI surgeries

• treats the most common organisms responsible for UTI though rarely used

3rd generation cephalosporins 

• ceftriaxone (IV, IM)

• cefotaxime (IV, IM)

• ceftazidime (IV)

• cefdinir(oral)

• cefpodoxime (oral) 

• cefixime (oral) 

main uses of the 3rd generation cephalosporins

• continues to have good activity against Streptococcus groups A-G

  • including Streptococcus pneumoniae

• continues gram negative activity against PEK

  • continues gram negative activity against HNPEKM

  • adds gram negative activity against serratia, shigella, salmonella, morganella, and providencia

which 3rd generation is the only one with Pseudomonas activity?

ceftazidime

when do we avoid use of 3rd generation cephalosporins?

• MSSA

• listeria spp, atypical organisms, MRSA, enterococcus

• anaerobes

• citrobacter, enterobacter, acinetobacter

pharmacokinetics of 3rd generation cephalosporins

• widely distributed into most body tissues

• some secreted in the urine: Cefpodoxime, Cefotaxime, Ceftazidime

• ceftriaxone is excreted via biliary excretion

what 3rd generation cephalosporin do we want to avoid in neonates?

Ceftriaxone

which 3rd generation cephalosporin is preferred in neonates?

Cefotaxime

which antibiotic should NOT be infused at the same time as calcium?

Ceftriaxone

adverse effects with 3rd generation cephalosporins

• painful local injection site locations with IM formulations 

• rash/allergic reaction

• fever 

• oral agents: high likelihood of causing diarrhea 

which 3rd generation cephalosporins can treat CNS infections and what formulation?

• ceftriaxone

• cefotaxime

• ceftazidime

• IV formulations ONLY

what is the only 3rd generation cephalosporin that treats Pseudomonas spp?

Ceftazidime

which antibiotic can cause red stools when combined with iron?

cefdinir

which 3rd generation cephalosporin is useful in UTIs?

cefpodoxime 

4th generation cephalosporin

cefepime (IV)

cefepime main uses

• excellent streptococcus spp activity

  • includes streptococcus pneumoniae

• MSSA activity!!

• PEK, HNPEKM gram negative activity

  • also includes gram negative activity against Serratia, Acinetobacter, Citrobacter, Enterobacter including Klebsiella aerogenes, Shigella, Salmonella, Morganella, and Providencia

• possesses pseudomonas activity 

when do we avoid use of cefepime?

• Listeria spp, atypical organisms, MRSA, enterococcus, ESBL producing organisms 

• anaerobes 

pharmacokinetics of cefepime

• widely distributed into most body tissues and bloodstream

• excreted renally ~needs to be dose adjusted and good for UTIs

adverse effects of cefepime

• Neurotoxicity : CNS side effects and possible seizures

• rash/allergic reactions

• fever

clinical pearls of cefepime 

• similar spectrum to Zosyn minus anaerobes

• good CNS penetration 

• good tissue penetration 

• good blood stream concentrations 

• good urinary tract concentrations 

• excellent for Enterobacter (also Klebsiella aerogenes), Serratia, Citrobacter spp

5th generation cephalosporins

• Ceftaroline (IV)

• Ceftobiprole (IV)

main uses of 5th generation cephalosporins

• continues great Streptococcus spp activity

  • includes Streptococcus pneumoniae

• MSSA activity + MRSA activity

• Gram negative activity: H. influenzae, Moraxella catarrhalis, Proteus, E.coli, Klebsiella, Enterobacter, and Morganella

what is the ONLY cephalosporin that has activity against MRSA? 

Ceftaroline and Ceftobiprole 

when do we avoid use of 5th generation cephalosporins?

• Listeria spp, Atypical organisms, and Enterococcus

• anaerobes

pharmacokinetics of 5th generation cephalosporins

• widely distributed into most body tissues

• ex

clinical pearls for 5th generation cephalosporins 

• should be reserved for patients at risk for MRSA that can NOT take any other MRSA treatments 

Cefiderocol Main Uses

• Indicated for treatment of complicated UTIs and lung infections caused by susceptible organisms

• activity against PEK (including ESBLs)

• activity against SPACE

  • Acinetobacter baumannii

  • Pseudomonas aeruginosa

• carbapenemase producing organisms

when do we want to avoid use of Cefiderocol? 

• infections caused by any Gram positive organisms 

• Anaerobes 

Pharmacokinetics of Cefiderocol

renally eliminated so it needs to be dose adjusted

adverse effects of Cefiderocol

• Diarrhea

• Neurotoxicity

• C.difficle associated diarrhea (CDAD)

clinical pearls of cefiderocol

• doses are infused over 3 hours

• currently only indicated for UTIs and hospital-acquired and ventilator-associated pneumonia

cephalosporin + B-lactamse inhibitor combos

• Ceftazidime + Avibactam (IV)

• Ceftolozane + Tazobactam (IV)

• Cefepime + Enmetazobactam (IV)

main uses of cephalosporin + B lactamase inhibitors

• same activity as the parent

• mainly target gram negative infections

• can treat Pseudomonas infections

• indicated for UTI

clinical pearls of cephalosporin + B-lactamase inhibitor combos 

• ALL can treat ESBL producing bugs (E.coli and Klebsiella) 

• Ceftazidime + Avibactam can target carbapenemase producing organisms 

• Ceftolozane + Tazobactam has activity against gut anaerobes 

Carbapenems

• Imipenem + Cilastatin (IV)

• meropenem (IV)

• Ertapenem (IV)

mechanism of action of carbapenems

interferes with bacterial cell wall synthesis during active multiplication, causing cell wall death and resultant bactericidal activity against susceptible bacteria

main uses of carbapenems 

• overall good activity against Streptococcus (including Streptococcus pneumoniae) 

• MSSA activity(not 1st choice) 

• good activity against mouth anaerobes (dental procedures)

• excellent gram negative activity 

  • HNPEKM

  • serratia, citrobacter, enterobacter

• imipenem and Meropenem have activity against Pseudomonas

• activity against gut anaerobes

which class of antibiotics do we need to avoid in patient taking valproic acid and why?

carbapenems b/c they can significantly decrease the levels

adverse effects of carbapenems

• rash 

• anaphylaxis 

• fever

• C. difficile associated diarrhea (CDAD) 

• seizures: most commonly associated with Imipenem + Cilastatin 

clinical pearls of carbapenems

• excellent broad-spectrum

• should be reserved for penicillin allergy patients or those with multi-drug resistant bacteria

• drugs of choice for Extended Spectrum Beta Lactamase producing bugs (Klebsiella and E.coli)

• Ertapenem is the ONLY one with NO activity against Pseudomonas

Meropenem + Vaborbactam

• approved for complicated UTIs

• has activity against carbapenemase producing gram negative bacteria

Imipenem + Relebactam 

• currently approved for complicated UTIs and intrabdominal infections and hospital-acquired pneumonia 

• has activity against carbapenemase producing gram negative bacteria 

sulfbactam + durlobactam

treatment of hospital-acquired bacterial pneumonia caused by Acinetobacter baumannii-calcoaceticus complex (CRAB)

adverse effects of sulbactam + durlobactam

• diarrhea

• anemia

• hypokalemia

• abnormal hepatic function tests

Aztreonam main uses 

• ONLY gram negative activity 

  • HNPEKM

  • SPACE

  • also Klebsiella aerogenes

adverse effects of Aztreonam

• rash

• anaphylaxis

• fever

• neutropenia

• increased hepatic transaminases (AST and ALT) 

clinical pearls of Aztreonam

• especially helpful in treating patients with gram negative bacteria and a severe penicillin allergy

• no cross reactivity with penicillins

• has activity against Pseudomonas

aminoglycosides

• gentamicin (IV, IM) 

• Tobramycin (IV, IM, inhalation) 

• Amikacin (IV, IM, inhalation) 

• Plazomicin (IV) 

• Streptomycin (IM) 

• Neomycin (oral) 

mechanism of action of aminoglycosides

inhibits bacterial protein synthesis by binding directly to the 30S subunit causing faulty peptide sequence to form in the protein chain

main uses if aminoglycosides

• used in combo with cell wall active agents as synergy against gram positive organisms (MRSA, enterococcus spp)

  • usually gentamicin and streptomycin are used in this manner

  • NEVER used alone for gram positive organisms

• gentamicin, tobramycin, and amikacin have excellent activity against gram negative organisms

  • HNPEKM and SPACE

    • has activity against Pseudomonas