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Antibiotics overview

This document provides an overview of antibiotics and their appropriate use. It discusses general principles like only using antibiotics when clinically indicated. It then covers different classes of antibiotics like beta-lactams, penicillins, cephalosporins and provides examples of drugs within each class. It describes the spectrum of coverage and recommended uses for different generations of cephalosporins.

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Antibiotics An Overview Tahseen J. Siddiqui, M.D Chicago Infectious Disease Physicians
General Principles of Antimicrobial Prescribing ◼ Use only when clinically indicated ◼ Use only when risk/benefit balance is favorable ◼ Antibiotics are not a substitute for source control of infection ◼ Choose the narrowest spectrum drug that is effective: ◼ Escalation- For mild infections, start with single narrow spectrum agent and broaden up the coverage if treatment fail and as clinically indicated ◼ De-escalate- step down to the single narrow-spectrum agent as guided by the culture results and clinical picture ◼ Always be aware of local resistance patterns (antibiogram) ◼ Colonization does not always need systemic abx treatment ◼ Change from IV to oral in a timely manner (e-g afebrile ~48h/tolerating po/bio- available drug))
Colonization vs Infection ◼ Infection is suggested by signs of local inflammation AND infection PLUS ◼ Systemic sx of fever, chills, diaphoresis vomiting, hypotension, and leukocytosis or elevated procalcitonin.
Oral vs. Parenteral? ◼ Oral therapy is acceptable, provided that the infection is mild, drugs are highly bioavailable, the organisms are susceptible, and the patient will be compliant to the treatment. ◼ Examples of highly bioavailable drugs are clindamycin, ciprofloxacin, cephalexin, rifampin, trimethoprim and linezolid.
Antimicrobial Classes
Classification Of Antibiotics
Beta-Lactam Antibiotics ◼ Mechanism of action – Interfere with the synthesis of the bacterial cell wall- Bactericidal – Target the penicillin-binding proteins (PBPs) ◼ Advantages – Diverse spectrum of activity – IV and oral forms available – Favorable efficacy/toxicity profile – Good tissue penetration ◼ Disadvantages – Allergic reactions (up to 10% of patients) – Frequency of administration – Development of resistance – Only effective against rapidly growing organisms that synthesize that synthesize peptidoglycan. (Ineffective against mycobacteria.) – Share Immediate hypersensitivity reaction
Beta-Lactam Antibiotics ◼ Penicillins – Penicillin G – Amino-penicillins – Anti-staphylococcal penicillins* – Anti-pseudomonal penicillins* ◼ Cephalosporins ◼ Monobactams – Aztreonam ◼ Carbapenems – Imipenem/cilastatin, meropenem, ertapenem
Penicillins (PNC)
Natural Penicillins ◼ Narrow spectrum ◼ Indicated in place of broad spectrums for – S pyogenes Group A Strep (TSS/NF), S viridans, peptostrep – S pneumoniae sensitive to PCN ▪ For moderately resistant use ceftriaxone, cefotaxime ▪ High level PCN resistant S pneumo = must use vancomycin – C perfringens, C tetani, N meningitides, Listeria, Actinomycosis, B anthracis, Syphilis ◼ Penicillin G iv; Benzathine Penicillin G im = latent syphilis, S pyogenes pharyngitis ◼ PCN G (IV/IM;$12/day))►PCN V (Oral; PCN V; $0.52/day)
Aminopenicillins ◼ Moderately broad spectrum ◼ Urine excreted- dose adjust needed ◼ Amoxacillin (PO) AOM- outpatient – Acute bacterial sinusitis/otitis- outpatient – Fails to cover H influenza or Moraxella, which are common bugs in otitis, sinusitis→ if no improvement in 3 days, switch to broader drug→ amoxacillin- clavulanate – More convenient orally than ampicillin ◼ Ampicillin (IV) Listeria monocytogenes – Enterococci (preferred over vancomycin) – In endocarditis, combine w/ gentamicin – Proterus mirabilis – Salmonella, Shigella
Aminopenicillins ◼ Amoxacillin-clavulanate (Augmentin) (PO) ◼ Broad spectrum – Toxicity: diarrhea more than the others – Clavulanate is a β-lactamase inhibitor that helps against: ▪ MSSA ▪ Moraxella catarrhalis ▪ H influenzae – Frequently used to treat: ▪ Otitis media/Bacterial sinusitis ▪ UTI ▪ Bite wounds ◼ Ampicillin-sulbactam (Unasyn) (IV) – IV prep w/ same spectrum as augmentin – Sulbactam inhibits beta lactamase action
Anti-Staph PCN ◼ Narrow spectrum drugs ◼ Resist degradation by penicillinase Nafcillin iv, oxacillin iv, dicloxacillin, cloxacillin po ◼ Methicillin is rarely used due to toxicity. (Interstitial nephritis) CNS tox, marrow suppression-only used for sensitivity testing ◼ Recommended for – MSSA-( S pyogenes) – Soft tissue infection/Cellulitis/Surgical phlx./endocarditisdon’t use po for S aureus bacteremia ◼ ► Dicloxacillin ($0.87/day) ◼ ► Nafcillin ($15/day)
Anti-Pseudomonal PCN Carboxypenicillins, Ureidopenicillins ◼ Very broad spectrum. Renally cleared ◼ Zosyn (pipercillin/tazobactam) iv ◼ Timentin (Ticarcillin/clavulanate (iv) ◼ Resist gram negative β-lactamases, allows killing of: ◼ Pseudomonas (combined w/ an aminoglycoside) – Enterobacter,Morganella,Proteus,E. coli, klebsiella, serratia – Anaerobes- includes B.fragilis → requires high doses – Lower activity against gram positives (MSSA) – Recommended to treat – Mixed infections = MSSA, Gram neg organisms, and anaerobes including ▪ Nosocomial aspiration pneumonia ▪ Moderate/severe intra-abdominal infection ▪ Mixed soft tissue, bone infection ▪ ENT infections ▪ Gynecologic infections
Cephalosporins ◼ Bactericidal. Binds PBP. Require active bacterial growth to be cidal ◼ Semisynthetic B-lactams ◼ More resistant to B- lactamases ◼ More safer ◼ Broader spectrum (opportunistic infections (candidiasis, C. difficile colitis) ◼ 5-10% cross-sensitivity with pcn allergic pts ◼ If it was a delayed hypersensitivity rxn, cephalosporins used only if necessary, as allergic cross rxns to cephalosporins are rarely severe.
1st Generation Cephalosporins ◼ Narrow spectum ◼ renally excreted ◼ Spectrum: Most gram positive cocci ( Spectrum: Most gram positive cocci; Strep, S. aureus (MSSA) and GNB; E. coli, Proteus, Klebsiella. Oral cavity anaerobes- not B fragilis ◼ Recommended uses: Skin/soft tissue infection, surgical prophylaxis, UTI (community acquired/Preg) ◼ Standard for surgical prophylx ◼ Cephazolin (Ancef IV)) ◼ Cephalexin (Keflex PO), $0.78/day ◼ Cephradine – oral ◼ Cephadroxil 100% po absorption- longer dosing interval allowed
2nd Generation Cephalosporins ◼ Moderately broad spectrum ◼ Spectrum: – H influenzae, N meningitidis/gonorrheae, Moraxella – MSSA, nonenterococcal strep – E coli, Klebs, some Proteus strains: Cefoxitin, cefotetan are good – Anaerobes- B fragilis: cefoxitin, cefotetan are good ◼ Cefoxitin (mefoxin ), cefotetan recommended for – GU infx-PID combined w/ doxycycline (Chlamydia) – GI -Intra abdominal infection – Outpatient txt of uncomplicated UTIs – Mixed aerobe/anaerobe soft tissue – diabetic foot infections *Cefuroxime po/ (Ceftin; IV) *Not as effective against S. aureus as the 1st gen
3rd Generation Cephalosporins ◼ Coverage-Gram negative > gram positive. *MDR-Strep Pneumo (along with vancomycin) *Not anaerobes. *Acinetobacter/Enterobacter but not Serratia marcescens. *Ceftazidime active against pseudomonas. ◼ Oral cefpodoxime (vantin), cefdinar (omnicef ) ◼ Ceftriaxone (Rocephin; IM/IV) ◼ Cefotaxime (peds)
3rd Generation Cephalosporins Ceftriaxone (Rocephin) / Cefotaxime - Empiric txt: CAP, CA bact meningitis, N gonorrhoeae, MSSA infections, + gentamicin for bacterial endocarditis - QD-home iv therapy - crosses b-b-b - no dose adjustment in renal failure (CTX) ◼ Ceftizoxime-Covers larger % of B.fragilis than ceftriaxon ◼ Cefixime-2nd line for CAP, alternative to PCN for bacterial pharyngitis, Oral route; renal dosing ◼ Ceftazidime – Only 3rd generation w/ excellent activity vs Pseudomonas aeruginosa – Not good for S aureus, poor against B fragilis – Use for sever gram neg infections – Crosses b-b-b (Pseudomonas aeruginosa meningitis) – Resistance+++
3rd Generation Cephalosporins Ceftazidime/Avibactum (Avecaz) ◼ IV/Expensive/renally adjusted/restricted to ID ◼ Alternate for carbapenems for resistant gram-negative bacteria including Pseudomonas, AmpC- and extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae, and Klebsiella pneumoniae carbapenemase (KPC)–producing organisms. ◼ Intra-abdominal Infections ◼ Indicated in combination with metronidazole for complicated intra-abdominal infections (cIAIs) caused by susceptible gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, and Pseudomonas aeruginosa ◼ Urinary Tract Infections (Complicated) caused by resistant Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii complex, Proteus mirabilis, and Pseudomonas aeruginosa ◼ Bacterial Pneumonia ◼ HCAP/VAP- (HABP/VABP) -caused by susceptible gram negative microorganisms: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Haemophilus influenzae in patients aged ≥18 years
4th Generation Cephalosporins ◼ Cefepime is the only 4G available in USA (IV) ◼ Very broad spectrum ◼ Gram neg bacilli- Pseudomonas aeruginosa ◼ Excellent for S pneumoniae,S pyogenes, MSSA, Neisseria spp ◼ Not for Listeria, MRSA, or B fragilis (anaerobes) ◼ Recommended for: – Febrile neutropenic pts as single agent – Excellent agent for initial empiric coverage of nosocomial infections (Pneumonia-HCAP/VAP) – Crosses b-b-b of inflamed meninges (GN/PSA meningitis) – Renal adjust needed
5th Generation Cephalosporins Ceftaroline (Teflaro) IV ◼ Community-acquired bacterial pneumonia (CABP) caused by: ◼ Streptococcus pneumoniae, ◼ Methicillin-susceptible Staphylococcus aureus (MSSA ONLY) ◼ Haemophilus influenzae, ◼ Klebsiella pneumoniae, ◼ Klebsiella oxytoca, and ◼ Escherichia coli. ◼ Acute bacterial Skin and soft tissue infections (ABBSI) caused by the following organisms: ◼ methicillin-susceptible (MSSA) and methicillin-resistant isolates Staphylococcus aureus (MRSA) ◼ Streptococcus pyogenes, ◼ Streptococcus agalactiae, ◼ Escherichia coli, ◼ Klebsiella pneumoniae, and ◼ Klebsiella oxytoca.
5th Generation Cephalosporins Ceftolozane-Tazobactum ( Zerbaxa) IV ◼ (HABP/VABP) -Hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia) Caused by the following susceptible Gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Serratia marcescens. ◼ (cUTI)-Complicated urinary tract infections including pyelonephritis, caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa. ◼ (cIAI) Complicated intra-abdominal infections- in combination with metronidazole caused by the following susceptible Gram-negative and Gram-positive microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius.
Monobactams Aztreonam (Azactam) B-lactamase resistant. ◼ Narrow antibacterial spectrum. ◼ Aerobic gram negative rods including Pseudomonas aeruginosa. ◼ Non-nephrotoxic replacement for aminoglycosides, but no synergy w/ penicillins for Enterococcus ◼ Ineffective against gram positive and anaerobic organisms. ◼ Safe alternative for pcn allergic patients as very little cross- allergenicity with other beta-lactam abx ◼ Recommended for: – Gram neg bacteremia, nosocomial pneumonia, pyelonephritis, intra- abdominal infections (With Flagyl) – For empiric txt of seriously ill patient→ combine w/ vancomycin, clindamycin, erythromycin, or a PCN to cover possible gram positives/anaerobes. ◼ Cleared by kidneys; penetrates tissue well; crosses b-b-b ◼ Adverse reactions; Gram positive superinfection (20-30%)
Aztreonam and Avibactam (ATM-AVI) ◼ Aztreonam is a monobactam that has activity against metallo β-lactamase (MBL)-producing Gram-negative pathogens. Although aztreonam is bactericidal against MBL, these pathogens commonly express serine-β- lactamases that can inactivate aztreonam. Thus, the combination with avibactam inhibits the serine-β-lactamases and allows aztreonam to work against MBL-producing pathogens ◼ (FDA) has granted Qualified Infectious Disease Product (QIDP) designation and Fast Track designation for the treatment of complicated intra-abdominal infections (cIAI), complicated urinary tract infections (cUTI), and hospital-acquired bacterial pneumonia (HABP)/ventilator- associated bacterial pneumonia (VABP). ◼ The Company is currently investigating ATM-AVI in phase 3 trials as a fixed-dose, intravenous combination therapy.
Carbapenems ◼ Very Broad spectrum B-lactam (gram +/gram – /anaerobic bacteria) - kills nearly all normal flora > increases risk of nosocomial infection w/ resistant pathogens ◼ Kills Pseudomonas (not ertapenem) and ESBL / GN bacteria (+ amikacin) ◼ Kills pathogens not covered by cephalosporins: Listeria, Nocardia, Legionella, MAI, Enterococcus ◼ Inhibits mucopeptide synthesis in the bacterial cell wall results in the formation of defective cell walls and osmotically unstable organism which leads to cell lysis. ◼ Carbapenem resistance is emerging worldwide, particularly in Pseudo. aeruginosa, Acinetobacter baumannii (CRAB- Carb-Resis A. Baum), and Enterobacteriaceae spp. (CRE- Carb-Resist Enterobact.) ◼ Resistance is mediated through production β-lactamases (carbapenemases), loss of porins, efflux pumps and alternation in PBPs. ◼ Txt recommended for – Seriously ill pt/GN septic shock – Empiric txt for sepsis, especially if resistant – polymicrobial bacteremia suspected ◼ Toxicities: Immediate hypersensitivity rxns are the most frequent toxicity; 3-7% of PCN allergic pts cross react . Risk of seizure in pt w/ CNS lesion, hx of seizure, renal insufficiency, old age, excessive doses. Seizure- Decreased incidence for meropenem compared to imipenem. ◼ C. difficile associated diarrhea ◼ Drug rash with eosinophilia
Meropenem ◼ Meropenem is considered drug of choice for the treatment of ESBL producing organisms. (lower mortality compared to zosyn) ◼ Slightly more active than imipenem/cilastatin against P. aeruginosa ◼ Advantage over imipenem for the treatment of meningitis with minimal seizure complications. ◼ MRSA, S. maltophilia, and E. faecium are generally resistant to meropenem. ◼ Intra-abdominal infections. (including Necrotizing pancreatitis) ◼ Complicated skin and soft tissue infections caused by S. aureus (MSSA only), S. pyogenes, Streptococcus agalactiae, viridans group streptococci,E. faecalis (not VRE), P. aeruginosa, E. coli, Proteus mirabilis, B. fragilis, and Peptostreptococcus species. ◼ Meningitis (children 3 months of age and older) caused by S. pneumoniae, H. influenzae, and N. meningitidis. ◼ Hospital-acquired pneumonia ◼ Obstetric and gynecologic infections ◼ Febrile neutropenia ◼ Sepsis and GN bacteremia ◼ Endocarditis caused by Gram-negative organisms (P. aeruginosa)
Meropenem/Vaborbactam(Vabomere) ◼ Combination of meropenem and vaborbactam, a beta- lactamase inhibitor. ◼ Best against KCPs (Klebsiella pneumoniae carbapenemase) or CRE (carbapenem-resistant Enterobacteriaceae) ◼ Higher cure rates compared to carbapenem alone, aminoglycoside, polymyxin B, colistin, tigecycline, or ceftazidime/avibactam (monotherapy only). ◼ Does not enhance activity against Pseudomonas aeruginosa or Acinetobacter spp. due to eflux/porin mutations[ ◼ Treatment of complicated urinary tract infections (cUTIs) including pyelonephritis
Imipenem/Cilastatin (Primaxin) ◼ Similar spectrum of coverage like meropenem but slightly less active against P. aeruginosa and more prone for GN resistance ◼ More active against E. faecalis, Nocardia, non-TB mycobacteria compared to meropenem. ◼ Imipenem in combination with vancomycin was less nephrotoxic than the combination of meropenem with vancomycin ◼ MRSA, S. maltophilia, Burkholderia cepacia and E. faecium are generally resistant to imipenem/cilastin ◼ Skin/soft tissue infections (not MRSA) ◼ Lower respiratory tract infections (pneumonia, bronchitis, COPD exacerbations) caused by S. pneumoniae and H. influenzae. ◼ Gynecologic infections ◼ Intra-abdominal infections ◼ Uncomplicated and complicated urinary tract infections (pyelonephritis) ◼ Bacterial endocarditis ◼ Bacterial septicemia ◼ Bone/joint infections ◼ Often used for the treatment of M. abscessus complex in combination with other agents,
Ertapenem (Invanz) ◼ Active against all anaerobes and many aerobic Gram-positive and Gram-negative organisms including extended spectrum beta-lactamase (ESBL) producing K. pneumoniae and E. coli ◼ It has poor activity vs P. aeruginosa and Acinetobacter ◼ It is not active against E. faecium and E. faecalis, S. epidermidis, MRSA, B. cepacia and S. maltophilia. ◼ Not recommended for meningitis because of poor CNS penetration. ◼ Convenient once-a-day outpatient IV antibiotic for mild to moderate infections ◼ Complicated intra-abdominal infections ◼ Community-acquired pneumonia (CAP) ◼ Complicated urinary tract infections ◼ Complicated skin and skin structure infections, including diabetic foot infections without osteomyelitis ◼ Elective colorectal surgical prophylaxis ◼ Acute pelvic infections (postpartum, septic abortion, and post-surgical gynecologic infections)
Doripenem (Doribax) ◼ Complicated intra-abdominal infection ◼ Complicated UTI ◼ Skin and soft tissue infections (not due to MRSA) ◼ Neutropenic fever ◼ Not recommended for ventilator-associated pneumonia ◼ active against all anaerobes and most GNB, including P. aeruginosa, inducible chromosomal beta-lactamases, and ESBL-producing organismssimilar spectrum of activity to imipenem/cilastatin and meropenem. ◼ Doripenem has an activity similar to that of meropenem against Pseudomonas, but 2 dilutions superior to imipenem ◼ Doripenem exhibited the greatest ability to prevent the emergence of the carbapenem-resistant mutant in vitro. ◼ Low risk of EEG changes and seizures in contrast to imipenem
Polymyxin/Polymycin (Colistin) Colistimethate sodium ◼ Colistin (polymyxin E) is an antibiotic that is structurally and pharmacologically related to polymyxin B ◼ Bactericidal - second line agent for VAP. ◼ Active against virtually all P. aeruginosa and Acinetobacter strains but Proteus spp. are usually resistant and may cause superinfection. ◼ Almost always used in combination since colistin monotherapy is probably suboptimal. ◼ May be synergistic with, carbapenems, tigecycline, and glycopeptides such as telavancin and rifampin. ◼ Inhaled use with resistant Pseudomonas aeruginosa or other Gram negative MDR infections in nosocomial pneumonia ◼ life-threatening infections caused by Gram-negative bacilli that are resistant to all available agents (MDR). ◼ Nephrotoxicity (ATN) reversible, Clostridium difficile-associated diarrhea. neurotoxic- neuromuscular blockade, which may result in respiratory arrest, ◼ Inactive against gram-positive bacteria, fungi, and viruses.
Fluoroquinolones ◼ Advantages – >90% oral bioavailablitiy – IV and oral dosage forms available – Once daily dosing (except ciprofloxacin) – Broad spectrum of activity – Good tissue/bone penetration – Favorable efficacy/toxicity profile ◼ Disadvantages – Development of resistance (QREC/QRGC) – NOT RECOMMENDED IN < 18. children – Limit use in pregnancy, nursing mothers – Impaired absorption if co-administered with multivalent cations – Arthropathy, tendonitis due to cartilage damage – Prolonged QT interval – C.Diff colitis (Galti > Levo)
Antibiotic Spectrum ◼ Effective vs. gram +, gram --, atypicals ◼ Respiratory quinolones (levofloxacin). Active against Strep pneumo (including penicillin--resistant forms), S. aureus (including some MRSA), H. flu, M. cat M. cat and atypicals ◼ Antipseudomonas (ciprofloxacin/Delafloxacin) ◼ Decreased activity against anaerobes. (Some with gati/moxi) ◼ Delaflox, Levo and Moxi have increased Staph activity ◼ Topicals used for otitis media/bact conjunctivitis
Fluoroquinolones Side Effects ◼ Fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions. ◼ Tendinitis, tendon rupture, with increased risk in elderly, patients taking corticosteroids and in patients with organ transplants ◼ Peripheral neuropathy ◼ CNS reactions such as seizures, increased intracranial pressure, dizziness, and tremors ◼ Exacerbation of myasthenia gravis, including death and requirement for ventilator ◼ increased risk of psychiatric adverse reactions, including toxic psychosis; hallucinations, or paranoia; depression, or suicidal thoughts or acts; delirium, disorientation, confusion, or disturbances in attention; anxiety, agitation, or nervousness; insomnia or nightmares; memory impairment. These adverse reactions may occur following the first dose. ◼ Clostridium difficile-associated diarrhea has been reported with severity ranging from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs. ◼ Increased risk of aortic aneurysm and dissection, especially in elderly patients. In patients with a known aortic aneurysm or patients who are at greater risk for aortic aneurysms, ◼ Dysglycemia- disturbances of blood glucose, including symptomatic hyperglycemia and hypoglycemia. Severe cases of hypoglycemia resulting in coma or death have been reported with other fluoroquinolones. Monitor blood glucose carefully in diabetic patients receiving oral hypoglycemic agents or insulin.
Ciprofloxacin ◼ Mainly gram neg bacilli, less GP coverage- no anaerobes ◼ Infections below the diaphragm ◼ Excellent against: – Pseudomonas aeruginosa- and other GNB – Salmonella, Shigella, Yersinia, Campylobacter ◼ Recommended txt for: – UTI/Pyelonephritis – Prostatitis, concentrates in prostate – Travelers diarrhea – Salmonella (typhoid fever) – Salmonella gastroenteritis if abx needed – Cat scratch dz – Bartonella henselae
Levofloxacin ◼ Better GP than cipro (Strep pneumo, S aureus, S pyogenes) ◼ Similar GN to cipro- Less active against pseudomonas ◼ Covers atypicals () –Not anaerobes ◼ Active for: ◼ Primary therapy for: – CAP in otherwise healthy adults – mild-moderate severity – Cases of levoquin resistant Strep pneumo emerging ◼ Alternative txt: soft tissue infections w/ mixed infection of G+/- ( as good as augmentin)- Anti-inflammatory properties ◼ MDR- and XDR TB (Multi-drug resist & Extremely drug-resist) TB ◼ Excellent bioavailability- PO/IV (750 mg dose)- renal dose adjustment
Moxifloxacin (Avelox) ◼ Best Anaerobic and mycobacterial activity among its class. ◼ Strep pneumo, H.influenza, Staph epi, MSSA, Moraxella, Legionella, Mycoplasma, Chlamydia, Rickettsia ◼ Shigella, Salmonella, Campylobacter, Yersinia, Vibrio cholera ◼ E coli, Proteus, Klebsiella, Morgagnella, Citrobacter, Enterobacter, Priovidentia ◼ 400 mg PO/IV qDay / no renal dose adjustment ◼ Indicated for: ◼ Acute Bacterial Sinusitis ◼ Community-Acquired Pneumonia- CAP ◼ Acute infectious Exacerbations of Chronic Bronchitis ◼ Skin & Skin Structure Intra-abdominal Infections ◼ Intra-abdominal Infections (only mild-moderate)- Add Flagyl for severe infections. ◼ MDR- TB (multi-drug resist TB and MAC (in combination of other drugs) ◼ Opthalmcic (Bacterial conjunctivitis) ◼ Pneumonic & Septicemic Plague ◼ Do not use for UTI- low urinary concentration. ◼ Less interaction with anticoagulants then other FQ ◼ May cause false positive opiate screening
Delafloxacin (Baxdela) ◼ Newest FQ with broad spectrum of activity against MRSA and Pseudomonas ◼ Acute bacterial skin and skin structure infections (ABSSSI) caused by the following susceptible microorganisms: Staphylococcus aureus (MRSA and MSSA), Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), Streptococcus pyogenes, and Enterococcus faecalis, Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa. ◼ Community-acquired bacterial pneumonia (CABP) caused by the following susceptible microorganisms: Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible [MSSA] isolates only), Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, Chlamydia pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae. ◼ Available as 450mg tablets and as 300mg IV dose.
Tetracyclines doxycycline/Minocycline ◼ Bacteriostatic- inhibit protein synthesis by mainly binding to 30S ribosomal subunit and blocking binding of aminoacyl transfer-RNA. ◼ Widely distributed into body tissues and fluids including pleural fluid, bronchial secretions, sputum, ascitic fluid, synovial fluid, aqueous and vitreous humor, and prostatic fluid. Poor CNS penetration. ◼ Cleared by liver; no renal dose adjustment needed. Doxycycline preferred in pts with renal insufficiency. ◼ May cause: – GI upset and diarrhea – Stains, deforms teeth in children < 8 yrs (including in fetuses when given to pregnant women). Contraindicated in pregnancy. – Note: short course doxycycline was not associated with any dental staining. – Hepatotoxicity (dose related, especially seen in pregnant women, pts w/ renal insufficiency, and with the use of expired medication) – Worsening azotemia (increased in patients with renal failure). – Esophageal ulcerations (pill-induced, avoid by not lying down after ingesting pill x 30 min). – Candidiasis (thrush and vaginitis) – Photosensitivity – Food interferes w/ absorption- impaired by calcium, magnesium antacids, milk, multivitamins – Minocycline- dizziness or vertigo
Clinical Indications – CAP (with Ceftriaxone to cover atypicals)- safe in patients with prolonged QTc. – Skin and soft tissue infections due to S. aureus including MRSA. ( Micocycline > Doxy against MRSA but less effective for Strep spp. – IV minocycline for acinetobacter infections after confirmation of minocycline in vitro susceptibility. – Bite wounds. PCN allergic patients. – Psittacosis caused by Chlamydia psittaci – Brucellosis: doxy + gentamycin = txt of choice – Vibrio infections – Borreliosis- Lyme diz, Relapsing fever – Rickettsial infections (Rocky mountain spotted fever (RMSF), spotted fever, Q fever, typhus fever, tick fevers , ehrlichiosis – Leptospirosis – Sexually Transmitted Infections: – Nongonococcal urethritis caused by Ureaplasma urealyticum – Syphilis in PCN allergic patients – PID + other abx in combo, endocervical or rectal infections, epididymitis, urethritis caused by Chlamydia trachomatis – Lymphogranuloma venereum caused by Chlamydia spp. – Trachoma, inclusion conjunctivitis cause by C. trachomatis. – Granuloma inguinale caused by Calymmatobacterium granulomatis – Anthrax – Bacillary angiomatosis: 100 mg twice daily x >3mos; – Malaria prophylaxis – *Tetracycline has role for the treatment of susceptible organisms causing UTIs since it achieves good urinary levels compared to the hepatically metabolized doxycycline, minocycline and tigecycline.
Tigecycline (Tygacil) ◼ Novel analog of minocycline-unaffected by tetracycline mechanisms of resistance ◼ Bacteriostatic agent that inhibits protein synthesis through 30s ribosomal binding thereby blocking aminocyl-tRNA. ◼ Very broad Spectrum of activity includes anaerobes, many MDR Gram-positive cocci (vancomycin-susceptible E. faecalis, VRE (E. faecium), MSSA/MRSA, S. pyogenes) and Gram-negative bacilli (ESBL /CRE-Carbapenem Resistant Enterobacteria/ CRAB-Carb-resist A. Baumanii) with the exception of Pseudomonas, Proteus, and Providencia. ◼ Complicated skin and skin structure infections ◼ Complicated intra-abdominal infections (as a single agent) ◼ CAP caused by S. pneumoniae (PCN-susceptible isolates), H. influenzae (beta-lactamase negative isolates), and Legionella pneumophila. (Last resort) ◼ HAP/VAP due to MDR GNR, but high rates of clinical failure .In critically ill patients, consider using tigecycline in combination with carbapenem or colistin. ◼ Has activity against Clostridium difficile, appears to be low risk for causing CDI. Some role as ancillary treatment of severe CDI. ◼ Avoid in severe infections +/- bacteremia. Should be combined with a second agent (e.g. colistin, carbapenem) ◼ Less reliable in UTI ◼ 100mg IV x 1 (load), then 50mg IV q12h x 5-14 days. (Higher doses in severe infecx)
Macrolides ◼ Drugs – Erythromycin (IV /Oral ) – Clarithromycin (Biaxin; IV/Oral ) – Azithromycin ((Zithromax, iv/po Z-PAK) ◼ Spectrum of activity – S. pneumoniae, S. aureus, H. influenzae, M. catarrhalis, N. gonorrhoeae, M. pneumoniae, Legionella sp., Chlamydia sp. Bordetella, Treponema, Bordetella – Clarithromycin: ►Similar to erythromycin. Increased activity against gram negatives (H. H. flu, Moraxellaflu, Moraxella) and atypicals. – Azithromycin:Azithromycin:►Decreased activity against gram positive cocci. .►Increased activity against Increased activity against H. fluH. fluand and M. catM ◼ Azithro preferred over erythromycin for – Legionella pneumophila- – MAI- can be used alone as prophylaxis in HIV pt w/ CD4 < 100 – Chancroid: single high dose 1gm is effective – C trachomatis urethritis, cervicitis, single 1gm dose – Ureaplasma urealyticum urethritis, single 1 gm dose
Macrolides ◼ Mechanism of action – Inhibits RNA-dependent protein synthesis by binding to the 50S ribosome ◼ Advantages – Convenient dosing schedule – Minimal renal elimination (no dose adjustment) – Good tissue penetration – IV and oral dosage forms available ◼ Disadvantages – Inhibits the CYP P450 system (clarithromycin) – GI side effects (erytho-much less with azithromycin) ◼ Clinical uses – Upper and lower respiratory tract infections – STDs(pelvic inflammatory disease, gonorrhea, Syphilis?) – Skin and soft tissue infections – MAC (mycobacterium avium) prophylaxis and treatment in HIV/ CD4 count < 100
Aminoglycosides ◼ Drugs – Gentamicin, tobramycin, amikacin ◼ Mechanism of action – Binds to 30S ribosome, interfering with the genetic code, and inhibiting protein synthesis ◼ Spectrum of activity – Mostly gram negatives – S. aureus (MSSA/MRSA),enterococcus fecalis, strep viridins,CNS (low dose synergy with PCN/VANCO) ◼ Clinical uses – Empiric txt severely ill w/ sepsis syndrome; combination use gives broad coverage for gram neg bacilli – In combination with beta-lactam for P. aeruginosa – In combination with beta-lactam or vancomycin for prophylaxis/treatment of endocarditis – Amikacin should be reserved for organisms resistant to gent and tobra or likely ESBL +VE. – Tularemia, Yersinia pestis; Streptomycin or gentamicin ◼ Streptomycin most effective drug for Yersinia pestis ◼ Spectinomycin effectively kills many strains of N gonorrhoeae
Aminoglycosides ◼ Advantages – Rapidly bactericidal – Inexpensive/low resistance profile – Exhibit synergy and post antibiotic effect – Concentration dependent bactericidal activity. They require a high peak/MIC ratio for bacterial killing. – Aminoglycosides have a post-antibiotic effect. They inhibit bacterial growth even after drug concentrations decrease to undetectable levels. ◼ Disadvantages – Renal toxicity, ototoxicity, neuromuscular blockade (minimized with once- daily dosing) – Do not cross biological membranes well/lung, pleura/soft tissues. – Require monitoring of drug levels – Gentamicin ($4.28/day),($4.28/day),Tobramycin ($6.77/day),($6.77/day),Amikacin ($7.81/day).($7.81/day). – (Additional $21.00/day (Additional $21.00/day with serum levels)with serum levels) ◼ Nebulized (Tobramycin 300 mg q 12h or)amikacin 500 mgs q12h ◼ Premed with albuterol to prevent bronchospasm ◼ (no need for therapeutic levels as not systemically absorbed
Aminoglycosides ◼ (Extended interval dosing-EID) ◼ Once-a-day dosing Gentamicin, tobramycin, amikacin – Gent 5-7mg/kg q24h (trough level at 24h <1 mcg/ml) – Equal or less nephrotoxic/ototoxic than conventional dosing
Vancomycin (IV) ◼ First line treatment of serious or severe infections caused by MRSA ◼ For treatment of serious infections caused by beta-lactam-resistant Gram- positive microorganisms (staph/strep/enterococcus) or in patients who have serious allergies to beta-lactam antimicrobials. ◼ Skin/soft tissue and bone and joint infections, including hardware- associated infections ◼ Pneumonia ◼ Septicemia and Endocarditis due to Gram-positive organisms ◼ Meningitis, CNS shunt infections ◼ No GN cover . Narrow spectrum ◼ Synergy with aminoglycosides. ◼ Antibiotic lock for cath-related blood stream infections (prophylactic or salvage therapy) ◼ Impregnated beads/cement in ortho hardware-related infections
Vancomycin (IV) ◼ Prophylaxis for endocarditis following certain procedures in pts at high risk for endocarditis. ◼ Prophylaxis for major surgical procedures involving implantation of prosthetic materials or devices (e.g., cardiac and vascular procedures and total hip replacement. ◼ A single dose of vancomycin administered immediately before surgery is sufficient unless the procedure lasts greater than 6 hrs, in which case the dose should be repeated. Prophylaxis should be discontinued after a maximum of 2 doses. Watch for: ◼ Red-man syndrome: flushing over chest/face +/- hypotension and pruritis ◼ Infusion over > 60 min/ pretreatment w/ antihistamine may reverse or prevent. ◼ Renal function impairment ◼ Most often implicated when given with concomitant aminoglycosides and piperacillin/tazobactam (zosyn) ◼ Associated with higher total daily doses, higher trough range, and prolonged therapy.
USUAL ADULT DOSING ◼ MRSA and other Gram-positive organisms: ◼ Typical-dose vancomycin: 15 mg/kg IV q12h ◼ Dose range is 15 - 20 mg/kg IV q8 - 12h and is dependent on patient creatinine clearance. ◼ Age, weight and site of infection should also be taken into consideration. ◼ Loading dose: 20 - 25 mg/kg ◼ Consider for critically ill patients, also endocarditis, VAP and CNS infections. ◼ Therapeutic drug monitoring: trough concentrations goals ◼ Troughs should be > 10 mcg/mL to prevent the development of resistance in S. aureus ◼ Skin and skin structure infections, neutropenic fever and non-S. aureus bacteremia: 10 - 15 mcg/mL ◼ Bacteremia, endocarditis, pneumonia, bone/joint infections, and meningitis: 15 - 20 mcg/mL ◼ Draw trough 30 - 60 minutes prior to the 4th or 5th dose of dosing regimen. ◼ Peak: no role in monitoring routinely
ADULT RENAL DOSING ◼ DOSING FOR GLOMERULAR FILTRATION OF 50-80 ◼ GFR >60 ml/min: Give 20 - 25 mg/kg loading dose if indicated, followed by 15 mg/kg IV q12h. Monitor serum trough concentrations; target Cmin > 10 mcg/ml. ◼ DOSING FOR GLOMERULAR FILTRATION OF 10-50 ◼ GFR 30-59 ml/min: Give 20 – 25 mg/kg loading dose if indicated, followed by 15 mg/kg IV q24h. Monitor serum trough concentrations; target Cmin > 10 mcg/ml. ◼ GFR 15-29 ml/min: Give 20 – 25 mg/kg loading dose if indicated, followed by 15 mg/kg IV q48h. Monitor serum trough concentrations; target Cmin > 10 mcg/ml. ◼ DOSING FOR GLOMERULAR FILTRATION OF < 10 ML/MIN ◼ 15 - 20 mg/kg IV, then redose based on serum concentrations. DOSING IN HEMODIALYSIS ◼ 15 - 20 mg/kg, loading dose then redose based on serum concentrations before dialysis ◼ Most require 5 - 10 mg/kg IV post-dialysis to maintain serum concentrations within goal range. ◼ Higher doses may be required in patients with residual renal function. DOSING IN PERITONEAL DIALYSIS ◼ 15 - 20 mg/kg IV x1 dose, the redose based on serum concentrations. ◼ Most patients will require a dose every 72 - 96 hours. Patients with residual renal function may require more frequent dosing. ◼ Alternatively, vancomycin 1 g can be given intraperitoneally followed by 30 mg/L dialysate.
New lipoglycopeptides ◼ Dalbavancin, Oritavancin and Telavancin ◼ Semisynthetic lipoglycopeptides (compared to Vancomycin, a glycopeptide antibiotic), for infections caused by multi-drug-resistant Gram-positive pathogens (vancomycin-resistant Staphylococcus aureus, MRSA, and Staph. epidermidis, Streptococcus spp ) ◼ Enterococci exhibiting the VanA phenotype (resistance to both vancomycin and teicoplanin) are resistant to both dalbavancin and telavancin, while oritavancin retains activity. ◼ All three exhibits activity against VanB vancomycin-resistant enterococci. ◼ Indicated in complicated skin and skin structure infections (cSSSIs) ◼ The most common adverse effects reported with dalbavancin use included nausea, diarrhea and constipation, while injection site reactions, fever and diarrhea were commonly observed with oritavancin therapy. ◼ All three of these agents are promising alternatives for the treatment of cSSSIs in cases where more economical options such as vancomycin have been ineffective, in cases of reduced vancomycin susceptibility or resistance, or where vancomycin use has been associated with adverse events
Anti-anaerobic Agents Metronidazole (Flagyl) – Gold standard anti-anaerobic agent. – Active against almost all anaerobes with exception of Actinomyces, Propionibacterium acnes, and Lactobacillus spp. – Oral: 500 mg q8-12h or IV 500 mg IV q8-12h – First-line agent for giardiasis, trichomoniasis, and amebiasis. – Amebiasis: 750 mg PO q8h x 5-10 d/ Giardiasis: 250 mg PO q8h x 5-10 d – H. pylori - resistance up to 20-30%. High metronidazole doses (1.5g/d) may overcome resistance. – Intra-abdominal infections. – C. difficile associated colitis- MILD (but not severe; oral vancomycin preferred, may add/substitute iv flagyl to oral vanco if severe colitis, ileus or patient NPO ) – C. difficile colitis: 500 mg PO/IV q8h x 10-14 d – Brain abscess- (In combination of other appropriate abx) – Bacterial vaginosis: 500 mg twice daily PO x 7d or Flagyl ER 750 mg PO once daily x 7d – Trichomoniasis: single 2 gm x 1 dose or 500 mg PO twice-daily x 7 d (more effective) – Toxicity: disulfram reaction/ P. Neuropathy chronic use – Interaction with warfarin/antiepileptics/Lopinavir and ritonovir
Anti-anaerobic Agents Clindamycin ◼ Inhibits protein synthesis by binding to 50S ribosomal subunits, interfering with transpeptidation and early chain termination. ◼ Distributed to many body tissues and fluids including ascites fluid, pleural fluid, synovial fluid, bone, bile and saliva. Poor CNS penetration. ◼ Active against most Gram-positive cocci (except Enterococcus), including Strep, MSSA, and most community-acquired MRSA (if CA-MRSA is resistant to erythromycin, D-test should be performed to confirm clindamycin sensitivity). ◼ Anaerobic gram-negative bacilli. Increasing resistance seen with B. fragilis. ◼ No GN coverage. ◼ May cause: Diarrhea (not due to C. difficile): occurs in 10-30%, commonly develops on days 4-9 of treatment and typically resolves 14 days after stopping the antibiotic ◼ C. difficile colitis: ~6%. Prescribe with caution in individuals with risk/history of C. diff. ◼ GI intolerance: nausea, vomiting and anorexia ◼ Generalized morbilliform rash
Clinical Indications & Doses ◼ Anti-toxin: Clindamycin is frequently added to beta-lactam antibiotics for severe infections caused by MRSA, S. pyogenes (Toxic shock syndrome), C. perfringens to suppresses toxin production. ◼ Skin and soft tissue infections (including animal or human bites): 300-450 mg PO q6h-8h or 600 mg IV q8h ◼ CA-MRSA- often used as an oral treatment option for soft tissue infection ◼ Necrotizing fasciitis including gangrene: 600-900 mg IV q8h ◼ Osteomyelitis: 600-900 mg IV q8h or 300-450 mg PO q6h- often used as step-down oral therapy, but rarely used as IV therapy. ◼ Surgical prophylaxis in contaminated wounds ( Gram pos/anaerobes) ◼ Aspiration Pneumonia- (empyema, and lung abscess) ◼ Acute bacterial sinusitis: 300 mg PO q6h ◼ ENT- Deep neck space infections, chronic tonsillo--pharyngitis, odontogenic abscesses. ◼ Actinomycosis: 600 mg IV q 8h x 2-6 weeks, then clindamycin 300 mg PO q6h x 6-12 months ◼ Pelvic inflammatory disease (endometritis, nongonococcal tubo-ovarian abscess, pelvic cellulitis, and post- surgical vaginal cuff infections) : 900 mg IV q8h (in combination with gentamicin) ◼ *Intrabdominal infex (Avoid due to B. Frag resistance- Flagyl is better), ◼ Endocarditis phlx in PCN allergic patients, ◼ PCP: clindamycin 600 mg IV q6h-q8h or 300-450 mg PO q6h-8h in combination with primaquine 15-30 mg (base) PO once daily. ( 2nd line in sulfa allergic patients) ◼ CNS toxoplasmosis: clindamycin 600 mg IV q6h or clindamycin 450 mg-600 mg PO q6h + pyrimethamine 200 mg PO loading dose, then 50-7 5mg PO q24hd + leucovorin 10-20 mg q24h ◼ Malaria: (in pregnant women)
Clindamycin Topical applications: ◼ Bacterial vaginosis ◼ Vaginal ovules: 1 ovule (100 mg) x 3 days ◼ Cleocin (vaginal cream) : one full applicator (100 mg) inserted intra-vaginally daily for 3-7 days in non-pregnant patients and for fr 7 days in pregnant patients ◼ Clindesse (vaginal cream): one full applicator inserted intra-vaginally as a single dose at any time during the day in non-pregnant patients ◼ Acne vulgaris: ◼ Cleocin T (gel, solution, lotion): apply twice daily to the affected area. ◼ Evoclin (foam): apply once daily to the affected area / Clindagel (gel): apply once daily to the affected area ◼ Hidradenitis suppurativa: apply twice daily to the affected area
Clindamycin-In CA-MRSA ◼ In skin/soft tissue infections due to community- acquired MRSA (CA-MRSA) Clinda is ~80% effective (<20% in HCA-MRSA) Provided no inducible macrolide resistance. ◼ Check D test (Double disk diffusion) The clindamycin induction test is performed on Staphylococcus spp. that test resistant to erythromycin and susceptible to clindamycin using routine antimicrobial susceptibility test methods. ◼ Do not use Clinda if D-test is positive ◼ Avoid clinda if macrilodes are resistant in vitro sensitivity (Clinda- erythron Discordance) and D test is not done. ◼ Tetracyclines and Bactrim, although active against many MRSA, are not recommended treatments for suspected Group A Strep (GAS) infections. POSITIVE D-test Double-disk diffusion test (D test) demonstrating erythromycin disk induction of clindamycin resistance; a blunting of the zone of inhibition around the clindamycin disk is produced that forms a D shape (arrow).
Linezolid (Zyvox) ◼ Linezolid is an oxazolidinone antibiotic active against nearly all antibiotic resistant Gram-positive bacteria and has a good short-term side effect profile. ◼ Pneumonia, hospital-acquired caused by MRSA, MSSA, and S. pneumoniae. ◼ Linezolid may be considered for MRSA infections with documented vancomycin failure or intolerance. ◼ Infections due to vancomycin-resistant Enterococcus faecium (VRE), with or without concurrent bacteremia. ◼ Concomitant use of another anti-infective may be appropriate if the documented or presumptive pathogens include gram-negative bacteria /anaerobes ◼ Complicated and uncomplicated skin and skin structure infection including diabetic foot ulcers (without osteomyelitis). ◼ Linezolid has activity against tuberculosis, including multi-drug resistant (MDR) and extensively drug resistant (XDR) strains ◼ Most indications: 600 mg IV q 12 or PO twice-daily ◼ Reversible bone marrow suppression (thrombocytopenia, anemia, leucopenia). ◼ Serotonin syndrome reported with SSRI co-administration
Tedizolid ◼ A novel oxazolidinone antibiotic similar to linezolid, once-daily,covers most Gram-positive organisms including VRE and MRSA. ◼ FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible Gram-positive organisms (staphylococci, streptococci, and enterococci, including strains resistant to vancomycin, daptomycin, and linezolid) ◼ Compared to linezolid, tedizolid has been shown to have 4- to 16-fold greater activity against MSSA, MRSA, streptococci, and enterococci (VRE) ◼ dose and duration dependent bone marrow suppression slightly lower than linezolid ◼ both oral and iv formulations, (200 mg once daily) No dosing adjustments in patients with renal or hepatic impairment.
Daptomycin (Cubicin) ◼ Bactericidal against virtually all Gram-positive organisms including E. faecalis and E. faecium (including VRE), S. aureus (including MRSA), S. epidermidis (including MRSE), S. pyogenes, S. agalactiae, S. dysgalactiae, C. jeikeium. ◼ Inactive against gram-negative bacteria. ◼ The synergistic effect with several β-lactams with the greatest synergistic activity with ampicillin and ceftaroline ◼ Complicated skin and skin structure infections (MSSA and MRSA). ◼ S. aureus bacteremia, including right-sided endocarditis, caused by MSSA and MRSA, VRE. ◼ Endocarditis caused by Enterococcus spp. resistant to vancomycin,(VRE) penicillin and aminoglycosides ◼ VRE causing intra-abdominal infections, urinary tract infections, SST ◼ Should not be used for pneumonia due to high failure rates (drug binds to surfactant). ◼ Myopathy with CK Elevation, Pseudomembranous Enterocolitis , Anemia, Constipation, Diarrhea, Headache, Hypokalemia, Injection Site Sequelae,
Oral vancomycin ◼ Antibiotic-associated pseudomembranous colitis caused by C. difficile and enterocolitis caused by S. aureus (including MRSA) ◼ C. difficile colitis: 125mg PO q6h x 10 d. ◼ Higher doses (250-500mg PO q6h) may be given in the setting of severe disease and/or ileus. ◼ Vancomycin must be given orally for C. difficile infection as the IV formulation does not penetrate the bowel wall. ◼ Oral preparations are not systemically absorbed, as only intraluminal, these formulations will not treat any infection other than colitis. ◼ Vancomycin powder (IV formulation) can be reconstituted and given orally in lieu of capsules to decrease drug costs. ◼ Staphylococcal enterocolitis-500-2000 mg PO per day in 3-4 divided doses x 7-10 d
Fidaxomicin (Dificid) ◼ Treatment of C. difficile-associated infection (CDI) ◼ Inhibits C. difficile RNA polymerases. ◼ 200 mg twice daily with or without food x 10 days ◼ The global cure rate (addressing initial response and recurrences within 25 days) was better for fidaxomicin (75.5%) compared to vancomycin (63.7%) in studies ◼ Does not have benefit in reducing relapses in patients with the NAP-1 strain of C.Diff. ◼ Fidaxomicin-resistant C. difficile has been reported in a patient with recurrent CDI. ◼ Cost ~$2600/course (~25 times the cost of oral vancomycin (when IV form is given orally).
Nitrofurantoin (Macrobid) ◼ Mostly active against E. coli, Citrobacter spp., S. saprophyticus, and E. faecalis. ◼ Urinary tract infection, uncomplicated/ cystitis. ◼ UTIs- recurrent [women]/ch suppression (50-100 mg PO once daily) ◼ Asymptomatic bacteriuria in pregnancy ◼ Prophylaxis of UTI ◼ Don’t use in pyelonephritis due to poor penetration into renal parenchyma. ◼ Don’t use in patients with CrCl ≤ 60 ml/min. ◼ Don’t use in geriatric patients ≥ 65 years with a CrCl ≤ 30 (pulmonary toxicity) ◼ Associated with acute allergic pneumonitis w/ short-term treatment; interstitial fibrosis w/ long-term use ◼ Caution when used in G6PD-deficient patients
Fosfomycin ◼ Fosfomycin interferes with bacterial wall synthesis (Bactericidal) ◼ Broad-spectrum of activity includes all common uropathogenic bacteria ◼ VRE/ MRSA ◼ ESBL/ CRE-Carbapenemase-producing Enterobacteriaceae ◼ MDR Pseudomonas aeruginosa (more dependent on local antibiogram profiles) ◼ Oral dosing: (IV Fosfomycin is not approved for use in the USA) ◼ Uncomplicated UTI: 3 gm sachet PO x 1 dose - (FDA indication). ◼ Complicated UTI: 3 gm sachet PO every 2-3 days (up to 21 days) on an empty stomach preferred. ◼ Duration: typically, three doings ◼ May also administer as 0.5–1 g administered every 6–8 h, which may be better tolerated. ◼ Mix sachet powder in 120 mL of cool water until dissolved. ◼ DOSING FOR GLOMERULAR FILTRATION OF 10-50 ◼ (Don't use if GFR<10)- Re-dose after dialysis, due to removal during HD. ◼ Useful drug for the treatment of uncomplicated/resistant UTIs in the setting of pregnancy. (Cat B) ◼ Should not be used for severe pyelonephritis and urosepsis.

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Antibiotics overview

  • 1.
    Antibiotics An Overview Tahseen J.Siddiqui, M.D Chicago Infectious Disease Physicians
  • 2.
    General Principles ofAntimicrobial Prescribing ◼ Use only when clinically indicated ◼ Use only when risk/benefit balance is favorable ◼ Antibiotics are not a substitute for source control of infection ◼ Choose the narrowest spectrum drug that is effective: ◼ Escalation- For mild infections, start with single narrow spectrum agent and broaden up the coverage if treatment fail and as clinically indicated ◼ De-escalate- step down to the single narrow-spectrum agent as guided by the culture results and clinical picture ◼ Always be aware of local resistance patterns (antibiogram) ◼ Colonization does not always need systemic abx treatment ◼ Change from IV to oral in a timely manner (e-g afebrile ~48h/tolerating po/bio- available drug))
  • 3.
    Colonization vs Infection ◼Infection is suggested by signs of local inflammation AND infection PLUS ◼ Systemic sx of fever, chills, diaphoresis vomiting, hypotension, and leukocytosis or elevated procalcitonin.
  • 4.
    Oral vs. Parenteral? ◼Oral therapy is acceptable, provided that the infection is mild, drugs are highly bioavailable, the organisms are susceptible, and the patient will be compliant to the treatment. ◼ Examples of highly bioavailable drugs are clindamycin, ciprofloxacin, cephalexin, rifampin, trimethoprim and linezolid.
  • 5.
  • 6.
  • 7.
    Beta-Lactam Antibiotics ◼ Mechanismof action – Interfere with the synthesis of the bacterial cell wall- Bactericidal – Target the penicillin-binding proteins (PBPs) ◼ Advantages – Diverse spectrum of activity – IV and oral forms available – Favorable efficacy/toxicity profile – Good tissue penetration ◼ Disadvantages – Allergic reactions (up to 10% of patients) – Frequency of administration – Development of resistance – Only effective against rapidly growing organisms that synthesize that synthesize peptidoglycan. (Ineffective against mycobacteria.) – Share Immediate hypersensitivity reaction
  • 8.
    Beta-Lactam Antibiotics ◼ Penicillins –Penicillin G – Amino-penicillins – Anti-staphylococcal penicillins* – Anti-pseudomonal penicillins* ◼ Cephalosporins ◼ Monobactams – Aztreonam ◼ Carbapenems – Imipenem/cilastatin, meropenem, ertapenem
  • 9.
  • 10.
    Natural Penicillins ◼ Narrowspectrum ◼ Indicated in place of broad spectrums for – S pyogenes Group A Strep (TSS/NF), S viridans, peptostrep – S pneumoniae sensitive to PCN ▪ For moderately resistant use ceftriaxone, cefotaxime ▪ High level PCN resistant S pneumo = must use vancomycin – C perfringens, C tetani, N meningitides, Listeria, Actinomycosis, B anthracis, Syphilis ◼ Penicillin G iv; Benzathine Penicillin G im = latent syphilis, S pyogenes pharyngitis ◼ PCN G (IV/IM;$12/day))►PCN V (Oral; PCN V; $0.52/day)
  • 11.
    Aminopenicillins ◼ Moderately broadspectrum ◼ Urine excreted- dose adjust needed ◼ Amoxacillin (PO) AOM- outpatient – Acute bacterial sinusitis/otitis- outpatient – Fails to cover H influenza or Moraxella, which are common bugs in otitis, sinusitis→ if no improvement in 3 days, switch to broader drug→ amoxacillin- clavulanate – More convenient orally than ampicillin ◼ Ampicillin (IV) Listeria monocytogenes – Enterococci (preferred over vancomycin) – In endocarditis, combine w/ gentamicin – Proterus mirabilis – Salmonella, Shigella
  • 12.
    Aminopenicillins ◼ Amoxacillin-clavulanate (Augmentin)(PO) ◼ Broad spectrum – Toxicity: diarrhea more than the others – Clavulanate is a β-lactamase inhibitor that helps against: ▪ MSSA ▪ Moraxella catarrhalis ▪ H influenzae – Frequently used to treat: ▪ Otitis media/Bacterial sinusitis ▪ UTI ▪ Bite wounds ◼ Ampicillin-sulbactam (Unasyn) (IV) – IV prep w/ same spectrum as augmentin – Sulbactam inhibits beta lactamase action
  • 13.
    Anti-Staph PCN ◼ Narrowspectrum drugs ◼ Resist degradation by penicillinase Nafcillin iv, oxacillin iv, dicloxacillin, cloxacillin po ◼ Methicillin is rarely used due to toxicity. (Interstitial nephritis) CNS tox, marrow suppression-only used for sensitivity testing ◼ Recommended for – MSSA-( S pyogenes) – Soft tissue infection/Cellulitis/Surgical phlx./endocarditisdon’t use po for S aureus bacteremia ◼ ► Dicloxacillin ($0.87/day) ◼ ► Nafcillin ($15/day)
  • 14.
    Anti-Pseudomonal PCN Carboxypenicillins, Ureidopenicillins ◼Very broad spectrum. Renally cleared ◼ Zosyn (pipercillin/tazobactam) iv ◼ Timentin (Ticarcillin/clavulanate (iv) ◼ Resist gram negative β-lactamases, allows killing of: ◼ Pseudomonas (combined w/ an aminoglycoside) – Enterobacter,Morganella,Proteus,E. coli, klebsiella, serratia – Anaerobes- includes B.fragilis → requires high doses – Lower activity against gram positives (MSSA) – Recommended to treat – Mixed infections = MSSA, Gram neg organisms, and anaerobes including ▪ Nosocomial aspiration pneumonia ▪ Moderate/severe intra-abdominal infection ▪ Mixed soft tissue, bone infection ▪ ENT infections ▪ Gynecologic infections
  • 15.
    Cephalosporins ◼ Bactericidal. BindsPBP. Require active bacterial growth to be cidal ◼ Semisynthetic B-lactams ◼ More resistant to B- lactamases ◼ More safer ◼ Broader spectrum (opportunistic infections (candidiasis, C. difficile colitis) ◼ 5-10% cross-sensitivity with pcn allergic pts ◼ If it was a delayed hypersensitivity rxn, cephalosporins used only if necessary, as allergic cross rxns to cephalosporins are rarely severe.
  • 16.
    1st Generation Cephalosporins ◼Narrow spectum ◼ renally excreted ◼ Spectrum: Most gram positive cocci ( Spectrum: Most gram positive cocci; Strep, S. aureus (MSSA) and GNB; E. coli, Proteus, Klebsiella. Oral cavity anaerobes- not B fragilis ◼ Recommended uses: Skin/soft tissue infection, surgical prophylaxis, UTI (community acquired/Preg) ◼ Standard for surgical prophylx ◼ Cephazolin (Ancef IV)) ◼ Cephalexin (Keflex PO), $0.78/day ◼ Cephradine – oral ◼ Cephadroxil 100% po absorption- longer dosing interval allowed
  • 17.
    2nd Generation Cephalosporins ◼Moderately broad spectrum ◼ Spectrum: – H influenzae, N meningitidis/gonorrheae, Moraxella – MSSA, nonenterococcal strep – E coli, Klebs, some Proteus strains: Cefoxitin, cefotetan are good – Anaerobes- B fragilis: cefoxitin, cefotetan are good ◼ Cefoxitin (mefoxin ), cefotetan recommended for – GU infx-PID combined w/ doxycycline (Chlamydia) – GI -Intra abdominal infection – Outpatient txt of uncomplicated UTIs – Mixed aerobe/anaerobe soft tissue – diabetic foot infections *Cefuroxime po/ (Ceftin; IV) *Not as effective against S. aureus as the 1st gen
  • 18.
    3rd Generation Cephalosporins ◼Coverage-Gram negative > gram positive. *MDR-Strep Pneumo (along with vancomycin) *Not anaerobes. *Acinetobacter/Enterobacter but not Serratia marcescens. *Ceftazidime active against pseudomonas. ◼ Oral cefpodoxime (vantin), cefdinar (omnicef ) ◼ Ceftriaxone (Rocephin; IM/IV) ◼ Cefotaxime (peds)
  • 19.
    3rd Generation Cephalosporins Ceftriaxone(Rocephin) / Cefotaxime - Empiric txt: CAP, CA bact meningitis, N gonorrhoeae, MSSA infections, + gentamicin for bacterial endocarditis - QD-home iv therapy - crosses b-b-b - no dose adjustment in renal failure (CTX) ◼ Ceftizoxime-Covers larger % of B.fragilis than ceftriaxon ◼ Cefixime-2nd line for CAP, alternative to PCN for bacterial pharyngitis, Oral route; renal dosing ◼ Ceftazidime – Only 3rd generation w/ excellent activity vs Pseudomonas aeruginosa – Not good for S aureus, poor against B fragilis – Use for sever gram neg infections – Crosses b-b-b (Pseudomonas aeruginosa meningitis) – Resistance+++
  • 20.
    3rd Generation Cephalosporins Ceftazidime/Avibactum(Avecaz) ◼ IV/Expensive/renally adjusted/restricted to ID ◼ Alternate for carbapenems for resistant gram-negative bacteria including Pseudomonas, AmpC- and extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae, and Klebsiella pneumoniae carbapenemase (KPC)–producing organisms. ◼ Intra-abdominal Infections ◼ Indicated in combination with metronidazole for complicated intra-abdominal infections (cIAIs) caused by susceptible gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, and Pseudomonas aeruginosa ◼ Urinary Tract Infections (Complicated) caused by resistant Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii complex, Proteus mirabilis, and Pseudomonas aeruginosa ◼ Bacterial Pneumonia ◼ HCAP/VAP- (HABP/VABP) -caused by susceptible gram negative microorganisms: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Haemophilus influenzae in patients aged ≥18 years
  • 21.
    4th Generation Cephalosporins ◼Cefepime is the only 4G available in USA (IV) ◼ Very broad spectrum ◼ Gram neg bacilli- Pseudomonas aeruginosa ◼ Excellent for S pneumoniae,S pyogenes, MSSA, Neisseria spp ◼ Not for Listeria, MRSA, or B fragilis (anaerobes) ◼ Recommended for: – Febrile neutropenic pts as single agent – Excellent agent for initial empiric coverage of nosocomial infections (Pneumonia-HCAP/VAP) – Crosses b-b-b of inflamed meninges (GN/PSA meningitis) – Renal adjust needed
  • 22.
    5th Generation Cephalosporins Ceftaroline(Teflaro) IV ◼ Community-acquired bacterial pneumonia (CABP) caused by: ◼ Streptococcus pneumoniae, ◼ Methicillin-susceptible Staphylococcus aureus (MSSA ONLY) ◼ Haemophilus influenzae, ◼ Klebsiella pneumoniae, ◼ Klebsiella oxytoca, and ◼ Escherichia coli. ◼ Acute bacterial Skin and soft tissue infections (ABBSI) caused by the following organisms: ◼ methicillin-susceptible (MSSA) and methicillin-resistant isolates Staphylococcus aureus (MRSA) ◼ Streptococcus pyogenes, ◼ Streptococcus agalactiae, ◼ Escherichia coli, ◼ Klebsiella pneumoniae, and ◼ Klebsiella oxytoca.
  • 23.
    5th Generation Cephalosporins Ceftolozane-Tazobactum( Zerbaxa) IV ◼ (HABP/VABP) -Hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia) Caused by the following susceptible Gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Serratia marcescens. ◼ (cUTI)-Complicated urinary tract infections including pyelonephritis, caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa. ◼ (cIAI) Complicated intra-abdominal infections- in combination with metronidazole caused by the following susceptible Gram-negative and Gram-positive microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius.
  • 24.
    Monobactams Aztreonam (Azactam) B-lactamaseresistant. ◼ Narrow antibacterial spectrum. ◼ Aerobic gram negative rods including Pseudomonas aeruginosa. ◼ Non-nephrotoxic replacement for aminoglycosides, but no synergy w/ penicillins for Enterococcus ◼ Ineffective against gram positive and anaerobic organisms. ◼ Safe alternative for pcn allergic patients as very little cross- allergenicity with other beta-lactam abx ◼ Recommended for: – Gram neg bacteremia, nosocomial pneumonia, pyelonephritis, intra- abdominal infections (With Flagyl) – For empiric txt of seriously ill patient→ combine w/ vancomycin, clindamycin, erythromycin, or a PCN to cover possible gram positives/anaerobes. ◼ Cleared by kidneys; penetrates tissue well; crosses b-b-b ◼ Adverse reactions; Gram positive superinfection (20-30%)
  • 25.
    Aztreonam and Avibactam(ATM-AVI) ◼ Aztreonam is a monobactam that has activity against metallo β-lactamase (MBL)-producing Gram-negative pathogens. Although aztreonam is bactericidal against MBL, these pathogens commonly express serine-β- lactamases that can inactivate aztreonam. Thus, the combination with avibactam inhibits the serine-β-lactamases and allows aztreonam to work against MBL-producing pathogens ◼ (FDA) has granted Qualified Infectious Disease Product (QIDP) designation and Fast Track designation for the treatment of complicated intra-abdominal infections (cIAI), complicated urinary tract infections (cUTI), and hospital-acquired bacterial pneumonia (HABP)/ventilator- associated bacterial pneumonia (VABP). ◼ The Company is currently investigating ATM-AVI in phase 3 trials as a fixed-dose, intravenous combination therapy.
  • 26.
    Carbapenems ◼ Very Broadspectrum B-lactam (gram +/gram – /anaerobic bacteria) - kills nearly all normal flora > increases risk of nosocomial infection w/ resistant pathogens ◼ Kills Pseudomonas (not ertapenem) and ESBL / GN bacteria (+ amikacin) ◼ Kills pathogens not covered by cephalosporins: Listeria, Nocardia, Legionella, MAI, Enterococcus ◼ Inhibits mucopeptide synthesis in the bacterial cell wall results in the formation of defective cell walls and osmotically unstable organism which leads to cell lysis. ◼ Carbapenem resistance is emerging worldwide, particularly in Pseudo. aeruginosa, Acinetobacter baumannii (CRAB- Carb-Resis A. Baum), and Enterobacteriaceae spp. (CRE- Carb-Resist Enterobact.) ◼ Resistance is mediated through production β-lactamases (carbapenemases), loss of porins, efflux pumps and alternation in PBPs. ◼ Txt recommended for – Seriously ill pt/GN septic shock – Empiric txt for sepsis, especially if resistant – polymicrobial bacteremia suspected ◼ Toxicities: Immediate hypersensitivity rxns are the most frequent toxicity; 3-7% of PCN allergic pts cross react . Risk of seizure in pt w/ CNS lesion, hx of seizure, renal insufficiency, old age, excessive doses. Seizure- Decreased incidence for meropenem compared to imipenem. ◼ C. difficile associated diarrhea ◼ Drug rash with eosinophilia
  • 27.
    Meropenem ◼ Meropenem isconsidered drug of choice for the treatment of ESBL producing organisms. (lower mortality compared to zosyn) ◼ Slightly more active than imipenem/cilastatin against P. aeruginosa ◼ Advantage over imipenem for the treatment of meningitis with minimal seizure complications. ◼ MRSA, S. maltophilia, and E. faecium are generally resistant to meropenem. ◼ Intra-abdominal infections. (including Necrotizing pancreatitis) ◼ Complicated skin and soft tissue infections caused by S. aureus (MSSA only), S. pyogenes, Streptococcus agalactiae, viridans group streptococci,E. faecalis (not VRE), P. aeruginosa, E. coli, Proteus mirabilis, B. fragilis, and Peptostreptococcus species. ◼ Meningitis (children 3 months of age and older) caused by S. pneumoniae, H. influenzae, and N. meningitidis. ◼ Hospital-acquired pneumonia ◼ Obstetric and gynecologic infections ◼ Febrile neutropenia ◼ Sepsis and GN bacteremia ◼ Endocarditis caused by Gram-negative organisms (P. aeruginosa)
  • 28.
    Meropenem/Vaborbactam(Vabomere) ◼ Combination ofmeropenem and vaborbactam, a beta- lactamase inhibitor. ◼ Best against KCPs (Klebsiella pneumoniae carbapenemase) or CRE (carbapenem-resistant Enterobacteriaceae) ◼ Higher cure rates compared to carbapenem alone, aminoglycoside, polymyxin B, colistin, tigecycline, or ceftazidime/avibactam (monotherapy only). ◼ Does not enhance activity against Pseudomonas aeruginosa or Acinetobacter spp. due to eflux/porin mutations[ ◼ Treatment of complicated urinary tract infections (cUTIs) including pyelonephritis
  • 29.
    Imipenem/Cilastatin (Primaxin) ◼ Similarspectrum of coverage like meropenem but slightly less active against P. aeruginosa and more prone for GN resistance ◼ More active against E. faecalis, Nocardia, non-TB mycobacteria compared to meropenem. ◼ Imipenem in combination with vancomycin was less nephrotoxic than the combination of meropenem with vancomycin ◼ MRSA, S. maltophilia, Burkholderia cepacia and E. faecium are generally resistant to imipenem/cilastin ◼ Skin/soft tissue infections (not MRSA) ◼ Lower respiratory tract infections (pneumonia, bronchitis, COPD exacerbations) caused by S. pneumoniae and H. influenzae. ◼ Gynecologic infections ◼ Intra-abdominal infections ◼ Uncomplicated and complicated urinary tract infections (pyelonephritis) ◼ Bacterial endocarditis ◼ Bacterial septicemia ◼ Bone/joint infections ◼ Often used for the treatment of M. abscessus complex in combination with other agents,
  • 30.
    Ertapenem (Invanz) ◼ Activeagainst all anaerobes and many aerobic Gram-positive and Gram-negative organisms including extended spectrum beta-lactamase (ESBL) producing K. pneumoniae and E. coli ◼ It has poor activity vs P. aeruginosa and Acinetobacter ◼ It is not active against E. faecium and E. faecalis, S. epidermidis, MRSA, B. cepacia and S. maltophilia. ◼ Not recommended for meningitis because of poor CNS penetration. ◼ Convenient once-a-day outpatient IV antibiotic for mild to moderate infections ◼ Complicated intra-abdominal infections ◼ Community-acquired pneumonia (CAP) ◼ Complicated urinary tract infections ◼ Complicated skin and skin structure infections, including diabetic foot infections without osteomyelitis ◼ Elective colorectal surgical prophylaxis ◼ Acute pelvic infections (postpartum, septic abortion, and post-surgical gynecologic infections)
  • 31.
    Doripenem (Doribax) ◼ Complicatedintra-abdominal infection ◼ Complicated UTI ◼ Skin and soft tissue infections (not due to MRSA) ◼ Neutropenic fever ◼ Not recommended for ventilator-associated pneumonia ◼ active against all anaerobes and most GNB, including P. aeruginosa, inducible chromosomal beta-lactamases, and ESBL-producing organismssimilar spectrum of activity to imipenem/cilastatin and meropenem. ◼ Doripenem has an activity similar to that of meropenem against Pseudomonas, but 2 dilutions superior to imipenem ◼ Doripenem exhibited the greatest ability to prevent the emergence of the carbapenem-resistant mutant in vitro. ◼ Low risk of EEG changes and seizures in contrast to imipenem
  • 32.
    Polymyxin/Polymycin (Colistin) Colistimethate sodium ◼Colistin (polymyxin E) is an antibiotic that is structurally and pharmacologically related to polymyxin B ◼ Bactericidal - second line agent for VAP. ◼ Active against virtually all P. aeruginosa and Acinetobacter strains but Proteus spp. are usually resistant and may cause superinfection. ◼ Almost always used in combination since colistin monotherapy is probably suboptimal. ◼ May be synergistic with, carbapenems, tigecycline, and glycopeptides such as telavancin and rifampin. ◼ Inhaled use with resistant Pseudomonas aeruginosa or other Gram negative MDR infections in nosocomial pneumonia ◼ life-threatening infections caused by Gram-negative bacilli that are resistant to all available agents (MDR). ◼ Nephrotoxicity (ATN) reversible, Clostridium difficile-associated diarrhea. neurotoxic- neuromuscular blockade, which may result in respiratory arrest, ◼ Inactive against gram-positive bacteria, fungi, and viruses.
  • 33.
    Fluoroquinolones ◼ Advantages – >90%oral bioavailablitiy – IV and oral dosage forms available – Once daily dosing (except ciprofloxacin) – Broad spectrum of activity – Good tissue/bone penetration – Favorable efficacy/toxicity profile ◼ Disadvantages – Development of resistance (QREC/QRGC) – NOT RECOMMENDED IN < 18. children – Limit use in pregnancy, nursing mothers – Impaired absorption if co-administered with multivalent cations – Arthropathy, tendonitis due to cartilage damage – Prolonged QT interval – C.Diff colitis (Galti > Levo)
  • 34.
    Antibiotic Spectrum ◼ Effectivevs. gram +, gram --, atypicals ◼ Respiratory quinolones (levofloxacin). Active against Strep pneumo (including penicillin--resistant forms), S. aureus (including some MRSA), H. flu, M. cat M. cat and atypicals ◼ Antipseudomonas (ciprofloxacin/Delafloxacin) ◼ Decreased activity against anaerobes. (Some with gati/moxi) ◼ Delaflox, Levo and Moxi have increased Staph activity ◼ Topicals used for otitis media/bact conjunctivitis
  • 35.
    Fluoroquinolones Side Effects ◼Fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions. ◼ Tendinitis, tendon rupture, with increased risk in elderly, patients taking corticosteroids and in patients with organ transplants ◼ Peripheral neuropathy ◼ CNS reactions such as seizures, increased intracranial pressure, dizziness, and tremors ◼ Exacerbation of myasthenia gravis, including death and requirement for ventilator ◼ increased risk of psychiatric adverse reactions, including toxic psychosis; hallucinations, or paranoia; depression, or suicidal thoughts or acts; delirium, disorientation, confusion, or disturbances in attention; anxiety, agitation, or nervousness; insomnia or nightmares; memory impairment. These adverse reactions may occur following the first dose. ◼ Clostridium difficile-associated diarrhea has been reported with severity ranging from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs. ◼ Increased risk of aortic aneurysm and dissection, especially in elderly patients. In patients with a known aortic aneurysm or patients who are at greater risk for aortic aneurysms, ◼ Dysglycemia- disturbances of blood glucose, including symptomatic hyperglycemia and hypoglycemia. Severe cases of hypoglycemia resulting in coma or death have been reported with other fluoroquinolones. Monitor blood glucose carefully in diabetic patients receiving oral hypoglycemic agents or insulin.
  • 36.
    Ciprofloxacin ◼ Mainly gramneg bacilli, less GP coverage- no anaerobes ◼ Infections below the diaphragm ◼ Excellent against: – Pseudomonas aeruginosa- and other GNB – Salmonella, Shigella, Yersinia, Campylobacter ◼ Recommended txt for: – UTI/Pyelonephritis – Prostatitis, concentrates in prostate – Travelers diarrhea – Salmonella (typhoid fever) – Salmonella gastroenteritis if abx needed – Cat scratch dz – Bartonella henselae
  • 37.
    Levofloxacin ◼ Better GPthan cipro (Strep pneumo, S aureus, S pyogenes) ◼ Similar GN to cipro- Less active against pseudomonas ◼ Covers atypicals () –Not anaerobes ◼ Active for: ◼ Primary therapy for: – CAP in otherwise healthy adults – mild-moderate severity – Cases of levoquin resistant Strep pneumo emerging ◼ Alternative txt: soft tissue infections w/ mixed infection of G+/- ( as good as augmentin)- Anti-inflammatory properties ◼ MDR- and XDR TB (Multi-drug resist & Extremely drug-resist) TB ◼ Excellent bioavailability- PO/IV (750 mg dose)- renal dose adjustment
  • 38.
    Moxifloxacin (Avelox) ◼ BestAnaerobic and mycobacterial activity among its class. ◼ Strep pneumo, H.influenza, Staph epi, MSSA, Moraxella, Legionella, Mycoplasma, Chlamydia, Rickettsia ◼ Shigella, Salmonella, Campylobacter, Yersinia, Vibrio cholera ◼ E coli, Proteus, Klebsiella, Morgagnella, Citrobacter, Enterobacter, Priovidentia ◼ 400 mg PO/IV qDay / no renal dose adjustment ◼ Indicated for: ◼ Acute Bacterial Sinusitis ◼ Community-Acquired Pneumonia- CAP ◼ Acute infectious Exacerbations of Chronic Bronchitis ◼ Skin & Skin Structure Intra-abdominal Infections ◼ Intra-abdominal Infections (only mild-moderate)- Add Flagyl for severe infections. ◼ MDR- TB (multi-drug resist TB and MAC (in combination of other drugs) ◼ Opthalmcic (Bacterial conjunctivitis) ◼ Pneumonic & Septicemic Plague ◼ Do not use for UTI- low urinary concentration. ◼ Less interaction with anticoagulants then other FQ ◼ May cause false positive opiate screening
  • 39.
    Delafloxacin (Baxdela) ◼ NewestFQ with broad spectrum of activity against MRSA and Pseudomonas ◼ Acute bacterial skin and skin structure infections (ABSSSI) caused by the following susceptible microorganisms: Staphylococcus aureus (MRSA and MSSA), Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), Streptococcus pyogenes, and Enterococcus faecalis, Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa. ◼ Community-acquired bacterial pneumonia (CABP) caused by the following susceptible microorganisms: Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible [MSSA] isolates only), Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, Chlamydia pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae. ◼ Available as 450mg tablets and as 300mg IV dose.
  • 40.
    Tetracyclines doxycycline/Minocycline ◼ Bacteriostatic- inhibitprotein synthesis by mainly binding to 30S ribosomal subunit and blocking binding of aminoacyl transfer-RNA. ◼ Widely distributed into body tissues and fluids including pleural fluid, bronchial secretions, sputum, ascitic fluid, synovial fluid, aqueous and vitreous humor, and prostatic fluid. Poor CNS penetration. ◼ Cleared by liver; no renal dose adjustment needed. Doxycycline preferred in pts with renal insufficiency. ◼ May cause: – GI upset and diarrhea – Stains, deforms teeth in children < 8 yrs (including in fetuses when given to pregnant women). Contraindicated in pregnancy. – Note: short course doxycycline was not associated with any dental staining. – Hepatotoxicity (dose related, especially seen in pregnant women, pts w/ renal insufficiency, and with the use of expired medication) – Worsening azotemia (increased in patients with renal failure). – Esophageal ulcerations (pill-induced, avoid by not lying down after ingesting pill x 30 min). – Candidiasis (thrush and vaginitis) – Photosensitivity – Food interferes w/ absorption- impaired by calcium, magnesium antacids, milk, multivitamins – Minocycline- dizziness or vertigo
  • 41.
    Clinical Indications – CAP(with Ceftriaxone to cover atypicals)- safe in patients with prolonged QTc. – Skin and soft tissue infections due to S. aureus including MRSA. ( Micocycline > Doxy against MRSA but less effective for Strep spp. – IV minocycline for acinetobacter infections after confirmation of minocycline in vitro susceptibility. – Bite wounds. PCN allergic patients. – Psittacosis caused by Chlamydia psittaci – Brucellosis: doxy + gentamycin = txt of choice – Vibrio infections – Borreliosis- Lyme diz, Relapsing fever – Rickettsial infections (Rocky mountain spotted fever (RMSF), spotted fever, Q fever, typhus fever, tick fevers , ehrlichiosis – Leptospirosis – Sexually Transmitted Infections: – Nongonococcal urethritis caused by Ureaplasma urealyticum – Syphilis in PCN allergic patients – PID + other abx in combo, endocervical or rectal infections, epididymitis, urethritis caused by Chlamydia trachomatis – Lymphogranuloma venereum caused by Chlamydia spp. – Trachoma, inclusion conjunctivitis cause by C. trachomatis. – Granuloma inguinale caused by Calymmatobacterium granulomatis – Anthrax – Bacillary angiomatosis: 100 mg twice daily x >3mos; – Malaria prophylaxis – *Tetracycline has role for the treatment of susceptible organisms causing UTIs since it achieves good urinary levels compared to the hepatically metabolized doxycycline, minocycline and tigecycline.
  • 42.
    Tigecycline (Tygacil) ◼ Novelanalog of minocycline-unaffected by tetracycline mechanisms of resistance ◼ Bacteriostatic agent that inhibits protein synthesis through 30s ribosomal binding thereby blocking aminocyl-tRNA. ◼ Very broad Spectrum of activity includes anaerobes, many MDR Gram-positive cocci (vancomycin-susceptible E. faecalis, VRE (E. faecium), MSSA/MRSA, S. pyogenes) and Gram-negative bacilli (ESBL /CRE-Carbapenem Resistant Enterobacteria/ CRAB-Carb-resist A. Baumanii) with the exception of Pseudomonas, Proteus, and Providencia. ◼ Complicated skin and skin structure infections ◼ Complicated intra-abdominal infections (as a single agent) ◼ CAP caused by S. pneumoniae (PCN-susceptible isolates), H. influenzae (beta-lactamase negative isolates), and Legionella pneumophila. (Last resort) ◼ HAP/VAP due to MDR GNR, but high rates of clinical failure .In critically ill patients, consider using tigecycline in combination with carbapenem or colistin. ◼ Has activity against Clostridium difficile, appears to be low risk for causing CDI. Some role as ancillary treatment of severe CDI. ◼ Avoid in severe infections +/- bacteremia. Should be combined with a second agent (e.g. colistin, carbapenem) ◼ Less reliable in UTI ◼ 100mg IV x 1 (load), then 50mg IV q12h x 5-14 days. (Higher doses in severe infecx)
  • 43.
    Macrolides ◼ Drugs – Erythromycin(IV /Oral ) – Clarithromycin (Biaxin; IV/Oral ) – Azithromycin ((Zithromax, iv/po Z-PAK) ◼ Spectrum of activity – S. pneumoniae, S. aureus, H. influenzae, M. catarrhalis, N. gonorrhoeae, M. pneumoniae, Legionella sp., Chlamydia sp. Bordetella, Treponema, Bordetella – Clarithromycin: ►Similar to erythromycin. Increased activity against gram negatives (H. H. flu, Moraxellaflu, Moraxella) and atypicals. – Azithromycin:Azithromycin:►Decreased activity against gram positive cocci. .►Increased activity against Increased activity against H. fluH. fluand and M. catM ◼ Azithro preferred over erythromycin for – Legionella pneumophila- – MAI- can be used alone as prophylaxis in HIV pt w/ CD4 < 100 – Chancroid: single high dose 1gm is effective – C trachomatis urethritis, cervicitis, single 1gm dose – Ureaplasma urealyticum urethritis, single 1 gm dose
  • 44.
    Macrolides ◼ Mechanism ofaction – Inhibits RNA-dependent protein synthesis by binding to the 50S ribosome ◼ Advantages – Convenient dosing schedule – Minimal renal elimination (no dose adjustment) – Good tissue penetration – IV and oral dosage forms available ◼ Disadvantages – Inhibits the CYP P450 system (clarithromycin) – GI side effects (erytho-much less with azithromycin) ◼ Clinical uses – Upper and lower respiratory tract infections – STDs(pelvic inflammatory disease, gonorrhea, Syphilis?) – Skin and soft tissue infections – MAC (mycobacterium avium) prophylaxis and treatment in HIV/ CD4 count < 100
  • 45.
    Aminoglycosides ◼ Drugs – Gentamicin,tobramycin, amikacin ◼ Mechanism of action – Binds to 30S ribosome, interfering with the genetic code, and inhibiting protein synthesis ◼ Spectrum of activity – Mostly gram negatives – S. aureus (MSSA/MRSA),enterococcus fecalis, strep viridins,CNS (low dose synergy with PCN/VANCO) ◼ Clinical uses – Empiric txt severely ill w/ sepsis syndrome; combination use gives broad coverage for gram neg bacilli – In combination with beta-lactam for P. aeruginosa – In combination with beta-lactam or vancomycin for prophylaxis/treatment of endocarditis – Amikacin should be reserved for organisms resistant to gent and tobra or likely ESBL +VE. – Tularemia, Yersinia pestis; Streptomycin or gentamicin ◼ Streptomycin most effective drug for Yersinia pestis ◼ Spectinomycin effectively kills many strains of N gonorrhoeae
  • 46.
    Aminoglycosides ◼ Advantages – Rapidlybactericidal – Inexpensive/low resistance profile – Exhibit synergy and post antibiotic effect – Concentration dependent bactericidal activity. They require a high peak/MIC ratio for bacterial killing. – Aminoglycosides have a post-antibiotic effect. They inhibit bacterial growth even after drug concentrations decrease to undetectable levels. ◼ Disadvantages – Renal toxicity, ototoxicity, neuromuscular blockade (minimized with once- daily dosing) – Do not cross biological membranes well/lung, pleura/soft tissues. – Require monitoring of drug levels – Gentamicin ($4.28/day),($4.28/day),Tobramycin ($6.77/day),($6.77/day),Amikacin ($7.81/day).($7.81/day). – (Additional $21.00/day (Additional $21.00/day with serum levels)with serum levels) ◼ Nebulized (Tobramycin 300 mg q 12h or)amikacin 500 mgs q12h ◼ Premed with albuterol to prevent bronchospasm ◼ (no need for therapeutic levels as not systemically absorbed
  • 47.
    Aminoglycosides ◼ (Extended intervaldosing-EID) ◼ Once-a-day dosing Gentamicin, tobramycin, amikacin – Gent 5-7mg/kg q24h (trough level at 24h <1 mcg/ml) – Equal or less nephrotoxic/ototoxic than conventional dosing
  • 48.
    Vancomycin (IV) ◼ Firstline treatment of serious or severe infections caused by MRSA ◼ For treatment of serious infections caused by beta-lactam-resistant Gram- positive microorganisms (staph/strep/enterococcus) or in patients who have serious allergies to beta-lactam antimicrobials. ◼ Skin/soft tissue and bone and joint infections, including hardware- associated infections ◼ Pneumonia ◼ Septicemia and Endocarditis due to Gram-positive organisms ◼ Meningitis, CNS shunt infections ◼ No GN cover . Narrow spectrum ◼ Synergy with aminoglycosides. ◼ Antibiotic lock for cath-related blood stream infections (prophylactic or salvage therapy) ◼ Impregnated beads/cement in ortho hardware-related infections
  • 49.
    Vancomycin (IV) ◼ Prophylaxisfor endocarditis following certain procedures in pts at high risk for endocarditis. ◼ Prophylaxis for major surgical procedures involving implantation of prosthetic materials or devices (e.g., cardiac and vascular procedures and total hip replacement. ◼ A single dose of vancomycin administered immediately before surgery is sufficient unless the procedure lasts greater than 6 hrs, in which case the dose should be repeated. Prophylaxis should be discontinued after a maximum of 2 doses. Watch for: ◼ Red-man syndrome: flushing over chest/face +/- hypotension and pruritis ◼ Infusion over > 60 min/ pretreatment w/ antihistamine may reverse or prevent. ◼ Renal function impairment ◼ Most often implicated when given with concomitant aminoglycosides and piperacillin/tazobactam (zosyn) ◼ Associated with higher total daily doses, higher trough range, and prolonged therapy.
  • 50.
    USUAL ADULT DOSING ◼MRSA and other Gram-positive organisms: ◼ Typical-dose vancomycin: 15 mg/kg IV q12h ◼ Dose range is 15 - 20 mg/kg IV q8 - 12h and is dependent on patient creatinine clearance. ◼ Age, weight and site of infection should also be taken into consideration. ◼ Loading dose: 20 - 25 mg/kg ◼ Consider for critically ill patients, also endocarditis, VAP and CNS infections. ◼ Therapeutic drug monitoring: trough concentrations goals ◼ Troughs should be > 10 mcg/mL to prevent the development of resistance in S. aureus ◼ Skin and skin structure infections, neutropenic fever and non-S. aureus bacteremia: 10 - 15 mcg/mL ◼ Bacteremia, endocarditis, pneumonia, bone/joint infections, and meningitis: 15 - 20 mcg/mL ◼ Draw trough 30 - 60 minutes prior to the 4th or 5th dose of dosing regimen. ◼ Peak: no role in monitoring routinely
  • 51.
    ADULT RENAL DOSING ◼DOSING FOR GLOMERULAR FILTRATION OF 50-80 ◼ GFR >60 ml/min: Give 20 - 25 mg/kg loading dose if indicated, followed by 15 mg/kg IV q12h. Monitor serum trough concentrations; target Cmin > 10 mcg/ml. ◼ DOSING FOR GLOMERULAR FILTRATION OF 10-50 ◼ GFR 30-59 ml/min: Give 20 – 25 mg/kg loading dose if indicated, followed by 15 mg/kg IV q24h. Monitor serum trough concentrations; target Cmin > 10 mcg/ml. ◼ GFR 15-29 ml/min: Give 20 – 25 mg/kg loading dose if indicated, followed by 15 mg/kg IV q48h. Monitor serum trough concentrations; target Cmin > 10 mcg/ml. ◼ DOSING FOR GLOMERULAR FILTRATION OF < 10 ML/MIN ◼ 15 - 20 mg/kg IV, then redose based on serum concentrations. DOSING IN HEMODIALYSIS ◼ 15 - 20 mg/kg, loading dose then redose based on serum concentrations before dialysis ◼ Most require 5 - 10 mg/kg IV post-dialysis to maintain serum concentrations within goal range. ◼ Higher doses may be required in patients with residual renal function. DOSING IN PERITONEAL DIALYSIS ◼ 15 - 20 mg/kg IV x1 dose, the redose based on serum concentrations. ◼ Most patients will require a dose every 72 - 96 hours. Patients with residual renal function may require more frequent dosing. ◼ Alternatively, vancomycin 1 g can be given intraperitoneally followed by 30 mg/L dialysate.
  • 52.
    New lipoglycopeptides ◼ Dalbavancin,Oritavancin and Telavancin ◼ Semisynthetic lipoglycopeptides (compared to Vancomycin, a glycopeptide antibiotic), for infections caused by multi-drug-resistant Gram-positive pathogens (vancomycin-resistant Staphylococcus aureus, MRSA, and Staph. epidermidis, Streptococcus spp ) ◼ Enterococci exhibiting the VanA phenotype (resistance to both vancomycin and teicoplanin) are resistant to both dalbavancin and telavancin, while oritavancin retains activity. ◼ All three exhibits activity against VanB vancomycin-resistant enterococci. ◼ Indicated in complicated skin and skin structure infections (cSSSIs) ◼ The most common adverse effects reported with dalbavancin use included nausea, diarrhea and constipation, while injection site reactions, fever and diarrhea were commonly observed with oritavancin therapy. ◼ All three of these agents are promising alternatives for the treatment of cSSSIs in cases where more economical options such as vancomycin have been ineffective, in cases of reduced vancomycin susceptibility or resistance, or where vancomycin use has been associated with adverse events
  • 55.
    Anti-anaerobic Agents Metronidazole (Flagyl) –Gold standard anti-anaerobic agent. – Active against almost all anaerobes with exception of Actinomyces, Propionibacterium acnes, and Lactobacillus spp. – Oral: 500 mg q8-12h or IV 500 mg IV q8-12h – First-line agent for giardiasis, trichomoniasis, and amebiasis. – Amebiasis: 750 mg PO q8h x 5-10 d/ Giardiasis: 250 mg PO q8h x 5-10 d – H. pylori - resistance up to 20-30%. High metronidazole doses (1.5g/d) may overcome resistance. – Intra-abdominal infections. – C. difficile associated colitis- MILD (but not severe; oral vancomycin preferred, may add/substitute iv flagyl to oral vanco if severe colitis, ileus or patient NPO ) – C. difficile colitis: 500 mg PO/IV q8h x 10-14 d – Brain abscess- (In combination of other appropriate abx) – Bacterial vaginosis: 500 mg twice daily PO x 7d or Flagyl ER 750 mg PO once daily x 7d – Trichomoniasis: single 2 gm x 1 dose or 500 mg PO twice-daily x 7 d (more effective) – Toxicity: disulfram reaction/ P. Neuropathy chronic use – Interaction with warfarin/antiepileptics/Lopinavir and ritonovir
  • 56.
    Anti-anaerobic Agents Clindamycin ◼ Inhibitsprotein synthesis by binding to 50S ribosomal subunits, interfering with transpeptidation and early chain termination. ◼ Distributed to many body tissues and fluids including ascites fluid, pleural fluid, synovial fluid, bone, bile and saliva. Poor CNS penetration. ◼ Active against most Gram-positive cocci (except Enterococcus), including Strep, MSSA, and most community-acquired MRSA (if CA-MRSA is resistant to erythromycin, D-test should be performed to confirm clindamycin sensitivity). ◼ Anaerobic gram-negative bacilli. Increasing resistance seen with B. fragilis. ◼ No GN coverage. ◼ May cause: Diarrhea (not due to C. difficile): occurs in 10-30%, commonly develops on days 4-9 of treatment and typically resolves 14 days after stopping the antibiotic ◼ C. difficile colitis: ~6%. Prescribe with caution in individuals with risk/history of C. diff. ◼ GI intolerance: nausea, vomiting and anorexia ◼ Generalized morbilliform rash
  • 57.
    Clinical Indications &Doses ◼ Anti-toxin: Clindamycin is frequently added to beta-lactam antibiotics for severe infections caused by MRSA, S. pyogenes (Toxic shock syndrome), C. perfringens to suppresses toxin production. ◼ Skin and soft tissue infections (including animal or human bites): 300-450 mg PO q6h-8h or 600 mg IV q8h ◼ CA-MRSA- often used as an oral treatment option for soft tissue infection ◼ Necrotizing fasciitis including gangrene: 600-900 mg IV q8h ◼ Osteomyelitis: 600-900 mg IV q8h or 300-450 mg PO q6h- often used as step-down oral therapy, but rarely used as IV therapy. ◼ Surgical prophylaxis in contaminated wounds ( Gram pos/anaerobes) ◼ Aspiration Pneumonia- (empyema, and lung abscess) ◼ Acute bacterial sinusitis: 300 mg PO q6h ◼ ENT- Deep neck space infections, chronic tonsillo--pharyngitis, odontogenic abscesses. ◼ Actinomycosis: 600 mg IV q 8h x 2-6 weeks, then clindamycin 300 mg PO q6h x 6-12 months ◼ Pelvic inflammatory disease (endometritis, nongonococcal tubo-ovarian abscess, pelvic cellulitis, and post- surgical vaginal cuff infections) : 900 mg IV q8h (in combination with gentamicin) ◼ *Intrabdominal infex (Avoid due to B. Frag resistance- Flagyl is better), ◼ Endocarditis phlx in PCN allergic patients, ◼ PCP: clindamycin 600 mg IV q6h-q8h or 300-450 mg PO q6h-8h in combination with primaquine 15-30 mg (base) PO once daily. ( 2nd line in sulfa allergic patients) ◼ CNS toxoplasmosis: clindamycin 600 mg IV q6h or clindamycin 450 mg-600 mg PO q6h + pyrimethamine 200 mg PO loading dose, then 50-7 5mg PO q24hd + leucovorin 10-20 mg q24h ◼ Malaria: (in pregnant women)
  • 58.
    Clindamycin Topical applications: ◼ Bacterialvaginosis ◼ Vaginal ovules: 1 ovule (100 mg) x 3 days ◼ Cleocin (vaginal cream) : one full applicator (100 mg) inserted intra-vaginally daily for 3-7 days in non-pregnant patients and for fr 7 days in pregnant patients ◼ Clindesse (vaginal cream): one full applicator inserted intra-vaginally as a single dose at any time during the day in non-pregnant patients ◼ Acne vulgaris: ◼ Cleocin T (gel, solution, lotion): apply twice daily to the affected area. ◼ Evoclin (foam): apply once daily to the affected area / Clindagel (gel): apply once daily to the affected area ◼ Hidradenitis suppurativa: apply twice daily to the affected area
  • 59.
    Clindamycin-In CA-MRSA ◼ Inskin/soft tissue infections due to community- acquired MRSA (CA-MRSA) Clinda is ~80% effective (<20% in HCA-MRSA) Provided no inducible macrolide resistance. ◼ Check D test (Double disk diffusion) The clindamycin induction test is performed on Staphylococcus spp. that test resistant to erythromycin and susceptible to clindamycin using routine antimicrobial susceptibility test methods. ◼ Do not use Clinda if D-test is positive ◼ Avoid clinda if macrilodes are resistant in vitro sensitivity (Clinda- erythron Discordance) and D test is not done. ◼ Tetracyclines and Bactrim, although active against many MRSA, are not recommended treatments for suspected Group A Strep (GAS) infections. POSITIVE D-test Double-disk diffusion test (D test) demonstrating erythromycin disk induction of clindamycin resistance; a blunting of the zone of inhibition around the clindamycin disk is produced that forms a D shape (arrow).
  • 60.
    Linezolid (Zyvox) ◼ Linezolidis an oxazolidinone antibiotic active against nearly all antibiotic resistant Gram-positive bacteria and has a good short-term side effect profile. ◼ Pneumonia, hospital-acquired caused by MRSA, MSSA, and S. pneumoniae. ◼ Linezolid may be considered for MRSA infections with documented vancomycin failure or intolerance. ◼ Infections due to vancomycin-resistant Enterococcus faecium (VRE), with or without concurrent bacteremia. ◼ Concomitant use of another anti-infective may be appropriate if the documented or presumptive pathogens include gram-negative bacteria /anaerobes ◼ Complicated and uncomplicated skin and skin structure infection including diabetic foot ulcers (without osteomyelitis). ◼ Linezolid has activity against tuberculosis, including multi-drug resistant (MDR) and extensively drug resistant (XDR) strains ◼ Most indications: 600 mg IV q 12 or PO twice-daily ◼ Reversible bone marrow suppression (thrombocytopenia, anemia, leucopenia). ◼ Serotonin syndrome reported with SSRI co-administration
  • 61.
    Tedizolid ◼ A noveloxazolidinone antibiotic similar to linezolid, once-daily,covers most Gram-positive organisms including VRE and MRSA. ◼ FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible Gram-positive organisms (staphylococci, streptococci, and enterococci, including strains resistant to vancomycin, daptomycin, and linezolid) ◼ Compared to linezolid, tedizolid has been shown to have 4- to 16-fold greater activity against MSSA, MRSA, streptococci, and enterococci (VRE) ◼ dose and duration dependent bone marrow suppression slightly lower than linezolid ◼ both oral and iv formulations, (200 mg once daily) No dosing adjustments in patients with renal or hepatic impairment.
  • 62.
    Daptomycin (Cubicin) ◼ Bactericidalagainst virtually all Gram-positive organisms including E. faecalis and E. faecium (including VRE), S. aureus (including MRSA), S. epidermidis (including MRSE), S. pyogenes, S. agalactiae, S. dysgalactiae, C. jeikeium. ◼ Inactive against gram-negative bacteria. ◼ The synergistic effect with several β-lactams with the greatest synergistic activity with ampicillin and ceftaroline ◼ Complicated skin and skin structure infections (MSSA and MRSA). ◼ S. aureus bacteremia, including right-sided endocarditis, caused by MSSA and MRSA, VRE. ◼ Endocarditis caused by Enterococcus spp. resistant to vancomycin,(VRE) penicillin and aminoglycosides ◼ VRE causing intra-abdominal infections, urinary tract infections, SST ◼ Should not be used for pneumonia due to high failure rates (drug binds to surfactant). ◼ Myopathy with CK Elevation, Pseudomembranous Enterocolitis , Anemia, Constipation, Diarrhea, Headache, Hypokalemia, Injection Site Sequelae,
  • 63.
    Oral vancomycin ◼ Antibiotic-associatedpseudomembranous colitis caused by C. difficile and enterocolitis caused by S. aureus (including MRSA) ◼ C. difficile colitis: 125mg PO q6h x 10 d. ◼ Higher doses (250-500mg PO q6h) may be given in the setting of severe disease and/or ileus. ◼ Vancomycin must be given orally for C. difficile infection as the IV formulation does not penetrate the bowel wall. ◼ Oral preparations are not systemically absorbed, as only intraluminal, these formulations will not treat any infection other than colitis. ◼ Vancomycin powder (IV formulation) can be reconstituted and given orally in lieu of capsules to decrease drug costs. ◼ Staphylococcal enterocolitis-500-2000 mg PO per day in 3-4 divided doses x 7-10 d
  • 64.
    Fidaxomicin (Dificid) ◼ Treatmentof C. difficile-associated infection (CDI) ◼ Inhibits C. difficile RNA polymerases. ◼ 200 mg twice daily with or without food x 10 days ◼ The global cure rate (addressing initial response and recurrences within 25 days) was better for fidaxomicin (75.5%) compared to vancomycin (63.7%) in studies ◼ Does not have benefit in reducing relapses in patients with the NAP-1 strain of C.Diff. ◼ Fidaxomicin-resistant C. difficile has been reported in a patient with recurrent CDI. ◼ Cost ~$2600/course (~25 times the cost of oral vancomycin (when IV form is given orally).
  • 65.
    Nitrofurantoin (Macrobid) ◼ Mostlyactive against E. coli, Citrobacter spp., S. saprophyticus, and E. faecalis. ◼ Urinary tract infection, uncomplicated/ cystitis. ◼ UTIs- recurrent [women]/ch suppression (50-100 mg PO once daily) ◼ Asymptomatic bacteriuria in pregnancy ◼ Prophylaxis of UTI ◼ Don’t use in pyelonephritis due to poor penetration into renal parenchyma. ◼ Don’t use in patients with CrCl ≤ 60 ml/min. ◼ Don’t use in geriatric patients ≥ 65 years with a CrCl ≤ 30 (pulmonary toxicity) ◼ Associated with acute allergic pneumonitis w/ short-term treatment; interstitial fibrosis w/ long-term use ◼ Caution when used in G6PD-deficient patients
  • 66.
    Fosfomycin ◼ Fosfomycin interfereswith bacterial wall synthesis (Bactericidal) ◼ Broad-spectrum of activity includes all common uropathogenic bacteria ◼ VRE/ MRSA ◼ ESBL/ CRE-Carbapenemase-producing Enterobacteriaceae ◼ MDR Pseudomonas aeruginosa (more dependent on local antibiogram profiles) ◼ Oral dosing: (IV Fosfomycin is not approved for use in the USA) ◼ Uncomplicated UTI: 3 gm sachet PO x 1 dose - (FDA indication). ◼ Complicated UTI: 3 gm sachet PO every 2-3 days (up to 21 days) on an empty stomach preferred. ◼ Duration: typically, three doings ◼ May also administer as 0.5–1 g administered every 6–8 h, which may be better tolerated. ◼ Mix sachet powder in 120 mL of cool water until dissolved. ◼ DOSING FOR GLOMERULAR FILTRATION OF 10-50 ◼ (Don't use if GFR<10)- Re-dose after dialysis, due to removal during HD. ◼ Useful drug for the treatment of uncomplicated/resistant UTIs in the setting of pregnancy. (Cat B) ◼ Should not be used for severe pyelonephritis and urosepsis.