Newer Antibiotics and How We Should Use Them

Mahesh C. Patel, M.D.

Division of Infectious Diseases

February 3, 2010

Antibacterials

Timeline

Concentration-Dependent vs. Time-Dependent Killing

• Time-Dependent (or Conc. Independent)– Eliminate bacteria only when time during

which drug concentration is greater than MIC

• Concentration-Dependent– Eliminate bacteria when their concentrations

are above the MIC of the organism– Post-antibiotic effect

MIC vs. MBC

Bacteriostatic vs. Bactericidal

• Bactericidal: Kill bacteria• Bacteriostatic: Reversibly inhibit growth• Continuum• No rigorous studies exist showing

superiority of one type over another• However, -cidal agents preferred in

endocarditis, meningitis, neutropenic hosts, sepsis

• Static: MIC<MBC; Cidal: MIC=MBC

-Static vs. -Cidal

• Bacteriostatic– Tetracyclines– Sulphonamides– Trimethoprim– Chloramphenicol– Macrolides– Linosamides

(clindamycin)

• Bactericidal– Beta-Lactams– Daptomycin– FQs– Aminoglycosides– Metronidazole– TMP/SMX– Nitrofurantoin

Linezolid (Zyvox)

• Oxazolidinone• Inhibits Protein

Synthesis• Bacteriostatic• 600mg po/iv• No renal adjustment• Time-Dependent

Killing

Linezolid Spectrum of Activity

• Clinically important Gram + organisms– MSSA/MRSA, Coag – Staph, E. faecium and

faecalis, Strep. (bactericidal)– MTb, MAI

Linezolid: What to use it for

• Complicated skin and soft tissue structure infections (does not include osteomyelitis)

• Nosocomial Pneumonia (MRSA)

• VRE (including bacteremia)

• DO NOT USE for bacteremias

• **(Osteomyelitis, endocarditis, meningitis, intraabdominal infections, etc.)—ID consult

Linezolid: Side Effects

• Relatively well-tolerated with GI symptoms• Serotonin Syndrome

– Fever, agitation, MS changes, tremors if on serotonergic agents

– Reversible, nonselective monoamine oxidase inhibitor • Reversible myelosuppresion

– Thrombocytopenia (47% if >10d or rx) >>anemia>neutropenia

– Duration of treatment > 2 weeks• Neuropathy (peripheral, optic, etc.); Lactic

Acidosis, …

Daptomycin

• First in a novel class: cyclic lipopeptides• Side-lined in 1991 as Phase II trials showd

skeletal muscle toxicity with Q12H dosing• Binds to cell membranes of Gram + organisms • Bactericidal• Concentration-Dependent• Pregnancy Category B• 4 to 6 mg/kg iv Q24H (Q48H if CrCl<30 mL/min)

Daptomycin (Cubicin)

Daptomycin: Spectrum of Activity

• Like Glycopeptides, though works on organisms where vancomycin is not effective

• MSSA/MRSA, E faecalis and faecium, Coag negative Staph, Strep.

• Resistance emerging: If decreased sens to vancomycin, greater likelihood of decreased sens to daptomycin.

• Development of resistance during treatment of Enterococcal infections

Daptomycin: What to use it for

• Complicated SSTI (4mg/kg)• S. aureus bacteremia and endocarditis (6mg/kg)• Osteoarticular infections (but would use higher

dose of 8-10mg/kg and use another agent given lower bone levels and resistance emergence on therapy

• Enterococcal infections• DO NOT USE: Pulmonary infections (inactivated

by surfactant)

Daptomycin: Side Effects

• No increased GI• Paresthesias, dysesthesias, and peripheral

neuropathies• No QTc issues • Muscle toxicity

– Begin 7 days after therapy– Resolve during therapy or about 3 days after

daptomycin is stopped– Monitor CK when used with other “muscle toxic”

agents (ie HMG-CoA reductase inhibs)

Tigecycline (Tygacil)

• Tetracycline class • Inhibit bacterial protein

synthesis (30S)• Bacteriostatic• 100mg iv once, then

50mg iv Q12H with no adjustment needed for renal issues

• Pregnancy Category D (bone growth and teeth staining)

Tigecycline: Spectrum of Activity

• Broad range of pathogens– NO Pseudomonas, Proteus, Morganella, or

Providencia– Acinetobacter– MRSA/MSSA, VRE– Anaerobes– Resistance by efflux pumps or ribosomal

changes

Tigecycline: What to use it for

• FDA Approved:

• Skin and soft tissue infections– Intra-Abdominal infections– Community-acquired pneumonia– NOT indicated for blood stream infections

• At NBHN, reserved for patients with resistant GNRod infections (non-bacteremic)

Tigecycline: Side Effects

• Nausea (35%)• Vomiting (25%)• Phlebitis• Increased LFTs (6%)• Thrombocytopenia, increased PTT and

INR, eosinophilia• Headache, somnolence, taste perversion• Remember: No kids under 8yo

Ertapenem (Invanz)

• Beta-Lactam

• Bind to PCN-binding proteins (PBPs)

• Concentration-Dependent Killing

• Bactericidal

• Long half life of 4h permits QD dosing

• Renal adjustment required

Ertapenem: Spectrum of Activity

• Kinda like ceftriaxone and metronidazole

• Gram + bacteria, Enterobacteriaceae, MSSA, Anaerobes

• NOT: MRSA, Enterococcus; No Pseudomonas, Acinetobacter

• Resistance: Alteration in PBPs, Beta Lactamase production, Efflux pumps, decreased permeability

Ertapenem: What to use it for

• Intraabdominal infections

• Pneumonia

• Bacteremia

• Bone and soft tissue infections

• Complicated UTIs

• OB/Gyn infections

Doripenem (Doribax)

• Much greater Enterobacteriaceae activity including Pseudomonas, Acinetobacter

• Lower MICs for GNRs than imipenem or meropenem

• Resistance to Imipenem does not mean resistance to Doripenem or meropenem, or vice versa

• Less beta-lactamase unstable

Carbapenem: Side Effects

• Rash, urticaria, cross-reaction with PCNs, nausea, immediate hypersensitivity

• Less epileptogenic than imipenem

Polymyxins

• Very old drugs (1947)• Fell into disuse by 1980 due to nephrotoxicity;

topical and oral use• Polymyxin B and Polymyxin E (Colistin)

– Polymyxin B (colistemethate) iv– Colistin for inhalation therapy

• Penetrate into cell membranes and disrupt• Bactericidal and Concentration-Dependent• Renal adjustment necessary• Poor levels in pleura, joint, CSF, biliary tract

Polymyxins: Spectrum of Activity

• Broad GNR coverage

• Gram +, Gram – cocci, and most anaerobes are RESISTANT

• Has been used intrathecally and intraventricularly

• Colistimethate as efficacious as piperacillin, imipenem, and ciprofloxacin for treatment of Pseudomonas

Polymyxins: Side Effects

• Dose-Related Reversible Nephrotoxicity

• Dose-Related Reversible Neurotoxicity manifest as neuromuscular blockade

Telavancin (Vibativ)

• FDA-approved on Sept 11, 2009• Lipoglycopeptide• Synthetic derivative of vancomycin• Bactericidal• Inhibits cell wall synthesis; bacterial

membrane depolarizer• Once daily iv (10mg/kg)• Renal adjustment needed

Telavancin: Spectrum of Activity and Uses

• MRSA

• Gram positives (but not VRE)

• Uses– cSSSI– Nosocomial Pneumonia (with Gram negative

coverage; non-FDA approved)

Telavancin: Side Effects

• Mild taste disturbance (33%)• Nausea (27%) and Vomiting (14%)• Insomnia• Coagulation test interference: PT/INR, PTT,

Factor Xa; BUT NO increased risk of bleeding• Less common: Headache, Red-man Syndrome,

Nephrotoxicity, Diarrhea, Foamy Urine (13%)• QTc prolongation in 1.5% (vs. 0.6% in

vancomycin)

Anti-Fungals

Echinocandins

• Caspofungin (Cancidas), Micafungin (Mycamine), Anidulafungin (Eraxis)

• Inhibit glucan synthesis (in cell wall); like “PCN of antifungals”

• Pregnancy category C

• No renal adjustment required

Echinocandins: Spectrum of Activity

• Candida spp of all types (fungicidal)

• Aspergillus spp (fungistatic)

• Anidalufungin likley with fewer drug-drug interactions

• Micafungin has most data in kids

• Caspofungin was 1st

• Caspofungin vs. Micafungin for invasive Candidiasis similar results

Echinocandins: Uses

• Invasive and esophageal candidiasis– Caspo, Anidal., Mica.

• Prophylaxis in HSCT patients– Mica.

• Invasive aspergillosis in refractory or intolerant patients– Caspo

• Fever and neutropenia– Caspo

Echinocandins: Side Effects

• Not cytochrome P450 metabolized

• NOT nephrotoxic or hepatotoxic

• Relatively few/minor side effects

Newer Azoles

• Voriconazole (VFend), Posaconazole (Noxafil)

• Many clinically relevant drug-drug interactions (P450)

• Voriconazole is available in both iv and po formulations

• Posaconzole available in suspension• Both with extensive distribution and

penetration into tissues.

Voriconazole

• Invasive aspergillosis (superior to Ampho B deoxycholate)

• Invasive fusarium and scedosporum

• Esophageal candidiasis (not licensed)

• NOT FDA approved for fever and neutropenia and possibly inferior to liposomal Ampho B

Voriconazole: Side Effects

• Similar to other triazoles, EXCEPT:• Visual disturbance unique

– 30% reported altered or enhanced light perception for ½ hour 30 mins after dose

– Blurred vision, color vision changes, photophobia– Rarely results in discontinuation– Mechanism unknown

• Hallucinations (12 of 72 in one study) within 24hrs

• Photosensitivity, QTc prolongation (rare)

Posaconazole (Noxafil)

• Only available orally and bioavailability affected by food (fat increases absorption)

• No dose adjustment for renal issues• “Moderate” number of drug-drug interactions• Indications:

– Prophylaxis of Invasive fungal infections in high risk patients

– Oropharyngeal candidiasis– Molds (Aspergillosis, fusariosis, Coccidi.,

eumycetoma, chromoblastomycosis)• Side Effects: GI and headache