A Review of Antibiotic Classes

Ali J. Olyaei, PharmD

Gram-Positive Aerobes COCCI clusters - Staphylococci pairs - S. pneumoniae chains - group and viridans streptococci pairs and chains Enterococcus sp.

BACILLI Bacillus sp. Corynebacterium sp. Listeria monocytogenes Nocardia sp.

Gram-Negative Aerobes COCCI Moraxella catarrhalis Neisseria gonorrhoeae Neisseria meningitidis Haemophilus influenzae

BACILLI E. coli, Enterobacter sp. Citrobacter, Klebsiella sp. Proteus sp., Serratia Salmonella, Shigella Acinetobacter, Helicobacter Pseudomonas aeruginosa*

Anaerobes “Above Diaphragm” Peptococcus sp. Peptostreptococcus sp. Prevotella Veillonella Actinomyces

“Below Diaphragm” Clostridium perfringens, tetani, and difficile Bacteroides fragilis, disastonis, ovatus, thetaiotamicron Fusobacterium

Other Bacteria 

Atypical Bacteria » » » »

Legionella pneumophila Mycoplasma pneumoniae Chlamydia pneumoniae Spirochetes » Treponema pallidum (syphilis)

Common Bacterial Pathogens by Site of Infection 



Certain bacteria have a propensity to commonly cause infection in particular body sites or fluids Antibiotic may be chosen before results of the culture are available based on some preliminary information » Site of infection and likely causative organism » Gram-stain result (does result correlate with potential organism above)

Bacteria by Site of Infection Mouth

Skin/Soft Tissue

Bone and Joint

Peptococcus Peptostreptococcus Actinomyces

S. aureus S. pyogenes S. epidermidis Pasteurella

S. aureus S. epidermidis Streptococci N. gonorrhoeae Gram-negative rods

Abdomen

Urinary Tract

Upper Respiratory

E. coli, Proteus Klebsiella Enterococcus Bacteroides sp.

E. coli, Proteus Klebsiella Enterococcus Staph saprophyticus

S. pneumoniae H. influenzae M. catarrhalis S. pyogenes

Lower Respiratory Community

Lower Respiratory Hospital

Meningitis

S. pneumoniae H. influenzae K. pneumoniae Legionella pneumophila Mycoplasma, Chlamydia

K. pneumoniae P. aeruginosa Enterobacter sp. Serratia sp. S. aureus

S. pneumoniae N. meningitidis H. influenza Group B Strep E. coli Listeria

General Use of Oral Cephalosporins Pharyngitis Bronchitis Sinusitis CAP Otitis media SSTI UTI Gonorrhea

1st Gen. X

X X

2nd Gen. X X X**

X** X X** X**

3rd Gen. X X X X** X X X** X**

**Not all drug in class have FDA approved indication

Active against susceptible strains of S. pneumoniae, H. influenzae, Moraxella catarrhalis, MSSA, S. pyogenes

First-Generation Cephalosporins: What do they cover?  Cefazolin (Kefzol) and cephalexin (Keflex)

 Activity includes:  Methicillin susceptible staphylococci  Streptococci excluding enterococci  E. coli, Klebsiella sp., and P. mirabilis  Many anaerobes excluding B. fragilis

Where do you think they should be used?    

Simple mixed aerobic infections. In penicillin allergic (not immediate) patients. Surgical prophylaxis. Convenience drug for S. aureus and streptococci?

What about second generation cephalosporins?  Cefuroxime

 Cefoxitin/cefotetan  Think Haemophilus in  1st generation plusaddition to 1st anaerobes generation specturm  A mixed, non-serious  A respiratory drug infection surgeon drug  Think cefazolin/metro which is what we would use

Third-Generation Cephalosporins  Cefotaxime, ceftriaxone (IV)  Enhanced activity against Enterobacteriaceae  Enhanced activity against streptococci, including penicillin resistant S. pneumoniae.  Long half life favors ceftriaxone  Less diarrhea favors cefotaxime

 Ceftazidime (IV)  Active against P. aeruginosa.  Decreased activity against gram positive cocci.

Fourth generation cephalosporins  Cefepime  Marginal improvements  Active against P. aeruginosa.

Oral Cephalosporins  1st generation  Cephalexin (Keflex®) 

$4 plan

 Cefadroxil (Duricef®) 

$96 / 10 days

 3rd generation  Cefdinir (Omnicef®)  $80 / 10 days

 Cefpodoxime (Vantin®)  $110 / 10 days

 2nd generation  Cefaclor (Raniclor®) 

$93 / 10 days

 Cefprozil (Cefzil®) 

$145 / 10 days

 Cefuroxime (Ceftin®) 

 Ceftibuten (Cedax) 

Unable to find

 Cefixime (Suprax®)  $187 / 10 days

 Cefditoren (Spectracef®)  $120 / 10 days

$155 / 10 days

Patient cash prices from various pharmacies in Portland 2011

When to use carbapenems?  Life threatening polymicrobial infections  Intra abdominal sepsis in ICU esp nosocomial in origin  Gram negative/ nosocomial pneumonia in intubated patient

 Monotherapy of febrile neutropenia (high risk patients)

Carbapenems: What don’t they get?  Everything except:  MRSA and MRSE  Enterococcus faecium  Stenotrophomonas maltophilia  Burkholderia cepacia

Monobactams Spectrum of Activity

Aztreonam bind preferentially to PBP 3 of gram-negative aerobes; has little to no activity against gram-positives or anaerobes Gram-negative E. coli, K. pneumoniae, P. mirabilis, S. marcescens H. influenzae, M. catarrhalis Enterobacter, Citrobacter, Providencia, Morganella Salmonella, Shigella Pseudomonas aeruginosa

Mechanism of action of TMP-SMX

Inhibitors of metabolic pathways

 Trimethoprim/sulfamethoxazole (Septra, TMP/SMX) - good gram negative, some gram positive  block folic acid synthesis at two different points TMP and SMX act synergistically  Resistance may arise if the organism can “bypass” the pathway making it redundant

Fluoroquinolones • Novel group of synthetic antibiotics developed in response to growing resistance • Agents available today are all structural derivatives of nalidixic acid • The fluorinated quinolones (FQs) represent a major therapeutic advance:   

Broad spectrum of activity Improved PK properties – excellent bioavailability, tissue penetration, prolonged half-lives Overall safety

• Disadvantages: resistance, expense

The Available FQs Older FQs  Norfloxacin (Noroxin®) - PO  Ciprofloxacin (Cipro®) – PO, IV Newer FQs  Levofloxacin (Levaquin®) – PO, IV  Moxifloxacin (Avelox®) – PO, IV

Fluoroquinolones Adverse Effects • Gastrointestinal – 5 % 

Nausea, vomiting, diarrhea, dyspepsia

• Central Nervous System 

Headache, agitation, insomnia, dizziness, rarely, hallucinations and seizures (elderly)

• Hepatotoxicity 

LFT elevation (led to withdrawal of trovafloxacin)

• Phototoxicity (uncommon with current FQs) 

More common with older FQs (halogen at position 8)

• Cardiac  

Variable prolongation in QTc interval Led to withdrawal of grepafloxacin, sparfloxacin

Fluoroquinolones Drug Interactions • Divalent and trivalent cations – ALL FQs  Zinc,

Iron, Calcium, Aluminum, Magnesium  Antacids, Sucralfate, ddI, enteral feedings  Impair oral absorption of orally-administered FQs – may lead to CLINICAL FAILURE  Administer doses 2 to 4 hours apart; FQ first

• Theophylline and Cyclosporine - cipro  inhibition

of metabolism,  levels,  toxicity

• Warfarin – idiosyncratic, all FQs

Macrolides • Erythromycin is a naturally-occurring macrolide derived from Streptomyces erythreus – problems with acid lability, narrow spectrum, poor GI intolerance, short elimination half-life • Structural derivatives include clarithromycin and azithromycin:  



Broader spectrum of activity Improved PK properties – better bioavailability, better tissue penetration, prolonged half-lives Improved tolerability

Macrolides Adverse Effects

• Gastrointestinal – up to 33 %  Nausea,

vomiting, diarrhea, dyspepsia  Most common with erythro; less with new agents

• Cholestatic hepatitis - rare >

1 to 2 weeks of erythromycin estolate

• Thrombophlebitis – IV Erythro and Azithro  Dilution

of dose; slow administration

• Other: ototoxicity (high dose erythro in patients with RI); QTc prolongation; allergy

Aminoglycoside Structure

Aminoglycosides Spectrum of Activity

Gram-Positive Aerobes most S. aureus and coagulase-negative staph viridans streptococci Enterococcus sp.

Gram-Negative Aerobes (not streptomycin) E. coli, K. pneumoniae, Proteus sp. Acinetobacter, Citrobacter, Enterobacter sp. Morganella, Providencia, Serratia, Salmonella, Shigella Pseudomonas aeruginosa (amik>tobra>gent)

Mycobacteria  tuberculosis - streptomycin  atypical - streptomycin or amikacin

Aminoglycosides Adverse Effects Nephrotoxicity  nonoliguric azotemia due to proximal tubule damage; increase in BUN and serum Cr; reversible if caught early  risk factors: prolonged high troughs, long duration of therapy (> 2 weeks), underlying renal dysfunction, elderly, other nephrotoxins

Ototoxicity  8th cranial nerve damage - vestibular and auditory toxicity; irreversible  vestibular: dizziness, vertigo, ataxia – S, G, T  auditory: tinnitus, decreased hearing – A, N, G  risk factors: same as for nephrotoxicity

Vancomycin • Glycopopeptide class • Spectrum of activity: - Gram-positives * Staphylococcus (MRSA) * Enterococccus * Streptococcus

HO H3 C

NH 2

HO

O CH 3

O

Cl

O

O

H

H

HO

OH Cl

O O H

H

N H

O

H N

H N O

NH

H

N H

H

H2N O

OH

OH

H

NH NHCH 3

O O

HO

HO

•Pharmacokinetics - 2-3 compartment drug - T1/2 h 6-12 h - VD 0.6-1.0 L

CH 2 OH O

O

H

• ADME - Not orally absorbed - Elimination by renal route

OH

O

H

Vancomycin Clinical Uses • Infections due to methicillin-resistant staph including bacteremia, empyema, endocarditis, peritonitis, pneumonia, skin and soft tissue infections, osteomyelitis • Serious gram-positive infections in -lactam allergic patients • Infections caused by multidrug resistant bacteria • Endocarditis or surgical prophylaxis in select cases • Oral vancomycin for refractory C. difficile colitis

Vancomycin Adverse Effects

Red-Man Syndrome  flushing, pruritus, erythematous rash on face and upper torso  related to RATE of intravenous infusion; should be infused over at least 60 minutes  resolves spontaneously after discontinuation  may lengthen infusion (over 2 to 3 hours) or pretreat with antihistamines in some cases

Clindamycin Clindamycin is a semisynthetic derivative of lincomycin which was isolated from Streptomyces lincolnesis in 1962; clinda is absorbed better with a broader spectrum

Clindamycin Spectrum of Activity Gram-Positive Aerobes • Methicillin-susceptible Staphylococcus aureus (MSSA only) • Streptococcus pneumoniae (only PSSP) – resistance is developing • Group and viridans streptococci

Clindamycin Spectrum of Activity Anaerobes – activity against Above the Diaphragm Anaerobes (ADA)

Peptostreptococcus some Bacteroides sp Actinomyces Prevotella sp. Propionibacterium Fusobacterium Clostridium sp. (not C. difficile)

Other Bacteria – Pneumocystis carinii, Toxoplasmosis gondii, Malaria

Clindamycin Adverse Effects

• Gastrointestinal – 3 to 4 %  Nausea,

vomiting, diarrhea, dyspepsia

• C. difficile colitis – one of worst offenders  Mild

to severe diarrhea  Requires treatment with metronidazole

• Hepatotoxicity - rare  Elevated

transaminases

• Allergy - rare

Metronidazole Metronidazole is a synthetic nitroimidazole antibiotic derived from azomycin. First found to be active against protozoa, and then against anaerobes where it is still extremely useful.

Metronidazole Spectrum of Activity Anaerobic Bacteria (BDA) Bacteroides sp. (ALL) Fusobacterium Prevotella sp. Clostridium sp. (ALL) Helicobacter pylori

Anaerobic Protozoa Trichomonas vaginalis Entamoeba histolytica Giardia lamblia Gardnerella vaginalis

Metronidazole Adverse Effects

• Gastrointestinal  Nausea,

vomiting, stomatitis, metallic taste

• CNS – most serious  Peripheral

neuropathy, seizures, encephalopathy  Use with caution in patients with preexisting CNS disorders  Requires discontinuation of metronidazole

• Mutagenicity, carcinogenicity

Metronidazole Drug Interactions Drug

Interaction

Warfarin* Alcohol* Phenytoin Lithium Phenobarbital Rifampin

 anticoagulant effect Disulfiram reaction  phenytoin concentrations  lithium concentrations  metronidazole concentrations  metronidazole concentrations

Questions  Select appropriate empiric antibiotic therapy for       

Cellulitis Endocarditis Pneumonia PID Intra-abdominal infection Otitis Media UTI

Oseltamivir, Zanamivir

 Chemically related  Different routes of administration  Oseltamivir: tablet, suspension  Zanamivir: orally inhaled powder

 Mechanism of action:  Block active site of neuraminidase  Reduce the amount of viral particles released from infected cells

 Decrease shedding of influenza A and influenza B viruses

Oseltamivir adverse effects  Metabolized by liver, excreted in urine  Adverse effects  Gastrointestinal (nausea, vomiting)

 Dosage reduction:  Kidney disease

Acyclovir  Prototype antiviral drug  Purine analog  Requires activation by viral thymidine kinase to inhibit DNA polymerase and block replication  DNA polymerase of herpesviruses differ in their degree of sensitivity to ACV  HSV>VZV>CMV>EBV

Amphotericin B Structure Drug of Choice for most systemic fungal infections. Even those susceptible to others but where the disease rapidly progressive, in Immunocompro mized or involves CNS.

Amphotericn B

Hydrophobic

Hydrophilic

Hydrophobic

Amphotericin B Toxicity Infusion-related reactions

Nephrotoxicity

 chills / rigors

  GFR

 fever

 Renal tubular acidosis

 nausea / vomiting

  renal concentrating ability

 cardiorespiratory reactions

 Hypokalemia, hypomagnesemi

 phlebitis

Utz JP, Bennett JE, Brandriss MW, et al. 1964. Ann. Intern. Med. 61(2):334-354 Maddux MS, Barriere SL. 1980. Drug Intell. Clin. Pharm. 14:177-181 Grasela TH, Goodwin SD, Walawander MK, et al. 1990. Pharmacotherapy. 10(5):341-348 Gallis HA, Drew RH, Pickard WW. 1990. Rev. Infect. Dis. 12(2):308-329

Key Biopharmaceutical Characteristics of the Triazole Antifungals Fluconazole Spectrum of Activity

C. albicans, C. tropicalis +/- C. glabrata No C. krusei No Aspergillus

Oral form (%F)

Tablet (>90%)

Itraconazole

Voriconazole

Posaconazole

Similar Candida coverage as fluconazole, + Aspergillus

Broad, includes most Candida spp., Aspergillus, Fusarium but no Zygomycosis

Broadest spectrum, activity against Candida, Aspergillus, Fusarium and Zygomycosis

Capsule (6-25%)

Tablet (>90%)

Suspension (unknown)

Solution (20-60%)

IV formulation

Available, no solubilizer

Available, cyclodextrin

Available, cyclodextrin

In development

Clearance

Renal (80%)

Hepatic 3A4

Hepatic 2C19, 3A4

Unchanged feces (>80%)

Serum t1/2 (hr)

24

24 - 30

6 - 24

8 – 24

CSF penetration

Excellent

Poor

Excellent

Unknown

CYP 3A4 inhibition

Weak

Strong

Moderate-Strong

Moderate-Strong

Adverse events

N&V, hepatic

N&V, diarrhea (solution), hepatic, CHF

N&V, visual disturbances, hepatic, rash, QTC prolongation

N&V, fever

R.E. Lewis 2002. Exp Opin Pharmacother 3:1039-57.

Key Characteristics of the Echinocandin Antifungals Anidulafungin

Caspofungin

Micafungin

Oral Absorption

poor

< 2%

poor

Distribution (Vd)

30-50 L

9.67 L

4.95 L

85%

97% albumin

99.8% albumin

200 mg LD then 100 mg daily

70 mg LD then 35 – 50 mg (100 mg)

50 – 150 mg (896 mg)

Protein binding Dosing (MTD)

Major metabolic pathway

Degradation

Peptide hydrolysis, slow N-acetylation

Catechol-O-methyltransferase enzyme system (COMT)

t 1/2

24-36 hours

9-11 hours

14.7 hours after single infusion 14.6 hours after multiple doses

CNS penetration

Probably poor

Probably poor

Rat study: levels in brain approximately 2% plasma

Dosage adjustment

None for renal or hepatic impairment

Moderate hepatic insufficiency (Child Pugh 7-9)

Children < 8 years of age

Common ADR

LFTS (2%)

Hepatotoxicity (1.9 – 10.3%)

Hepatotoxicity (2 – 4%)

Anemia (0.9 – 10%)

Anemia (2 – 4%)

 Tacrolimus (20%), Cyclosporine increases

Sirolimus and nifedipine levels are

caspofungin levels (35%), Caspofungin levels may be decreased by inducers

increased by micafungin (