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Common Bacteria by Site of Infection. Beta-Lactam Structure.

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Presentation on theme: "Common Bacteria by Site of Infection. Beta-Lactam Structure."— Presentation transcript:

1 Common Bacteria by Site of Infection

2 Beta-Lactam Structure

3  -Lactam Characteristics Same MOA: Inhibit cell wall synthesis Bactericidal (except against Enterococcus sp.) Short elimination half-life Primarily renally eliminated (except nafcillin, oxacillin, ceftriaxone, cefoperazone) Cross-allergenicity - except aztreonam

4  -Lactams Adverse Effects Hypersensitivity – 3 to 10 %  Higher incidence with parenteral administration or procaine formulation  Mild to severe allergic reactions – rash to anaphylaxis and death  Antibodies produced against metabolic by- products or penicillin itself  Cross-reactivity exists among all penicillins and even other  -lactams  Desensitization is possible

5  -lactams Pharmacology Absorption: Variable depending on product Distribution  Widely distributed into tissues and fluids  Pens only get into CSF in the presence of inflamed meninges; parenteral 3 rd and 4 th generation cephs, meropenem, and aztreonam penetrate the CSF Elimination  most eliminated primarily by the kidney, dosage adj required in the presence of renal insufficiency  Nafcillin, oxacillin, ceftriaxone-eliminated by the liver  ALL  -lactams have short elimination half-lives except for a few cephalosporins (ceftriaxone)

6  -Lactams Adverse Effects Neurologic – especially with penicillins and carbapenems (imipenem and meropenem)  Especially in patients receiving high doses in the presence of renal insufficiency  Irritability, confusion, seizures Hematologic  Leukopenia, neutropenia, thrombocytopenia – prolonged therapy (> 2 weeks)

7  -Lactams Adverse Effects Gastrointestinal  Increased LFTs, nausea, vomiting, diarrhea, pseudomembranous colitis (C. difficile diarrhea) Interstitial Nephritis  Cellular infiltration in renal tubules (Type IV hypersensitivity reaction – characterized by abrupt increase in serum creatinine; can lead to renal failure  Especially with methicillin or nafcillin

8 Natural Penicillins (penicillin G, penicillin VK) Gram-positive Gram-negative pen-susc S. pneumoniaeNeisseria sp. Group A/B/C/G strep Anaerobes viridans streptococciAbove the diaphragm EnterococcusClostridium sp. Other Treponema pallidum (syphilis)

9 Penicillinase-Resistant Penicillins (nafcillin, oxacillin, methicillin) Developed to overcome the penicillinase enzyme of S. aureus which inactivated natural penicillins G ram-positive Methicillin-susceptible S. aureus Penicillin-susceptible strains of Streptococci

10 Aminopenicillins (ampicillin, amoxicillin) Developed to increase activity against gram-negative aerobes Gram-positive Gram-negative pen-susc S. aureusProteus mirabilis Pen-susc streptococciSalmonella, viridans streptococcisome E. coli Enterococcus sp.  L- H. influenzae Listeria monocytogenes

11 Carboxypenicillins (carbenicillin, ticarcillin) Developed to further increase activity against resistant gram-negative aerobes Gram-positiveGram-negative marginalProteus mirabilis Salmonella, Shigella some E. coli  L- H. influenzae Enterobacter sp. Pseudomonas aeruginosa

12 Ureidopenicillins (piperacillin, azlocillin) Developed to further increase activity against resistant gram-negative aerobes Gram-positiveGram-negative viridans strepProteus mirabilis Group strepSalmonella, Shigella some EnterococcusE. coli  L- H. influenzae Anaerobes Enterobacter sp. Fairly good activityPseudomonas aeruginosa Serratia marcescens some Klebsiella sp.

13  -Lactamase Inhibitor Combos (Unasyn, Augmentin, Timentin, Zosyn) Developed to gain or enhance activity against  - lactamase producing organisms (some better than others). Provides some or good activity against: Gram-positiveGram-negative S. aureus (MSSA)H. influenzae E. coli Anaerobes Proteus sp. Bacteroides sp.Klebsiella sp. Neisseria gonorrhoeae Moraxella catarrhalis

14 Classification and Spectrum of Activity of Cephalosporins Divided into 4 major groups called “Generations” Are divided into Generations based on  antimicrobial activity  resistance to beta-lactamase

15 First Generation Cephalosporins Best activity against gram-positive aerobes, with limited activity against a few gram- negative aerobes Gram-positive Gram-negative meth-susc S. aureusE. coli pen-susc S. pneumoniaeK. pneumoniae Group A/B/C/GstreptococciP. mirabilis viridans streptococci

16 Second Generation Cephalosporins Spectrum of Activity Gram-positiveGram-negative meth-susc S. aureusE. coli pen-susc S. pneumoniaeK. pneumoniae Group A/B/C/G strepP. mirabilis viridans streptococciH. influenzae M. catarrhalis Neisseria sp.

17 Second Generation Cephalosporins Spectrum of Activity The cephamycins (cefoxitin and cefotetan) are the only 2nd generation cephalosporins that have activity against anaerobes Anaerobes Bacteroides fragilis Bacteroides fragilis group

18 Third Generation Cephalosporins Spectrum of Activity In general, are even less active against gram- positive aerobes, but have greater activity against gram-negative aerobes Ceftriaxone and cefotaxime have the best activity against gram-positive aerobes, including pen-resistant S. pneumoniae

19 Third Generation Cephalosporins Spectrum of Activity Gram-negative aerobes E. coli, K. pneumoniae, P. mirabilis H. influenzae, M. catarrhalis, N. gonorrhoeae (including beta-lactamase producing); N. meningitidis Citrobacter sp., Enterobacter sp., Acinetobacter sp. Morganella morganii, Serratia marcescens, Providencia Pseudomonas aeruginosa (ceftazidime and cefoperazone)

20 Fourth Generation Cephalosporins 4th generation cephalosporins for 2 reasons  Extended spectrum of activity  gram-positives: similar to ceftriaxone  gram-negatives: similar to ceftazidime, including Pseudomonas aeruginosa; also covers beta-lactamase producing Enterobacter sp.  Stability against  -lactamases; poor inducer of extended-spectrum  -lactamases Only cefepime is currently available

21 Carbapenems (Imipenem, Meropenem and Ertapenem) Most broad spectrum of activity of all antimicrobials Have activity against gram-positive and gram- negative aerobes and anaerobes Bacteria not covered by carbapenems include MRSA, VRE, coagulase-negative staph, C. difficile, Nocardia Additional ertapenem exceptions: Pseudomonas and Enterococcus

22 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

23 Fluoroquinolones Novel group of synthetic antibiotics developed in response to growing resistance 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

24 FQs Spectrum of Activity Gram-positive – newer FQs with enhanced potency Methicillin-susceptible Staphylococcus aureus Streptococcus pneumoniae (including PRSP) Group A/B/C/G and viridans streptococci – limited activity Enterococcus sp. – limited activity

25 FQs Spectrum of Activity Gram-Negative – all FQs have excellent activity (cipro=levo>gati>moxi) Enterobacteriaceae – including E. coli, Klebsiella sp, Enterobacter sp, Proteus sp, Salmonella, Shigella, Serratia marcescens, etc. H. influenzae, M. catarrhalis, Neisseria sp. Pseudomonas aeruginosa – significant resistance has emerged; ciprofloxacin and levofloxacin with best activity

26 FQs Spectrum of Activity Atypical Bacteria – all FQs have excellent activity against atypical bacteria including: Legionella pneumophila - DOC Chlamydia sp. Mycoplasma sp. Ureaplasma urealyticum Other Bacteria – Mycobacterium tuberculosis, Bacillus anthracis

27 Fluoroquinolones Pharmacology Concentration-dependent bacterial killing Absorption  Most FQs have good bioavailability after oral administration  Cmax within 1 to 2 hours; coadministration with food delays the peak concentration Distribution  Extensive tissue distribution – prostate; liver; lung; skin/soft tissue and bone; urinary tract  Minimal CSF penetration Elimination – renal and hepatic; not removed by HD

28 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

29 Fluoroquinolones Adverse Effects Articular Damage  Arthopathy including articular cartilage damage, arthralgias, and joint swelling  Observed in toxicology studies in immature dogs  Led to contraindication in pediatric patients and pregnant or breastfeeding women  Risk versus benefit Other adverse reactions: tendon rupture, dysglycemias, hypersensitivity

30 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

31 Macrolides Mechanism of Action  Inhibits protein synthesis by reversibly binding to the 50S ribosomal subunit  Suppression of RNA-dependent protein synthesis  Macrolides typically display bacteriostatic activity, but may be bactericidal when present at high concentrations against very susceptible organisms  Time-dependent activity

32 Macrolide Spectrum of Activity Gram-Positive Aerobes – erythromycin and clarithromycin display the best activity (Clarithro>Erythro>Azithro) Methicillin-susceptible Staphylococcus aureus Streptococcus pneumoniae (only PSSP) – resistance is developing Group A/B/C/G and viridans streptococci Bacillus sp., Corynebacterium sp.

33 Macrolide Spectrum of Activity Gram-Negative Aerobes – newer macrolides with enhanced activity (Azithro>Clarithro>Erythro) H. influenzae (not erythro), M. catarrhalis, Neisseria sp., Campylobacter jejuni, Bordetella pertussis Do NOT have activity against any Enterobacteriaceae or Pseudomonas

34 Macrolide Spectrum of Activity Anaerobes – activity against upper airway anaerobes Atypical Bacteria – all macrolides have excellent activity against atypical bacteria including: Legionella pneumophila - DOC Chlamydia sp. Mycoplasma sp. Ureaplasma urealyticum Other Bacteria – Mycobacterium avium complex (MAC – only A and C), Treponema pallidum, Campylobacter, Borrelia, Bordetella, Brucella. Pasteurella

35 Macrolides Pharmacology Absorption  Erythromycin – variable absorption (15-45%); food may decrease the absorption Base: destroyed by gastric acid; enteric coated Esters and ester salts: more acid stable  Clarithromycin – acid stable and well-absorbed, 55% bioavailable regardless of presence of food  Azithromycin –acid stable; 38% bioavailable; food decreases absorption of capsules

36 Macrolides Pharmacology Distribution  Extensive tissue and cellular distribution – clarithromycin and azithromycin with extensive penetration  Minimal CSF penetration Elimination  Clarithromycin is the only macrolide partially eliminated by the kidney (18% of parent and all metabolites); requires dose adjustment when CrCl < 30 ml/min  Hepatically eliminated: ALL  NONE of the macrolides are removed during hemodialysis!  Variable elimination half-lives (1.4 hours for erythro; 3 to 7 hours for clarithro; 68 hours for azithro)

37 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

38 Macrolides Drug Interactions Erythromycin and Clarithromycin ONLY– are inhibitors of cytochrome p450 system in the liver; may increase concentrations of: TheophyllineDigoxin, Disopyramide CarbamazepineValproic acid CyclosporineTerfenadine, Astemizole PhenytoinCisapride WarfarinErgot alkaloids

39 Aminoglycosides Mechanism of Action Multifactorial, but ultimately involves inhibition of protein synthesis Irreversibly bind to 30S ribosomes –must bind to and diffuse through outer membrane and cytoplasmic membrane and bind to the ribosome –disrupt the initiation of protein synthesis, decreases overall protein synthesis, and produces misreading of mRNA Are bactericidal

40 Aminoglycosides Spectrum of Activity Gram-Positive Aerobes most S. aureus and coagulase-negative staph (but not DOC) viridans streptococci (in combination with a cell-wall agent) Enterococcus sp. (only in combination with a cell-wall agent) 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

41 Aminoglycosides Pharmacology Absorption - poorly absorbed from gi tract Distribution –primarily in extracellular fluid volume; are widely distributed into body fluids but NOT the CSF –distribute poorly into adipose tissue, use LBW for dosing Elimination –eliminated unchanged by the kidney via glomerular filtration; 85-95% of dose –elimination half-life dependent on renal fxn  normal renal function to 4 hours  impaired renal function - prolonged

42 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 and saturable –vestibular: dizziness, vertigo, ataxia –auditory: tinnitus, decreased hearing –risk factors: same as for nephrotoxicity

43 Vancomycin Mechanism of Action Inhibits bacterial cell wall synthesis at a site different than beta-lactams Inhibits synthesis and assembly of the second stage of peptidoglycan polymers Binds firmly to D-alanyl-D-alanine portion of cell wall precursors Bactericidal (except for Enterococcus)

44 Vancomycin Spectrum of Activity Gram-positive bacteria –Methicillin-Susceptible AND Methicillin-Resistant S. aureus and coagulase-negative staphylococci –Streptococcus pneumoniae (including PRSP), viridans streptococcus, Group A/B/C/G streptococcus –Enterococcus sp. –Corynebacterium, Bacillus. Listeria, Actinomyces –Clostridium sp. (including C. difficile), Peptococcus, Peptostreptococcus No activity against gram-negative aerobes or anaerobes

45 Vancomycin Pharmacology Absorption –absorption from GI tract is negligible after oral administration except in patients with intense colitis –Use IV therapy for treatment of systemic infection Distribution –widely distributed into body tissues and fluids, including adipose tissue; use TBW for dosing –inconsistent penetration into CSF, even with inflamed meninges Elimination –primarily eliminated unchanged by the kidney via glomerular filtration –elimination half-life depends on renal function

46 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

47 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

48 Vancomycin Adverse Effects Nephrotoxicity and Ototoxicity –rare with monotherapy, more common when administered with other nephro- or ototoxins –risk factors include renal impairment, prolonged therapy, high doses, ? high serum concentrations, other toxic meds Dermatologic - rash Hematologic - neutropenia and thrombocytopenia with prolonged therapy Thrombophlebitis

49 Oxazolidinones Linezolid (Zyvox ® ) is the first available agent which received FDA approval in April 2000; available PO and IV Developed in response to need for agents with activity against resistant gram-positives (MRSA, GISA, VRE)

50 Linezolid Mechanism of Action Binds to the 50S ribosomal subunit near to surface interface of 30S subunit – causes inhibition of 70S initiation complex which inhibits protein synthesis Bacteriostatic (cidal against some bacteria)

51 Linezolid Spectrum of Activity Gram-Positive Bacteria –Methicillin-Susceptible, Methicillin-Resistant AND Vancomycin-Resistant Staph aureus and coagulase- negative staphylococci –Streptococcus pneumoniae (including PRSP), viridans streptococcus, Group streptococcus –Enterococcus faecium AND faecalis (including VRE) –Bacillus. Listeria, Clostridium sp. (except C. difficile), Peptostreptococcus, P. acnes Gram-Negative Aerobes – relatively inactive Atypical Bacteria –Mycoplasma, Chlamydia, Legionella

52 Linezolid Pharmacology Concentration-independent bactericidal activity Absorption – 100% bioavailable Distribution – readily distributes into well- perfused tissue; CSF penetration  70% Elimination – both renally and nonrenally, but primarily metabolized; t½ is 4.4 to 5.4 hours; no adjustment for RI; not removed by HD

53 Linezolid Adverse Effects Gastrointestinal – nausea, vomiting, diarrhea (6 to 8 %) Headache – 6.5% Thrombocytopenia – 2 to 4% –Most often with treatment durations of > 2 weeks –Therapy should be discontinued – platelet counts will return to normal

54 Linezolid (Zyvox®) Drug–Drug/Food interactions Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Tyramine rich foods, adrenergic drugs and serotonergic drugs should be avoided due to the potential drug-food and drug-drug interactions. A significant pressor response has been observed in normal adult subjects receiving linezolid and tyramine doses of more than 100 mg. Therefore, patients receiving linezolid need to avoid consuming large amounts of foods or beverages with high tyramine content.

55 Linezolid and Tyramine cont Foods high in tyramine content include those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor, such as aged cheeses (0 to 15 mg tyramine per ounce); fermented or air- dried meats such as pepperoni (0.1 to 8 mg tyramine per ounce); sauerkraut (8 mg tyramine per 8 ounces); soy sauce (5 mg tyramine per 1 teaspoon); tap beers (4 mg tyramine per 12 ounces); red wines (0 to 6 mg tyramine per 8 ounces). The tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.

56 Clindamycin Mechanism of Action  Inhibits protein synthesis by binding exclusively to the 50S ribosomal subunit  Binds in close proximity to macrolides – competitive inhibition  Clindamycin typically displays bacteriostatic activity, but may be bactericidal when present at high concentrations against very susceptible organisms

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

58 Clindamycin Spectrum of Activity Anaerobes – activity against Above the Diaphragm Anaerobes (ADA) Peptostreptococcussome Bacteroides sp Actinomyces Prevotella sp. Propionibacterium Fusobacterium Clostridium sp. (not C. difficile) Other Bacteria – Toxoplasmosis gondii, Malaria

59 Clindamycin Pharmacology Absorption – available IV and PO  Rapidly and completely absorbed (90%); food with minimal effect on absorption Distribution  Good serum concentrations with PO or IV  Good tissue penetration including bone; minimal CSF penetration Elimination  Clindamycin primarily metabolized by the liver; half- life is 2.5 to 3 hours  Clindamycin is NOT removed during hemodialysis

60 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

61 New Guys on the Block Tigecycline (Tygacil®) Daptomycin (Cubicin®)

62 Tigecycline Mechanism of Action Binds to the 30S ribosomal subunit of susceptible bacteria, inhibiting protein synthesis.

63 Tigecycline Spectrum of Activity Broad spectrum of activity Treatment of complicated skin and skin structure infections caused by susceptible organisms, including methicillin-resistant Staphylococcus aureus and vancomycin-sensitive Enterococcus faecalis; treatment of complicated intra- abdominal infections

64 Tigecycline Pharmacokinetics Metabolism: Hepatic, via glucuronidation, N- acetylation, and epimerization to several metabolites, each <10% of the dose Half-life elimination: Single dose: 27 hours; following multiple doses: 42 hours Excretion: Urine (33%; with 22% as unchanged drug); feces (59%; primarily as unchanged drug) – No dose adjustment required in renal dysfunction

65 Tigecycline Adverse Effects >10%: Gastrointestinal: Nausea (25% to 30%), diarrhea (13%) 2% to 10%: Cardiovascular: Hypertension (5%), peripheral edema (3%), hypotension (2%) Central nervous system: Fever (7%), headache (6%), dizziness (4%), pain (4%), insomnia (2%) Dermatologic: Pruritus (3%), rash (2%) Endocrine: Hypoproteinemia (5%), hyperglycemia (2%), hypokalemia (2%) Hematologic: Thrombocythemia (6%), anemia (4%), leukocytosis (4%) Hepatic: SGPT increased (6%), SGOT increased (4%), alkaline phosphatase increased (4%), amylase increased (3%), bili increased (2%), LDH increased (4%) Neuromuscular & skeletal: Weakness (3%) Renal: BUN increased (2%) Respiratory: Cough increased (4%), dyspnea (3%)

66 Daptomycin Mechanism of Action  Daptomycin binds to components of the cell membrane of susceptible organisms and causes rapid depolarization, inhibiting intracellular synthesis of DNA, RNA, and protein.  Daptomycin is bactericidal in a concentration- dependent manner

67 Daptomycin Spectrum of Activity Gram-Positive Aerobes Treatment of complicated skin and skin structure infections caused by susceptible aerobic Gram-positive organisms; Staphylococcus aureus bacteremia, including right- sided infective endocarditis caused by MSSA or MRSA

68 Daptomycin Pharmacokinetics Absorption – available IV only Half-life elimination: 8-9 hours (up to 28 hours in renal impairment) Excretion: Urine (78%; primarily as unchanged drug); feces (6%) Dosage adjustment in renal impairment: –Clcr <30 mL/minute: Administer dose q48hr

69 Daptomycin Adverse Effects Hematologic: Anemia (2% to 13%) Gastrointestinal: –Diarrhea (5% to 12%) –vomiting (3% to 12%) –constipation (6% to 11%)

70 FDA Categorization of Antibiotics in Pregnancy Category A –Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote. Category B –Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters). Category C –Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus. Category D –There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). Category X –Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

71 Antibiotics in Pregnancy FDA CategoryAntibiotics in Category A BPenicillins, Cephalosporins, Carbapenems (except Imipenem), Daptomycin, Vancomycin (oral), Clindamycin, Erythromycin, Azithromycin, Metronidazole (avoid first trimester), Nitrofurantoin, Acyclovir, Amphoterocin B, Ethambutol CQuinolones, Chloramphenicol, Clarithromycin, Imipenem, Linezolid, Trimethoprim/Sulfa (D if used near term), Vancomycin (IV), Rifampin, INH, PZA, PAS, Fluconazole, Caspofungin DTetracyclines (Doxy, Tige, Mino), Voriconazole, Aminoglycosides (some put gentamicin as a category C) XRibavarin

72 Antibiotics Penetration into Eucaryotic Cells (esp. Macrophages) Antibiotic ClassIntracellular Accumulation Ratio Predominant Subcellular Localization Beta Lactams<1Cytosol Glycopeptides (Vancomycin) 8 (after 24 hrs)Lysosomes Oxazolidinones (linezolid) 1Unknown Aminoglycosides2-4 (after several days)Lysosomes Macrolides4-300Lysosomes/cytosol Fluoroquinolones4-10Cytosol Clindamycin5-20Unknown Tetracyclines1-4Unknown Antibiotics in bold print are generally considered most effective for intracellular organisms

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