Antibiotics

Patawee Boontanondha M.D.

Case 1

> A 27 YO male, MSM, presented with non-productive

cough, weight loss and fever for 1 month

> 30/10/2017, he met GP at OPD, tuberculosis was the

most likely diagnosis. However levofloxacin was given

as a monotherapy.

> 2/11/2017, he came to follow up with improvement.

Levofloxacin was continue.

> 9/11/2017 Chest X-ray revealed partially

improvement.

Case 1

> 10/11/2017, he visited OPD due to worsening of

symptoms. Single i.v. Amox/clav was prescribed and

clarithromycin was started.

> 13/11/2017, he presented at ED with fever and

dyspnea. Ceftriaxone was given as empirical antibiotic

for 3 days.

> 16/11/2017, he met pulmonologist who suspected

tuberculosis in this patient. IRZE were started.

> 29/11/2017, the patient met ID at HCC clinic.

Case 1

> A 27 YO male, MSM, presented with non-productive

cough, weight loss and fever for 1 month

> 30/10/2017, he met GP at OPD, tuberculosis was the

most likely diagnosis. However levofloxacin was given

as a monotherapy.

> 2/11/2017, he came to follow up with improvement.

Levofloxacin was continue.

> 9/11/2017 Chest X-ray revealed partially

improvement.

Case 1

> 10/11/2017, he visited OPD due to worsening of

symptoms. Single i.v. Amox/clav was prescribed and

clarithromycin was started.

> 13/11/2017, he presented at ED with fever and

dyspnea. Ceftriaxone was given as empirical antibiotic

for 3 days.

> 16/11/2017, he met pulmonologist who suspected

tuberculosis in this patient. IRZE were started.

> 29/11/2017, the patient met ID at HCC clinic.

What the ID Physician Thought?

Outline

> Choice of the proper antibiotics

> Basic microbiology

> Pharmacokinetic & pharmacodynamic

> Mechanism of action of antibiotic

What is Antibiotics?

Antibiotics

Choice of Proper Antimicrobial Agents

> Identify the infecting organism

> Susceptibility of the infecting organism

> Specific factors of the patient > H/O previous adverse reactions to antimicrobial agents

> Age

> Genetic or metabolic abnormalities

> Pregnancy

> Renal & hepatic function

> Site of infection

Basic Microbiology

Gram Positive Aerobe

Streptococcus pneumoniae

Streptococcus pyogenes

Streptococcus agalactiae

Streptococcus gallolyticus

Streptococcus dysagalactiae

Viridans streptococcus

Enterococcus spp.

Staphylococcus aureus

Staphylococcus epidemidis

Staphylococcus saprophyticus

Stapylocossus lugdunensis

Stapylococcus intermedius

Micrococcus spp.

Listeria monocytoges

Erysipilothrix rhusiopathieae

Corynebacterium diptherieae

Corynebacterium jikium

Actinomyces spp.

Nocardia spp.

Bacillus cereus

Bacillus anthracis

Gram stain

Gram Negative Rods (Aerobes)

Courtesy by Aj. Nantra Suwantarat

Growth on MacConkey No growth on MacConkey (fastidious)

LF Non- LF

TSI: A/A

TSI: A/A or K/A fermenters

TSI: K/K Non-fermenters

TSI: usually no

reaction

TSI: K/A glucose fermenters

EECK: E.coli Enterobacter Citrobacter Klebsiella

Some E.coli Enterobacter Citrobacter Proteus Providencia Morganella Hafnis Serratia Salmonella Shigella Yersinia Vibrio Aeromonas Plesiomonas Campylobacter (fastidious)

Oxidase + Pseudomonas Burkholderia Alcaligens Achromobacter Ralstonia Moraxella Chryseobacterium

Oxidase – Acinetobacter Stenotrophomonas Xanthomonas

Brucella Francisella Eikenella

Haemophilus Pasteurella Capnocytophaga Kingella Cardiobacterium Actinobaciilus Aggregatibacter

Stool pathogen

Gram negative cocci Neisseria spp Moroxella spp

Anaerobe

Peptostreptococcus spp Prevotella

Villionella

Propiobacterium acne Clostridium tetania

Clostridium perfringens

Clostridium septicum

Clostridium sordrellei

Actinomycetes spp.

Fusobacterium

Bifidobacterium

Bacteroides spp

Gram stain

Syndromes

Brain abscess Meningitis Post-traumatic, post-

neurosurgery meningitis

Encephalitis Endogenous

endophthalmitis

Streptococcus spp. Bacteroides spp Enterobacteriaceae

S. pneumoniae Meningococci L.monocytogenes S.agalactiae Gram-neg bacilli

S.epidemidis S.aureus Enterobacteriaceae P.acne Facultative and aerobic gram-neg bacilli

Herpes simplex Varicella zoster Tuberculosis Listeria Other virus

S.pneumoniae N.meningitidis S.aureus K.pneumoniae or other gram-negative Candida spp.

Orbital cellulitis Community-acquired pneumonia

HAP No co-morbidity Co-morbidity

S.pneumoniae H.influenzae M.catarrhalis S.aureus Anaerobes

S.pneumoniae Atypical pathogens Viral pathogens

Alcoholism: S.pneumoniae, anaerobes, coliforms, K.pneumoniae COPD: H.influenzae, M.cathrrhalis, S.pneumoniae, Legionella spp. IVDU: S.aureus Post CVA-aspiration: oral flora, S.pneumoniae, anaerobes Post-obstruction: S.pneumoniae, anaerobes Post-influenza: S.pneumoniae, S.aureus

MRSA Gram-negative enterics (often MDR) P.aeruginosa A.baumannii

Syndromes

Aspiration pneumonia

Empyema Bronchitis Bronchiectasis

Acute Subacute/chronic

Anaerobes Gram-positive cocci Streptococus milleri Gram-negative bacilli

S.pneumoniae Streptococcus spp S.aureus H.influenzae

Anaerobic Streptococci S.milleri group Bacteroides spp Enterobacteriaceae M.Tuberculosis

viral (common) M.pneumoniae C.pneumoniae Bordetella pertussis

H.influenzae M.catarrhalis P.aeruginosa S.aureus S.pneumoniae (rare)

Orbital cellulitis Odontogenic, tooth

infection

Cellulitis Seawater, brackish water-associated, contaminated skin Non-diabetes Diabetes

S.pneumonia H.influenza M.catarrhalis S.aureus Anaerobe (odentogenic source) Streptococcus sp.p (Group A) Gram-negative bacilli (post-trauma)

Viridans group streptococci Oral anaerobe: prptostreptococci, fusobacteria, Prevotella and Actinomyces S.pyogenes

S.ogenes gr. A, B, C, G S.aureus

S.pyogenes gr. A, B, C, G S.aureus Enterobacteriaceae Anaerobes

Vibrio vulnificus V.alginolyticus V.damsela

Syndromes

Pyelonephritis Perinephric abscess Acute prostatitis

Chronic prostatitis <35 years >35 years

Enterobacteriaceae Enterococci

S.aureus Enterobacteriaceae

N.gonorrhea C.trachomatis

Enterobacteriaeae Coliforms Enterococci

Enterobacteriacea Enterococci P.aeruginosa B.pseudomallei

Epididymo-orchitis Post-partum endometritis

PID Urethritis ≤ 35 years >35 years

N.gonorrhea C.trachomatis Enterobacteriaceae

Enterobacteriaceae Mycobacterium tuberculosis Brucellosis spp Mumps virus

Polymicrobic mixture of aerobe and anaerobe Aerobe: Gr.B streptococci, GNB Anarobe: Bacteroides spp., Peptostreptococci Clostidium spp. (C.perfringens, C.sordellii)

N.gonorrhea C. trachomatis Bacteroides spp. Enterobacteroaceae Streptococci spp.

N.gonorrhea C.trachomatis Trichomonas vaginalis Herpes simplex virus M.genitalum Ureaplasma urealyticum

Overview of Pharmacologic and Non-pharmacodynamic Factors

Pharmacokinetic

Absorption

Distribution

Metabolite

Elimination

Absorption

Good oral bioavailable

Impair absorption with

cation

Impair absorption with

elevation of gastric pH

Increase absorption with present of food

Decrease absorption with present of food

Fluoroquinolone (FQ)

FQ Itraconazole capsule

Posaconazole Azithromycin

Fluconazole Integrase inhibitors

Ketoconazole Rilpivirine

Voriconazole Cefuroxime

Metronidazole Cefpodoxime

Linezolid Atazanavir

Doxycyclin Rilpivirine

TMP-SMX

Distribution

> Not penetrate CNS > Piperacillin/tazobactam, cefazolin, aminoglycoside

> Anti-tuberculosis with good CNS penetration > Rifampicin, pyrazinamide, cycloserine, ethionamide

> Good tissue penetration > TMP-SMX, FQ

> Bad for pneumonia > Tigecycline, daptomycin

Elimination

No dosage adjustment in renal impairment

Antibacterial Antifungal Antiparasitic Anti-TB

Azithromycin Chloramphenicol Amphotericin B Albendazole Bedaquilline

Ceftriaxone Fidaxomicin Anidulafungin Artesunate Ethionamide

Clindamycin Fusidic acid Caspofungin Ivermectin Isoniazid

Dicloxacillin Quinupristin-dalfopristin

Isavuconazole Mefloquin Rifampin

Doxycycline Minocycline Itraconazole solution

Praziquantel Rifabutin

Linezolid Nafcillin Micafungin Primaquine Rifapentine

Moxifloxacin Posaconazole Pyrimethamine

Tigecycline Voriconazole

Adapt from The Sandford Guide to Antimicrobial therapy 2017. 47th edition.

Pharmacodynamic

> Simulated serum concentration-time profile of an antimicrobial agent > 3 g/day administered

Classif icat ion of Antibiotics

Mechanisms of Action of Antibiotics

> Inhibit cell wall synthesis

> Inhibit nucleic acid synthesis

> Interfere with cell membrane integrity

> Inhibit protein synthesis

> Inhibit metabolic pathways

Mechanisms of Action of Antibiotics

Inhibit cell wall synthesis

Mechanism of Action

Inhibit Cell Wall Synthesis

Campbell J, et al. Antimicrob. Agents Chemother.2012;56 :1810-1820.

Penicillin

*not produced β-lactamase E.coli, Shigella spp. Salmonella enteritica

Classification Antibiotics Spectrum

Natural penicillins Pen G, Pen V Non-β-lactamase-producing gram-positive bacteria, anaerobes Neisseria spp., Spirochete

Penicillinase-resistant penicillins Methicillin, nafcillin, cloxacillin S.aureus, S.epidemidis, Streptococci

Aminopenicillins Ampicillin, amoxicillin Pen G plus gram-negative cocci and Enterobacteriaceae* Enterococci, Listeria monocytogenes

Carboxypenicillins Carbenicillin, ticarcillin Against some ampicillin-resistant gram-negative aerobic rods: P.aeruginosa Acylureidopenicillins Piperacillin, azlicillin, mezlocillin

Syphilis Plurperal infection due to anaerobic streptococci or gr B streptococcus, genital clostidial infections Oral anaerobic microbiota including gram-positive and gram-negative cocci and actinomycetes

PK Properties pf Penicillins

Adverse Effect

> Hypersensitivity reaction

> Serum sickness

> Exfoliative dermatitis and SJS

> Allergic vasculitis

> Hematologic toxicity

> Renal toxicity: allergic agiitis, interstitial nephritis, hypokalemia

> CNS toxicity > GI side effect: alter the normal microbiota, hepatitis,

elevate ALP

Mechanism of Resistance

> Produce betalactamase enzyme

> Failure to penetrate outer membrane

> Efflux of drug

> Low-affinity to bind target PBPs

AMBLER Classification of β-lactamase Enzyme

Beta-lactamase Inhibitors

> Weak antibacterial activity

> Potent inhibitors of many class A β-lactamases

> Prevents hydrolysis of the antibiotic

Sulbactam Tazobactam Clavulanic acid Avibactam

Combination of BLBIs

BLBI Combination Clinical Use

Amoxicillin-Clavulanate Polymicrobial infection: bite wounds of human or animal in origin, diabetic foot, SSI, sinusitis and community-acquired pneumonia (CAP)

Ticarcillin-Clavulanate CAP, HAP/VAP, gynecologic infections, intraabdominal infections, SSI and osteomyelitis

Ampicillin-Sulbactam Similar amoxicillin-clavulanic acid Infection caused by A. baumannii

Piperacillin-Tazobactam Pneumonia, SSI, intraabdominal infections, polymicrobial infections and febrile neutropenia and ESBL-producing organism

Ceftazidime-avibactam FDA approved (2015): complicated intraabdominal infection in combination with metronidazole, complicated UTI Non-FDA approved: resistant gram negative infection >Carbapenemase-producing (KPC only) >ESBL-producing

Cephalosporin

>R1: microbial spectrum of activity >R2: alter the pharmacology of the compound

Cephalosporin

1st generation 2nd generation Cephamycins 3rd generation 4th generation MRSA-active

Parenteral Cephalosporins

Cefazolin Cephalothin Cephapirin Cephradine

Cefamandole Cefonicid Cefuroxime

Cefmetazole Cefotetan Cefoxitin

Cefoperazone Cefotaxime Ceftazidime Ceftriaxone Ceftizoxime Moxalactam

Cefepime Cefpirome

Ceftaroline Ceftobiprole

Oral Cephalosporins

Cefadroxil Cephalexin Cephradine

Cefaclor Cefprozil Cefuroxime Loracarbef

Cefdinir Cefditoren Cefixime Cefpodoxime Ceftinbuten

Clinical Use

Classification Clinical Use

1st generation cephalosporin Penicillin-allergic patients for serious staphylococcal infections, streptococcal infection SSI, prophylactic antibiotic Not effective against Bacteroides spp., animal bite and scratch

2nd generation cephalosporin Increase activity against S.pneumoniae, H.influenzae and M.catarrhalis SI, epiglottitis, complicated sinusiti and gynecologic infections

cephamycin Aerobic gram-negative and anaerobic organisms: intraabdominal, pelvic and gynecologic infections Prophylactic colorectal surgery

3rd generation cephalosporin Complicated skin and soft tissue infections, prosthetic joint infections, pneumonia, complicated UTI, intra-abdominal infection, meningitis, gonococcal infection

4th generation cephalosporin Enhanced activity against gram-negative bacilli: Enterobacter, Citrobacter and Serratia spp. P.aeruginosa infection

MRSA-active Activity against MRSA and ampicillin-susceptible strains of E.faecalis Activity against gram-negative bacilli similar to 3rd generation FDA approved: ABSSTI, CAP

Immunologic Adverse Effect

> Hypersensitivity reaction > Cross-reaction with other β-lactam less than 1%

> Depends on the similarity of the side chains

> Severity of the prior reaction

> Hematologic toxicities: eosinophilia, cytopenia, hemolysis

> Renal toxicities: interstitial nephritis

Non-immunologic Adverse Effect

> Hematologic > Bleeding disorder

> Impaired adenosine diphosphate-induced platelet aggregation

> MTT side change: cefamandole, cefotetan, Cefoperazone and moxalactam

> Patients with poor nutritional status, advanced age, recent GI surgery and renal failure

> GI toxicities: diarrhoea, hepatitis, obstructive biliary toxicity

> CNS: encephalopathy, seizure

Carbapenem

Antibiotic Spectrum

> Gram-positive cocci > Except MRSA, MRSE, E.fecium (E.faecalis)

> Gram-negative bacilli > Higher imipenem MIC: Morganella, Proteus > Ertapenem has no activity against P.aeruginosa and

A.baumannii

> Anaerobic bacteria except C.difficile

> Nocardia spp. > Except N.farcinica, N.otitidiscaviarum

> Non-tuberculous Mycobacterium

Clinical Use

> Most hospital-acquired infection

> Active against ESBL and Amp-C producing

> Imipenem, meropenem and doripenem have therapeutic equivalent

> Imipenem being slightly more active against gram-positive organisms

> Meropenem and doripenem slightly more active against gram-negative organisms

> Ertapenem > Poor activity against P.aeruginosa, A.baumannii

> Long half-life

Mechanism of Resistance

> Production of β-lactamase: S.maltophilia, Elizabethkingia

meningoseptica, Chryseobacterium indologenes

> Diminished permeability due to impaired expression of

certain outer membrane proteins: OprD [imipenem]

> Efflux of drug across the outer membrane: MexA-MexB-

OprM [meropenem, doripenem]

> Alter target site: gram-positive bacteria

> In gram-negative bacteria, resistance to carbapenem

mediates through multiple mechanism

Adverse Effect

> Seizure > Risk factors: renal failure, neurologic comorbidities

> More common with imipenem (1% to 2%)

> Carbapenems lead to subtherapeutic of valproic acid levels

> Hypersensitivity reaction <3%

Monobactam

> Aztreonam, the only monobactam approved by FDA

> Gram negative infection in who allergic to penicillin or other β-lactams

> Infection caused by Metallo-β-lactamase-producing gram-negative

> No activity against gram-positive and anaerobic organism

Glycopeptides

Vancomycin Teicoplanin

Spectrum of Vancomycin

> Gram-positive organisms > S.aureus, Enterococcus faecium, Enterococcus faecalis,

Streptococcus spp.

> Listeria monocytogenes, Bacillus spp., Corynebacterium spp., Rhodococcus equi

> Gram-positive anaerobic organisms > Peptostreptococcus spp., Actinomyces spp,

Proprionibacterium spp., Finegoldoa magna, Clostridium spp.

> Intrinsic resistant to vancomycin > Lactobacillus spp. (except L.acidophilus), Leuconostoc spp.

Pediococcus spp. Erysipelothrix rhusiopathiae

Clinical Use of Vancomycin

> Skin and soft tissue infections

> Bacteremia and endocarditis > Drug of choice for MRSA but not MSSA

> Ampicillin resistant enterococci

> Corynebacterium jeikeium

> Penicillin- and cephalosporin-resistant S.pneumoniae

> Meningitis and ventriculitis > Ceftriaxone-resistant S.pneumoniae

> Post-neurosurgery meningitis: with higher trough level

> MRSA pneumonia > Linezolid showed significant better cure rate in VAP

Clinical Use of Vancomycin

> Osteomyelitis

> Pseudomembranous colitis > Severe disease

> Not response to metronidazole

> Febrile neutropenia

> Prophylaxis in β-lactam allergic patients

Clinical PK/PD

> 24-h AUC/MIC ratio >400 is the best predictor of efficacy

> Trough conc. 15-20 µg/mL in serious MRSA infection > MIC of infecting strain ≤1 µg/mL

> TDM of vancomycin > Serious S.aureus infection > Concomitantly receiving another nephrotoxic agent > High dose vancomycin > Rapidly changing renal function > Undergoing hemodialysis

Antimicrobial Agent S I R

Vancomycin ≤ 2 4-8 ≥16

Adverse Effect of Vancomycin

> Ototoxicity

> Nephrotoxicity: > Associated with trough levels ≥15 µg/mL > Concomitant use of nephrotoxic agents > Duration of vancomycin therapy > Dose >4g/day > Weight greater than 101.4 kg > Pre-existing impaired renal function > Critically ill patients

> Hematologic toxicities: neutropenia, thrombocytopenia

> Cutaneous reaction

Adverse Effect of Vancomycin

> Red man syndrome > Infusion-related side effect

> Rapid onset of an erythematous rash or pruritus affecting the head, face, neck and upper trunk

> Angioedema

> Hypotension

> Reaction can be cessation with discontinuation of infusion

Teicoplanin

> Not approved by US. FDA

> High failure rate in severe MRSA infection

> Consider in > Mild to moderate SSI

> Continue the treatment of certain MRSA infections

> Prophylactic antibiotic

Inhibit DNA Synthesis

Quinolones

Drugs Oral dosing Parenteral dosing

Norfloxacin 400 mg q 12 h -

Ciprofloxacin 250-750 mg q 12 h 200-400 mg q 12 h*

Ofloxacin 200-400 mg q 12 h 200-400 mg q 12 h

Levofloxacin 250-750 mg q 24 h 250-750 mg q 24 h

Moxifloxacin 400 mg q 24 h 400 mg q 24 h

Gemifloxacin 320 md q 24 h -

*For P.aeruginosa: ciprofloxacin 400 mg q 8 h, however emergence of resistant was concerned with FQ monotherapy

Mechanism of Action

Spectrum of Quinolones

Enterobacteriaceae P.aeruginosa Gram-neg cocci Streptococci Anaerobe Atypical bacteria

Norfloxacin + - + - - +

Ciprofloxacin ++ + + - - +

Ofloxacin + - + - - +

Levofloxacin ++ + + + + +

Moxifloxacin + - + + + +

Gemifloxacin + - + + + +

Atypical pathogens: Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae, and Genital pathogens: Chlamydia trachomatis, Ureaplasma urealyticum, and Mycoplasma hominis

Clinical Use

Drugs Clinical Use

Norfloxacin UTI, urethral or cervical gonorrhea*

Ciprofloxacin UTI, chronic bacterial prostatitis, uncomplicated cervical and urethral gonorrhea*, complicated IAI¶, bacterial diarrhea, typhoid fever, acute bacterial sinusitis, lower respiratory tract infection, inhalation anthrax, SSI,and bone and joint infection

Ofloxacin UTI, bacterial prostatitis, uncomplicated cervical and urethral gonorrhea*, nongonococcal urethritis and cervicitis caused by Chlamydia trachomatis,CAP, uncomplicated SSI

Levofloxacin UTI, acute pyelonephritis, chronic bacterial prostatitis, CAP, HAP, inhalation anthrax, acute sinusitis, complicated and uncomplicated SSI

Moxifloxacin CAP, acute sinusitis, alternative agents for MDR-TB

Gamifloxacin CAP

*susceptible strains, ¶ intraabdominal infection

temafloxacin, sparfloxacin, grepafloxacin, trovafloxacin, and gatifloxacin were removed from clinical use after approval because of toxicities

Clinical Use

Drugs Clinical Use

Norfloxacin UTI, urethral or cervical gonorrhea*

Ciprofloxacin UTI, chronic bacterial prostatitis, uncomplicated cervical and urethral gonorrhea*, complicated IAI¶, bacterial diarrhea, typhoid fever, acute bacterial sinusitis, lower respiratory tract infection, inhalation anthrax, SSI,and bone and joint infection

Ofloxacin UTI, bacterial prostatitis, uncomplicated cervical and urethral gonorrhea*, nongonococcal urethritis and cervicitis caused by Chlamydia trachomatis,CAP, uncomplicated SSI

Levofloxacin UTI, acute pyelonephritis, chronic bacterial prostatitis, CAP, HAP, inhalation anthrax, acute sinusitis, complicated and uncomplicated SSI

Moxifloxacin CAP, acute sinusitis, alternative agents for MDR-TB

Gamifloxacin CAP

*susceptible strains, ¶ intraabdominal infection

Clinical Use

> Urinary tract infection but NOT moxifloxacin

> Prostatitis

> STI

> Gastrointestinal infection

> Intraabdominal infection

> Respiratory tract infection including anthrax

> Bone and joint infection

> Skin and soft tissue infection

Clinical Use

> Mycobacterium tuberculosis complex

> Non-tuberculous Mycobacterium

> Other use > Q fever

> Brucellosis

> Low-risk febrile neutropenia patient

PK of Quinolones

Drug-drug interactions

> Do not take oral formulation with cation: Al, Ca, Mg or Fe-containing compounds

> Avoid other agents that prolong QT interval

> Avoid concomitant use of tizanidine

> Variable interactions with warfarin

Adverse Effect

> GI side effect: > Abdominal discomfort, N/V

> Strong risk factor for C.difficile colitis with emerging of virulent strain

> CNS side effect > Mild headache, dizziness, insomnia

> Hallucination, delirium, psychosis and seizure

> Exacerbation of MG

> Musculoskeletal > Cartilage toxicity in young animal model

> Tendinitis: Achilles tendon rupture

Adverse Effect

> Retinal detachment

> QT prolongation

Polymyxin B and Colistin

> Cyclic cationic polypeptide detergents

> Penetrate into the outer cell membranes of bacteria

> Interact electrostatically with phospholipids in the membranes

> Quickly disrupt the membranes via competitive displacement of divalent cations

> Bind to the lipid A portion of cell wall

Antimicrobial Activity

> Gram-negative aerobic bacilli EXCEPT > Proteus, Providencia, Burkholderia, Serratia, Moraxella,

Helicobacter, Campylobacter, Vibrio, Brucella, Aeromonas, Morganella and Edwardsiella species

> Gram-positive, gram-negative cocci, and most anaerobes

> Multidrug-resistant (MDR) gram-negative bacilli > A.baumannii, P.aeruginosa, CRE

Clinical Use

> MRD gram-negative infection

> Inhalation therapy

> Post-neurosurgery meningitis > Intrathecal administration

> Oral therapy for gut decontamination

> Reserved for use when no other less toxic or potentially more effective drug is available

Adverse Effect

> Nephrotoxicity

> Neuromuscular blockade results in weakness and apnea

> Paresthesias around the lips, tongue and extrimities

Inhibit Protein Synthesis

Macrolides

Drugs Dosage

Erythromycin 250-500 mg q 6-12 h

Azithromycin 500 mg po day 1then 250 mg once daily

Clarithromycin 500 mg po q 12 h

Mechanism of Resistance

Mechanism Genes Phenotypes Organisms

Decreased Microbial Entry Decrease permeability of outer cell envelops

Enterobacteriaceae, P.aeruginosa, A.baumannii

Efflux pump msr (A) MSB phenotype S.epidermidis, S.aureus

mef (A) M phenotype S.pyogenes, S.pneumniae, group C streptococcus, enterococcal spp.

Target sites alterations erm MLSB phenotype

Drug inactivation mph Phosphotransferase S.aureus, E.coli, Norcardia spp

ere [A], ere [B]

Esterase E.coli, Klebsiella spp., Citrobacter spp, Enterobacter spp.

Antimicrobial Activity

Gram-positive bacteria Gram-negative bacteria Atypical bacteria

S.aureus, S.Pneumoniae Viridans streptococci, Listeria monocytogenes, Corynebacterium diphtheriae, Mycobacteriam (with clarithromycin and azithromycin)

Bordetella pertussis, N.meningitidis, N.gonorrhoea,

Ligeonella pneumophila, M.pneumoniae, Ureaplasma urealyticum, Rickettsia, Chlamydia trachomatis, C.pneumoniae

No breakpoint interpretative criteria for anaerobic bacteria

Other Activities of Erythromycin

> Motility-stimulating effect

> Anti-inflammatory effect

Macrolides as an Alternative

> Group A, C , G streptococcal infection

> S.pneumoniae

> M. catarrhalis

> H.influenzae

> Shigella

> Rheumatic fever prophylaxis

> Anthrax

> LGV

> Acne vulgaris

> Lyme disease

> Babesia microti

Major Indication for Use of Macrolides

> Bartonella infection

> Bordetella pertussis

> Campylobacter jejuni

> Chlamydia pneumoniae

> Chlamydia trachomatis

> Diphteria

> Chancroid

> H.pylori

> Legionella spp. Pneumonia

> MAC

> Mycoplasma pneumoniae

Adverse Effect

> Irritative reaction

> Cholestatic hepatitis

> Polymorphic ventricular tachycardia with QT prolongation

> Class Ia and III antiarrhythmics

> Electrolyte abnormality

> Prolong QT interval

> Infantile hypertrophic pyloric stenosis

Drug Interactions

Lincosamides

> Clindamycin & lincomycin

> No therapeutic advantages for lincomycin over clindamycin

> Bind 50S ribosome, interfere with the transpeptidation reaction

Activities

> Pneumococci, group A streptococci

> Anaerobic bacteria

> Toxoplasmosis > In combination with pyrimethamine

> Pneumocystis jirovecii > In combination with primaquin

> Plasmodium falciparum > In combination with quinine

Mechanism of Resistance

> Target site alteration > Methylation of adenosine, MLSB phenotype

> Inactivation of antibiotics

> Poor permeability of drug > Enterobacteriaceae, P.aeruginosa spp., Acinetobacter spp.

Double disc test or D-test

Indications

Conditions Comment

Polymicrobial IAI

• Increase resistance of B.fragilis

Gynecologic pelvic infections

• Use in combination with aminoglycosides

Gas gangrene

• Suppressing the alpha toxin activity from C.perfringens

Anaerobic bronchopulmonary infection

• These organisms are resistant to penicillin; B.fragilis, B.melaninogenicus, Prevotella ruminicola, B urelyticus

Staphylococcal infections • Oral therapy for CA-MRSA • β-lactam allergy for MSSA • Limited bactericidal rate compared with β-lactam • Emerging of clindamycin resistance • Better choices for MSSA and MRSA treatment other

than clindamycin are preferred

Adverse Effect

> Allergic reactions

> C.difficile colitis

> Reversible elevation of transaminase level

> Hematologic toxicities

> Hypotension and EKG change with lincosamide

> Local irritation

Aminoglycosides

Drugs Multiple daily dose Once daily dose

Amikacin 7.5 mg/kg q 12 h 15 mg/kg q 24 h

Gentamicin 2 mg/kg load, then 1.7-2 mg/kg q 8 h 5.1 mg/kg q 24 h (7 mg/kg q 24 h if critically ill)

Kanamycin 7.5 mg/kg q 12 h 15 mg/kg q 24 h

Netilmicin 1.7-2 mg/kg q 8 h 6.5 mg/kg q 24 h

Paromomycin 25-35 mg/kg/day po in 3 divided doses x 7 days

Streptomycin 10-15 mg/kg IV q 12 h for plague and tularaemia

1 g IM/IV q 24 h for brucellosis For M.TB 15 mg/kg q 24 h 25-30 mg/kg TM 2-3x/week

Tobramycin 5-7 mg/kg IV loading then 1.7-2 mg/kg q 8 h

5.1 mg/kg IV q 24 h (7 mg/kg q 24 h if critically ill)

Aminoglycosides

> Concentration-dependent killing

> Prolonged post-antibiotic effects

> Additive to or synergistic with β-lactam

> Once daily dosing of aminoglycosides > Efficacious as the traditional multiple-dose

> Lower but not eliminate nephrotoxicity and ototoxicity

> Should not be used in patients with enterococcal endocarditis

> Needs further study in selected population > Pregnancy, cystic fibrosis, meningitis, osteomyelitis

Activities

> Gram-negative bacilli > Enterobacteriaceae, P.aeruginosa, Acinetobacter spp. > Yersinia pestis, Francisella tularencis, brucellosis, bartonellosis

> Gram-positive bacteria > Enterococcus spp. (combined with penicillin or vancomycin)

> Mycobacteria

> Colonic protozoa (Entamoeba histolytica) and leishmaniasis

> Poromomycin

> NO activity against > Stenotrophomonas maltophilia, Burkholderia cepacia, MRSA,

S.pneumoniae, > All anaerobic bacteria

Indications of Use

Conditions Comments

Bacteremia • In combination with β-lactam • Enterococci and Streptococcal endocarditis

Pneumonia • Reserved for hospital-acquires infection, however benefit is

unclear.

Intra-abdominal infection • Combination of aminoglycoside and metronidazole are not

recommended • Alternative first choice is β-lactam/β-lactamase inhibitor

Urinary tract infection • Equally effective as comparators in terms of all-cause

mortality and treatment failure • Excrete unchanged in urine with concentration exceed MIC

Prophylaxis • Alternative in patients with β-lactam allergy • Genitourinary and gastrointestinal procedures

Orthopaedic surgery • Antibiotic-impregnated cement in primary hip and knee

arthroplasties

Adverse Effects

> Ototoxicity > Cochlear toxicity

> Vestibular toxicity

> Nephrotoxicity

> Neuromuscular blockade

Risk Factors for Aminoglycosides Nephrotoxicity

Patients-related factors

Concomitant drugs Aminoglycoside

factors Others

• Older patient • Pre-existing renal

disease • Female • Male

• Vancomycin • Amphotericin B • Furosemide • Clindamycin • Piperacillin • Clindamycin • Cephalosporins • Methoxyflurane • Foscarnet • Cyclosporin • Radiocontrast

• Recent aminoglycoside therapy

• Larger doses • Treatment for ≥3

days • Drug choice (e.g.

gentamicin) • Frequent dosing

interval

• Volume depletion • Hypotension • Hepatic dysfunction

Tetracyclines

Classes Drugs dosing

First generation (Short-acting)

Oxytetracycline Tetracycline

500 mg q 6 h 500 mg q 6 h

Intermediate-acting Democycline 150 mg q 6 h or 300 mg q 12 h

Second generation (Long-acting)

Doxycycline Minocycline

200 mg for first days, then 100 mg q 12 h 200 mg for first days, then 100 mg q 12 h

Third generation glycylcycline (Long-acting)

Tigecycline 100 mg then 50 mg q 12 h

Mechanism of Action

> Inhibiting bacterial protein synthesis

> Reversibly binding to the 30S ribosomal subunit

> Prevent peptides change elongation

> Bacteriostatic properties

> Doxycycline > Bind 70S ribosome that displays inhibition of protein

synthesis in mitochondria > Exhibit activity against various protozoa

Activities

Gram-positive bacteria Gram-negative bacteria Atypical bacteria

S.aureus CoNS S.pneumoniae L.monocytogenes A.Israelii

Enterobacteriaceae B.pseudomallei S.maltophlia A.hydrophila Brucella spp. Bartonella spp.

Mycoplasma spp. L. pneumophila Chlamydia spp.

Spirochetes & Rickettsiae Mycobacterium & nocardia Parasites

Borrelia burgdorferi Leptospira spp. Treponema pallidum Rickettsiae spp. Anaplasma phagocytophilum Ehrlichia chaffeensis Ehelichia canis

Mycobacterium fortuitum Mycobacterium abscessus M.\ycobacterium chelonae Nocardia farcinaca

Plasmodium falciparum Toxoplasma gondii Giardia lamblia Trichomonas vaginalis Leishmania major Entamoeba histolytica

Indications

Adverse Effects

> Gastrointestinal side effects > Nausea, vomiting, diarrhea, heartburn and epigastric pain

> Pill esophagitis, esophageal ulceration

> Photosensitivity and hyperpigmentation > Sun-exposed areas

> edema, papules, vesiculations and onycholysis

> Blue-black, muddy-brown pigmentation

> Teeth and bone > Teeth discoloration

> Enamel hypoplasia, inhibit bone growth in infant

> Hepatotoxicity

Adverse Effects

> Nephrotoxicity > Azotemia, hyperphosphatemia and acidosis

> Neurotoxicity > Reversible dizziness, vertigo, tinnitus

> Pseudotumor cerebri

> Hypersensitivity reactions

> Teratogenicity

Drug-drug Interaction

Interacting agent Effect Comments

Food Tetracycline Food may reduce absorption by 50% Doxycycline Absorption may reduced by up to 20% when taken with food or milk Minocycline Absorption may be reduced by up to 20% when taken with food or milk

Bioavailability is 60%-80% when taken on empty stomach Food effect not clinically significant Food effect not clinically significant

Divalent or trivalent cations: Al, Ca, Mg, Fe, Zn

Significant reduction of all tetracycline absorption

Should not be administered concurrently with foods or drugs containing divalent or trivalent cations (i.e., antacids, sucralfate, didanosine, multivitamins)

Kaolin and pectin Significant reduction of tetracycline absorption

Bismuth subsalicylate Significant reduction of tetracycline absorption Separate administration of tetracycline from divalent or trivalent cations by 2 h

Sodium bicarbonate May decrease absorption of tetracycline

Drug-drug Interaction

Interacting agent Effect Comments

Cimetidine Decreased tetracycline absorption Effect not clinically significant

Carbamazepine, phenytoin, barbiturates

Decreased half-life of doxycycline Increases hepatic metabolism

Chronic ethanol ingestion Decreased half-life of doxycycline but not tetracycline

Possible mechanism: induction of hepatic microsomal enzymes

Methoxyflurans or fluorinated anesthetic

Nephrotoxicity when administered with tetracycline agents

Diuretics Increased blood urea nitrogen Volume depletion may increase the nephrotoxic effects of tetracyclines by unknown mechanisms

Oral anticoagulants Increase risk of bleeding Tetracyclines may impair utilization of prothrombin and may decrease vitamin K production by intestinal bacteria; tigecycline decreases warfarin clearance, although a study found no effect in healthy volunteers

Glycyclines

> Tigecycline was approved by FDA in June 2005 > Complicated skin and skin structure infection

> Complicated intraabdominal infections

> Community-acquired bacterial pneumonia

> Reversible binding to bacterial 30S ribosomal subunits

> Inhibiting bacterial protein synthesis

> Bacteriostatic

Pharmacology

Pharmacokinetic Comment

Administration and dosing • Intravenous formulation • Poor oral absorption

• Loading 100 mg then 50 mg iv q 12 h

• Adjust dose in hepatic impairment

Drug distribution • Plasma protein binding 71% to 89%

• High volume of distribution 7 to 10 L/Kg

• Limited urinary recovery of active drug

• Extensively distribution into the tissues

Drug Elimination • Primary route of elimination is biliary excretion of unchanged

• 32% is eliminated in the urine

Antimicrobial Activity

Gram-Positive Bacteria

• Staphylococcus spp.

• Enterococcus spp.

• Streptococcus spp.

• L.monocytogenes

Gram-Negative Bacteria

• Non-ferment bacilli

• Enterobacteriaceae

• H.Influenzae

• Moroxella

• EXCEPT

• Proteus spp.

• Providencia spp.

• Morganella spp.

• P.aeruginosa

Anaerobic Bacteria

• Gram positive

• Gram negative

Atypical Bacteria

• C.pneumoniae

• C.trachomatis

• M.pneumoniae

• M.hominis

Adverse Effects

> GI toxicities

> Hepatotoxicity and pancreatitis

> Other side effects; headache, anemia, hypoproteinemia, asthesia, phlebitis, elevate BUN

FDA Warning

> In 2013 the FDA approved a new boxed warning about this risk of death and warned health care professionals to reserve tigecycline for use in situations when alternative treatments are not suitable

Sulfonamides & Trimethoprim

> Sulfonamides > Bacteriostatic

> Interfering with microbial folic synthesis

> Inhibit competitively the incorporation of PABA in to tetrahydropteroic acid synthase

Mechanism of Action

PABA

Sulfonamides

Dihydrofolic acid Tetrahydrofolic acid

Other precursors

DNA Purines

Tetrahydropteroic acid synthase

Dihydrofolate reductase

Trimethoprim

Indication

> Urinary tract infection

> Skin and soft tissue infection

> Gastrointestinal tract infection

> Other infections > Brucellosis, meliodosis, B. cepacia, S.maltophilia,

L.monocytoges nocardiasis, Mycobacterium chelonae, Mycobacterium fortuitum, Cyclospora cayetanensis, Cystoisopora belli, P.falciparum, P.jirovecii, Toxoplasma gondii, Acanthamaeba

Adverse Effects

> Hematologic toxicities > Impaired folate usage

> Magaloblastic marrow, thrombocytopenia, grnulocytopenia

> Methemoglobinemia

> Nephrotoxicities > Renal insufficiency, hyperkalemia, interstitial nephritis,

RTA

> Drug-induced cholestasis > Liver transplant recipient

Drug-drug Interaction

Increase TMP-SMX levels

• Carbamazepine

• Phenobarbital

• Phenytoin

• Rifampin

• Rifapentine

• Secobarbital

Increase toxicities of TMP-SMX

• ACEI/ARB

• Amantadine

• Methotrexate

• Pyrimethamine

• Sulfonylureas

• Warfarin

• Cyclosporin

Increase drug levels by TMP-

SMX

• Amiodarone

• Bosentan

• Fluoxetine

• Glimeperide

• Glipizide

• Losartan

• Montelukast

• Nateglinide

• Paclitaxel

• Phenytoin

Increase drug levels by TMP-

SMX

• Pioglitazone

• Repaglinide

• Rifampin

• Rosiglitazone

• Warfarin

• Zafirlukast