B UGS AND D RUGS A R EVIEW OF A NTIBIOTICS Curtis M. Grenoble, MHS, PA-C Lock Haven University

L ECTURE O UTLINE Mechanisms of Action Mechanisms of Resistance Bacterial Resistance Principles of Therapy Choosing an Antibiotic Gram positives, gram negatives & anaerobes Case Scenarios

M ECHANISMS OF A CTION Goal of antibiotic treatment: Limit host toxicity Maximize specific microbe toxicity Bacteriocidals kill bacteria Bacteriostatics inhibit further growth Allowing immune system to regain control

M ECHANISMS OF A CTION Common bacteriocidals β-Lactams Penicillins Cephalosporins Carbapenems Monobactams Aminoglycosides

M ECHANISMS OF A CTION Common bacteriostatics Sulphonamides Tetracyclines Chloramphenicol Macrolides Erythromycin Clarithromycin Azithromycin Trimethoprim (often used along with sulfonamides i.e. Bactrim)

M ECHANISMS OF R ESISTANCE Intrinsic Resistance Analogous to innate (non-specific) human immunity Examples: Obligate anaerobic bacteria to aminoglycosides Gram (–) bacteria to vancomycin Acquired Resistance Analogous to specific action of human immunity Bug, over time, develops resistance to specific mechanism of action Mutation of resident genes, or Acquire new genes and incorporate into own DNA Major problem with over-prescribing antibiotics Pt demands (stronger) antibiotic and practitioner gives in (viral URI, viral pharyngitis) Selects for those organisms with resistance, proliferation, further mutation

P RINCIPLES OF A NTIBACTERIAL THERAPY First, attempt to specifically ID the bug if accessible Obtain culture Stain specimen and ID under microscope Cocci Bacilli C&S Choose narrowest spectrum and most inexpensive drug that will effectively eliminate the infection.

P RINCIPLES O F A NTIBIOTIC T HERAPY Susceptibility If peak serum concentration of drug is 4-times the MIC (Minimum Inhibitory Concentration) Breakpoint Concentration of antibiotic that separates susceptible from resistant bacteria

P RINCIPLES OF A NTIBACTERIAL T HERAPY Pharmacodynamics Concentration dependent e.g. Aminoglycoside once daily Time dependent e.g. Amoxil for pneumococcal AOM Need to maintain high levels of abx over MIC x number of days More difficult for drug to reach inner ear Younger male with UTI TB therapy

P RINCIPLES OF A NTIBIOTIC T HERAPY Site of Infection – Difficult to treat Meningitis – blood-brain barrier, some don’t cross at all, others not enough Bacterial endocarditis – Growth may be difficult to penetrate and often possess both innate and acquired immunity Osteomylitis – dense tissue, low vascularity Intraocular infections – no blood in vitreous, special vessels mediate exchange of nutrients with vitreous Abscesses – encapsulated, thick, fibrous, poorly vascularized Need to I&D

P RINCIPLES OF A NTIBACTERIAL T HERAPY Site of Infection – Easy to Treat Urinary Tract Infection High drug concentration in urine due to elimination via kidneys In the past, PCN purified from urine to reuse before made synthetically

P RINCIPLES OF A NTIBACTERIAL T HERAPY Empiric Therapy Life-threatening infection Need to treat immediately with best guess of causative organism Based on signs, symptoms and epidemiology Need to know most likely causative organism in a given institution Community-acquired Infection Need to know most likely causative organism in: Community Population Age group

C HOICE OF A NTIBACTERIAL D RUGS β-Lactams Penicillins β-lactamase susceptible – Penicillin G (parenteral) V (oral), ampicillin, amoxicillin, ticarcillin β-lactamase resistant – Methicillin, oxacillin, nafcillin, cloxacillin, dicloxacillin Amoxicillin-Clavulanic acid (Augmentin) Cephalosporins 1 st Generation – Cephalexin, cephradine, cephadroxil 2 nd Generation – Cefaclor, cefoxitin, cefuroxime, cefdinir, ceftibuten 3 rd Generation – Ceftriaxone 4 th Generation - Cefepime Carbapenems Imipenem, meropenem, ertapenem Monobactams Aztreonam

C HOICE OF A NTIBACTERIAL D RUGS Non- β-Lactams Vancomycin Aminoglycosides – streptomycin, gentamicin, tobramycin Macrolides and Ketolides – erythromycin, azithro-, telithro- Licosamides – clindamycin Chloramphenicol Tetracyclines – tetracyclin, doxycycline, minocycline Fluoroquinolones – ciprofloxacin, gati-, moxi-, levo-, etc Rifampin Metronidazole

C HOICE OF A NTIBACTERIAL D RUGS Penicillin G and V Spectrum Spirochetes Treponema pallidum (Syphilis) Borrelia (Lyme Dz) Streptococci Groups A and B Many strains of S. pneumoniae Clostridium species Penicillin G and V Sensitive Diseases Syphilis Strept infections groups A and B Tetanus

C HOICE OF A NTIBACTERIAL D RUGS Ampicillin Spectrum Enterococcus faecalis Salmonella Haemophilus influenzae Ampicillin Diseases E. faecalis UTI Salmonellosis H. flu AOM & epiglottitis Amoxicillin-Clavulanic Acid (Augmentin) Pasturella multocida Dog/Cat bite Wounds obtained in wet environment

C HOICE OF A NTIBACTERIAL D RUGS 1 st Generation Cephalosporins Spectrum Escherichia Coli Klebsiella pneumoniae Proteus mirabilis 1 st Generation Cephalosporins Diseases Community acquired UTI UTI secondary to indwelling bladder catheter Klebsiella pneumoniae pneumonia (alcoholics, DM, lung dz) Abdominal infection Surgical site/soft tissue infection

C HOICE OF A NTIBACTERIAL D RUGS Oral 2 nd Generation Cephalosporins Spectrum Gram positive cocci (streptococci, staphylococci) Haemophilus influenzae Oral 2 nd Generation Cephalosporins Diseases Otitis media Sinusitis Lower respiratory tract infection

C HOICE OF A NTIBACTERIAL D RUGS Parenteral 3 rd Generation Cephalosporins Spectrum Enteric gram-negative rods Pseudomonas Listeria Parenteral 3 rd Generation Cephalosporins Diseases Gonorrhea (Ceftriaxone) Salmonellosis Listeria bacterial menningitis

C HOICE OF A NTIBACTERIAL D RUGS 4 th Generation Cephalosporins Spectrum Gram-positive bacteria Gram-negative bacteria P. aeruginosa Enterobacteriaceae 4 th Generation Cephalosporins Diseases Intra-abdominal infections Respiratory tract infections Skin infections

C HOICE OF A NTIBACTERIAL D RUGS Vancomycin Spectrum Gram-positive cocci (enterococci, streptococci, staphylococci) Vancomycin Diseases Methicillin-resistant staph aureus Second-line for most gram-positive P.O. in pseudomembranous colitis Not absorbed when taken P.O. Becomes “topical” tx for UC Use Vanco sparingly and only in demonstrated cases of resistance to β-lactams to prevent MRSA from developing resistance Not for routine empiric therapy

C HOICE OF A NTIBACTERIAL D RUGS Aminoglycoside spectrum Gram-negative aerobes Staph No activity against anaerobic bacteria or in acidic/low oxygen Aminoglycoside diseases SevereURI Gram-neg bacteremia Tularemia, plague, brucellosis – Streptomycin (2 nd line TB)

C HOICE OF A NTIBACTERIAL D RUGS Macrolides spectrum (bacteriostatic) Gram-positive bacteria Legionella Chlamydia Helicobacter pylori Macrolides diseases Strept pharyngitis in PCN-allergic (erythromycin- don’t need broader spectrum if not indicated) Community-acquired pneumococcal pneumonia Legionnaire’s disease Gastric ulcers

C HOICE OF A NTIBACTERIAL D RUGS Tetracyclines spectrum (bacteriostatic) Gram-positive bacteria Gram-negative bacteria Borrelia (Lyme disease) Chlamydia Tetracyclines diseases Bacterial chronic bronchitis Lyme disease Skin and soft-tissue infections Syphillis Acne vulgaris – suppresses resident P. acnes flora, prevents from chopping non-irritating long chain FA to irritating short-chain FA

C HOICE OF A NTIBACTERIAL D RUGS Sulfonamides & Trimethoprim spectrum E. Coli H. flu Other gram-neg bacteria Sulfonamides & Trimethoprim diseases Community-acquired UTI (Bactrim) Otitis media Bacterial URI

C HOICE OF A NTIBACTERIAL D RUGS Fluoroquinolones spectrum Pseudomonas aeruginosa Other gram-neg bacteria Fluoroquinolones diseases UTI Bacterial gastroenteritis Community-acquired pneumonia

C HOICE OF A NTIBACTERIAL D RUGS Metronidazole spectrum Anaerobic bacteria only Mostly gram-negative Bacteroides species Also an anti-parasitic Metronidazole diseases Tough to treat anaerobic abscesses of abdomen, brain or lung Bacterial vaginosis Drug of choice: Antibiotic-associated pseudomembranous colitis

D URATION OF T HERAPY & T REATMENT F AILURE V S. S UCCESS Treatment duration varies according to disease Refer to drug guides for dosage and duration No trials for many diseases, therefore duration not firmly established Duration Not too short – need to fully treat/resolve infection Need to avoid resistance Success = no relapse when treatment is d/c New infection with different organism is considered a success for initial infection Failure = recurrence of infection with identical organism Failures need >4 wk course & combination treatment

C OMMON S IDE -E FFECTS AND A DVERSE R EACTIONS All antibiotics can elicit allergic responses Mild, annoying rashes, etc. Anaphylaxis Stevens-Johnson syndrome All antibiotics target normal flora in addition to pathogens May lead to overgrowth of Candida – Yeast Infxn May lead to overgrowth of Clostridium difficile Mild diarrhea to severe life-threatening complications (pseudomembranous colitis) D/C offending antibiotic Supportive therapy Drug of choice: Metronidazole (Vancomycin 2 nd line)

C OMMON S IDE -E FFECTS AND A DVERSE R EACTIONS β-Lactams 1-4% of treatment courses result in allergic reaction Severe: anaphylaxis, TEN, Stevens-Jonhnson syndrome, pseudomembranous colitis (rare) Mild: rash, GI upset, diarrhea Vancomycin Red Man Syndrome – pruritus, flushing, erythema Phlebitis at infusion site Nephrotoxicity and Ototoxicity rare Aminoglycosides Nephrotixicity – accumulation in peritubular space Ototoxicity – can destroy hair cells, auditory/vestibular Neuromuscular depression with rare respiratory depression

C OMMON S IDE -E FFECTS AND A DVERSE R EACTIONS Macrolides Serious adverse reactions very rare GI side effects – burning, nausea, nomiting (up to 50% of pts) Hepatotoxicity and ototoxicity rare QT Prolongation Lincosamides GI distress Pseudomembranous colitis secondary to C. diff toxin (Metronidazole) Chloramphenicol Bone marrow suppression Gray syndrome (cyanosis, hypotension, death) – infants

C OMMON S IDE -E FFECTS AND A DVERSE R EACTIONS Tetracyclines Contraindicated in children <8 yrs old Mottling of permanent teeth Contraindicated in pregnancy – teratogenicity GI distress Phototoxic skin reactions Sulfonamides and Trimethoprim Generally safe Minor skin rashes to erythema multiforme and SJS, TEN Hematologic complications – agranulocytosis, anemia Renal insufficiency caused by crystal formation

C OMMON S IDE -E FFECTS AND A DVERSE R EACTIONS Fluoroquinolones GI distress – nausea, diarrhea (<5%) CNS effects – insomnia, dizziness (<5%) Phototoxicity Metronidazole GI distress – nausea Metallic taste, stomatitis, glossitis Contraindicated in pregnancy - mutagenicity Warning: Cautious use of Fluoroquinolones due to risk of tendon ruptures associated with their use. Contraindicated for use in pregnant women and patients < 18 yrs of age because of evidence of cartilage damage in developing joints.

C ASE S CENARIO 1 30 year-old male presents with dysuria and a painful, swollen testicle that is red and tender. Diagnosis? Bug? Drug?

C ASE S CENARIO 1 30 year-old male presents with dysuria and a painful, swollen testicle that is red and tender. Diagnosis? Orchitis Bug? Neisseria gonorrhoeae or Chlamydia trachomatis Drug? Ceftriaxone & Doxycycline

C ASE S CENARIO 2 A 50 year-old lifetime smoker presents with productive cough of dark, jelly-like sputum. He has rales in the right upper lung field. His CXR reveals a RUL infiltrate. Diagnosis? Bug? Drug?

C ASE S CENARIO 2 A 50 year-old lifetime smoker presents with productive cough of dark, jelly-like sputum. He has rales in the right upper lung field. His CXR reveals a RUL infiltrate. Diagnosis? Pneumonia Bug? H. influenza Drug? Levofloxacin (Levaquin) or Ceftriaxone or Augmentin

C ASE S CENARIO 3 A 12 year-old girl suffers a cat bite to her LIF (left index finger). The fingers are flexed and there is redness and tenderness along the flexor tendon surface extending into the forearm. She cannot extend the finger. Diagnosis? Tenosynovitis Bug? Pasturella Drug? Amoxicillin/Clavulanic Acid (Augmentin)

C ASE S CENARIO 4 A 35 year-old, healthy, recently sexually active female develops dysuria, urgency, and polyuria. She has suprapubic tenderness and is afebrile. Diagnosis? Bug? Drug?

C ASE S CENARIO 4 A 35 year-old, healthy, recently sexually active female develops dysuria, urgency, and polyuria. She has suprapubic tenderness and is afebrile. Diagnosis? UTI Bug? E. Coli Drug? Bactrim

C ASE S CENARIO 5 A 17 year-old returns from a rock concert where hundreds of people camped outside near a stream overnight. She has abdominal pain, high fever, and severe, bloody diarrhea. Diagnosis? Bug? Drug?

C ASE S CENARIO 5 A 17 year-old returns from a rock concert where hundreds of people camped outside near a stream overnight. She has abdominal pain, high fever, and severe, bloody diarrhea. Diagnosis? Gastroenteritis Bug? Shigella Drug? Ciprofloxacin

C ASE S CENARIO 6 A middle-aged man returns for a third episode of a painful, red, warm nodule on the nape of his neck tha recurs despite antibiotics and I&D. Diagnosis? Bug? Drug?

C ASE S CENARIO 6 A middle-aged man returns for a third episode of a painful, red, warm nodule on the nape of his neck tha recurs despite antibiotics and I&D. Diagnosis? Furuncle/Carbuncle Bug? MRSA Drug? Vancomycin

C ASE S CENARIO 7 A 32 year-old nonsmoker complains of a cough of 3 weeks duration. Placed on amoxicillin 10 days ago without relief. Pt is afebrile. Diagnosis? Bug? Drug?

C ASE S CENARIO 7 A 32 year-old nonsmoker complains of a cough of 3 weeks duration. Placed on amoxicillin 10 days ago without relief. Pt is afebrile. Diagnosis? Pertussis (whooping cough) Bug? Bordatella pertussis Drug? Erythromycin

C ASE S CENARIO 8 An elderly male from an ECF is hospitalized. He suffered a CVA and has altered consciousness. 2 days s/p admission, he becomes febrile and septic. CXR shows large upper lobe infiltrates. Diagnosis? Bug? Drug?

C ASE S CENARIO 8 An elderly male from an ECF is hospitalized. He suffered a CVA and has altered consciousness. 2 days s/p admission, he becomes febrile and septic. CXR shows large upper lobe infiltrates. Diagnosis? Aspiration pneumonia Bug? Bacteroides fragilis Drug? Clindamycin

C ASE S CENARIO 9 A healthy young adult male marathon runner steps on a nail that punctures his running shoe producing a wound in the sole of his left foot. The wound becomes reddened, warm and painful. The infection is localized around the puncture site on exam and the patient’s exam is otherwise normal. Diagnosis? Bug? Drug?

C ASE S CENARIO 9 A healthy young adult male marathon runner steps on a nail that punctures his running shoe producing a wound in the sole of his left foot. The wound becomes reddened, warm and painful. The infection is localized around the puncture site on exam and the patient’s exam is otherwise normal. Diagnosis? Puncture wound, wet environment Bug? Pseudomonas aeruginosa Drug? Augmentin (or Cefepime)

C ASE S CENARIO 10 A young healthy female was seen by you in the office one week ago for an uncomplicated acute cystitis. You prescribed a 3-day course of Macrodantin, which she finished. A day after finishing the medication, she developed severe diarrhea and sees you that day again in the office. She denies recent travel, dietary changes, or exposure to sick persons. She has a fever, looks sick, and has general abdominal tenderness. You admit her to the hospital for treatment. Diagnosis? Bug? Drug?

C ASE S CENARIO 10 A young healthy female was seen by you in the office one week ago for an uncomplicated acute cystitis. You prescribed a 3-day course of Macrodantin, which she finished. A day after finishing the medication, she developed severe diarrhea and sees you that day again in the office. She denies recent travel, dietary changes, or exposure to sick persons. She has a fever, looks sick, and has general abdominal tenderness. You admit her to the hospital for treatment. Diagnosis? Pseudomembranous colitis (abx enterocolitis) Bug? Clostridium difficile Drug? Metronidazole

C ASE S CENARIO 11 A 29 year-old sexually active heterosexual female returns from hiking in the Mid-Atlantic region in the spring. One day after hiking, she notes an attached, engorged tick on her body, and removes the tick. Seven days later she develops a bull’s eye rash on her trunk, myalgias, fatigue, and sees you in the office that day. She is otherwise healthy and her last menstrual period was two months ago. You are seeing her in a mobile medical van and do not have the availability of any immediate diagnostic tests. She has no signs of serious systemic infection but does have the described rash with no other skin abnormalities and a mild fever. Diagnosis? Bug? Drug?

C ASE S CENARIO 11 A 29 year-old sexually active heterosexual female returns from hiking in the Mid-Atlantic region in the spring. One day after hiking, she notes an attached, engorged tick on her body, and removes the tick. Seven days later she develops a bull’s eye rash on her trunk, myalgias, fatigue, and sees you in the office that day. She is otherwise healthy and her last menstrual period was two months ago. You are seeing her in a mobile medical van and do not have the availability of any immediate diagnostic tests. She has no signs of serious systemic infection but does have the described rash with no other skin abnormalities and a mild fever. Diagnosis? Lyme disease Bug? Borrelia burgdorferi Drug? Amoxicillin (not doxy – may be pregnant)