17 Dec, 2016
Antibiotics and Antifungals
 BACTERIA:
  1. Gram positive cocci includes staphlylococcus, streptococcus , enterococcus and micrococcus.
  2. Gram positive bacilli includes campylobacter, clostridium, corynebacterium, actinomyces, bacillus, listeria, lactobacillus and diptheroids
  3. Gram negative cocci includes nisseria and moraxella. 
  4. Gram negative anaerobic bacilli includes bacteroids, prevotella and fusobacterium. 
  5. Gram negative aerobic bacilli includes E.coli , pseudomonas, proteus, acinetobacter, enterobacter, morganella , klebsiella, hemophillus, legionella, campylobacter , salmonella, shigella and helicobacter.
  6.  Atypicals include Chlamydia and Mycoplasma
                     
 
ANTIBIOTICS
 
The main classes of antibiotics are:
1. Beta lactams
2. Flouroquinolones
3. Macrolides
4. Cyclic peptides like Vancomycin and polymyxin
5. Aminoglycosides
6. Tetracyclines
7. Anti-anerobes like metronidazole
8. Sulfur antibiotics
9. Linezolid
10. Tigecycline
11. Daptomycin
12. Clindamycin
13. Rifampin
 
Beta-lactam antibiotics are bactericidal drugs and they include:
a) Penicillins
b) Cephalosporins
c) Carbapenems
d) Monobactams
e) Beta-lactamase inhibitors (Beta-lactamases are enzymes that open the beta-lactam ring, inactivating the antibiotic).
 
PENCILLINS
 
The group can be divided in four subgroups:
1) Natural penicillins: They have narrow spectrum containing gram-positive and gram-negative cocci (streptococci, pneumococci, enterococci, meningococci), gram-positive bacilli (corynebacteria, L.monocytogenes), spirochetes (Leptospira sp., Treponema sp., Borrelia sp.), and most of anaerobes (peptostreptococci, clostridial species, Actinomyces). Eg: Procaine PCN, Benzathene PCN, Penicillin V
2) Anti-staphylococcal penicillins: They are resistant to staphylococcal beta-lactamase but not to other beta-lactamases produced by gram-negative microbes. Pencillinase producing staph aureus include both MSSA and MRSA. They are active only against MSSA. Eg: Nafcillin, Oxacillin, Dicloxacillin, methicillin
3) Aminopenicillins: The drugs owe spectrum similar to natural penicillin with extension against common gram-negative bacteria like E.Coli, Salmonella, Shigella, Proteus, Helicobacter pylori, or Haemophilus influenzae. They are more effective than natural penicillin against enterococci and listeriae. Eg: Ampicillin, Amoxicillin
4) Penicillins effective against pseudomonads: Like Carbenicillin, ticarcillin, azlocillin, mezlocillin, and piperacillin.
 
 
CEPHALOSPORINS:
 
Although cephalosporins are relatively broad-spectrum antibiotics, none of them is effective against enterococci and listeriae.
1) 1st generation: The drugs are used predominantly against gram-positive cocci (streptococci and staphylococci). Their spectrum further includes corynebacteria, meningococci, and some community-acquired stems of gram-negative rods like Escherichia coli or Proteus mirabilis. Eg: Cefazolin, cephalexin. Used mostly in skin and soft tissue infections, UTI, MSSA and post-OP prophylaxis.
2) 2nd generation: In addition to 1 st generation, they also cover some gram negative bacteria like Haemophilus influenzae, Moraxella catarrhalis, or less susceptible strains of E.coli. Eg: Cefuroxime, cefotetan and cefoxitin.
3) 3rd generation: They have similar spectrum as 2nd generation but with enhanced activity against gram-negative bacteria and weaker effect against staphylococci and other gram positives than 1st generation cephalosporins. Eg: Cefotaxime, cefpodoxime and ceftriaxone. Some of them like ceftazidime have anti-pseudomonas activity. Cefpodoxime is the only oral 3 rd generation cephalosporin.
Used in meningitis, PNA, UTI, Endocarditis, abdominal infections, Septic arthritis, gonorrhea and pseudomonas infections. Ceftriaxone can increase biliary sludge. Both 3 rd and 4 th generation have poor anaerobic coverage.
4) 4th generation: Antibiotics of this group have a broad spectrum summarizing the 1st, 2nd and 3rd generation. They can resist some potent beta-lactamases. Nevertheless, their activity against staphylococci is not better than with cephalexin and activity against Pseudomonas is not better than with ceftazidime. It also has poor anaerobic coverage. Eg: Cefepime. Used in febrile neutropenia and mixed aerobic infections.
5) 5 th generation: They are similar to ceftriaxone but with greater gram positive coverage, including MRSA. Ceftaroline is a broad- spectrum cephalosporin with activity against MRSA, which has been approved by the FDA for CAP, but not for CAP caused by MRSA, or for HAP, VAP, or HCAP. It has no activity on pseudomonas and acinetonbacter. It is used mainly for skin infections and pneumonia. Eg: Ceftaroline.
 
 
CARBAPENEMS
 
They have broad spectrum activity against Gram positives (Except MRSA), Gram negatives and excellent coverage for anaerobes. Eg: Imipenem, Meropenem, Doripenem, Ertapenem (No pseudomonas or acinetobacter activity). Doripenem has FDA warning against using it for pneumonia. 
 
Used mostly for the same indications as 4 th generation cephalosporins. Ertapenem is a once daily drug and a good choice in intra-abdominal infections. They also have some cross reactivity for PCN allergy. Imipenems can also lowerseizure threshold. 
 
Specifically indicated for ESBL (extended spectrum beta lactamase) producing enterobacteriaceae like E.coli, Klebsiella, pseudomonas, proteus, salmonella, shigella and enterobacter. ESBL are enzymes that confer resistance to PCN, cephalosporins and aztreonam.
 
Carbapenemases are carbapenem-hydrolyzing beta-lactamases that confer resistance to a broad spectrum of beta-lactam substrates, including carbapenems. Treatment of these infections is done with other gram negative drugs like polymyxin, amikacin, aztreonam, colistin, fosfomycin and tigecycline.
 
 
MONOBACTAMS (AZTREONAM)
 
Aztreonam is like ceftriaxone for PCN allergic patients. It has excellent activity against gram negative bacilli only including pseudomonas but no gram positive or anaerobic activity. Used in PNA, UTI, abdominal sepsis, and skin/soft tissue infections. 
 
 
MACROLIDES
 
Used to treat S.Pneumoniae, Chlamydia, hemophillus, legionella and other atypical pneumonias, mycoplasma and bronchitis. It has similar profile to respiratory fluoroquinolones except for pseudomonas.
  • Azithromycin: Active against gram positive/negative and atypical. Mainly used for respiratory infections, Chlamydia urethritis and skin infections.  It can cause QT prolongation.
 
FLOUROQUINOLONES
 
They can prolong QT interval, transaminitis, tendon rupture
  • CIPRO: Mainly covers gram negatives including pseudomonas. Has poor gram positive and anerobic coverage. Used for UTI, diarrhea, abdominal infections, gonorrhea and osteomyelitis.
  •  LEVAQUIN: Mainly covers gram negatives including pseudomonas but also has some gram positive coverage (pneumococcus) and atypical coverage. Used for respiratory infections, UTI and skin/soft tissue infections.
  • MOXIFLOXACIN: Same as levaquin but also has better gram positive coverage, atypical coverage and better anerobic activity but doesn’t penetrate into urine and has no pseudomonas coverage. Used for respiratory, abdominal and soft tissue infections. 
Cipro and Levaquin are eliminated by kidneys but moxifloxacin is excreted by non renal pathways. 
 
 
CLINDAMYCIN
 
Active against Gram positive (staph/strep), anaerobes including bacteroides and PCP. Used mainly for skin/soft tissue infections, aspiration PNA, lung abscess, necrotizing fasciitis, and MRSA skin infections.
 
 
METRONIDAZOLE
 
  • Active mainly against anerobes and protozoa. Used in abdominal/pelvic abscess, C.Diff, giardiasis and trichomonas vaginalis.
  • It can cause disulfiram like effects with alcohol and leave metallic taste in mouth.
 
 
VANCOMYCIN:
 
Bactericidal against most gram positives including MRSA and bacteriostatic against enterococci. Vancomycin has no activity against gram negatives. Used in MRSA infections, meningitis, nosocomial PNA, CLABSI and endocarditis.
  • The usual dose is 30mg/kg followed by 30-60 mg/kg/day in 2 (or 3) doses for patients with normal renal function. Vanco trough should be obtained just prior to the next dose at steady state reorder unless there is a significant change in renal function. Target trough for conditions (Usually before 4 th dose). Once an adequate trough is obtained do not most infections is 10-20 mcg/ml (15-20 for CNS infections, VAP, osteomyelitis and endocarditis). 
  • It can cause Redman syndrome if administered too fast, which is a histamine mediated allergic reaction. It can also cause nephrotoxicity at high doses. It should not be given any faster than 1000mg/hr.
  • An AUC/MIC of ≥400 has been promoted as the target predictive of successful therapy. For example, 1g every 12 hours for an individual with normal renal function and average weight of 80 kg would only yield a 24-hour drug AUC of approximately 250 mg/ hr/L. Unless the pathogen had a vancomycin MIC of ≤0.5 mg/L, this dosage regimen would not generate the targeted AUC/MIC of ≥400.
  • It is dosed as Qdaily in patients on CRRT.
 
 
LINEZOLID
 
  • It is bacteriostatic and mainly used for MRSA pneumonia and VRE. 
  • Oral linezolid has close to 100% bioavailability. 
  • It can cause thrombocytopenia and peripheral neuropathy and reversible bone marrow suppression. It can also cause serotonin syndrome.
 
 
AMINOGLYCOSIDES   (GENTAMYCIN/AMIKACIN/TOBRAMYCIN)
 
  1. Bactericidal against aerobic gram negative bacilli including pseudomonas. Used mainly in empiric therapy of gram negative bacilli. No activity against gram positives.
  2. Can cause ototoxicity, Nephrotoxicity and neurotoxicity. The toxicity is increased with elevated trough levels. 
  3. All aminoglycoside dosing is based on ideal body weight. If obese, use adjusted body weight. ABW (kg) = IBW + 0.4 (TBW – IBW)
  • Amikacin dose for severe infections is 8-12mg/kg followed by 8mg/kg Q8hrs. Maintain a peak level of 25-30 and trough less than 10. Check peak 30 mins after 3 rd dose and trough just before the 4 th dose. Dosing in IHD is 8mg/kg post IHD. Dosing in CRRT is 10mg/kg loading dose followed by 8mg/kg Q 24-48 hrs.
  • Gentamycin/Tobramycin: dose for severe infections is 3mg/kg followed by 2mg/kg Q8hrs. Maintain a peak level >8 and trough <2. For synergistic effect with beta-lactams, use 1mg/kg Q8hrs. 
Pulse (once daily) aminoglycoside dosing is usually preferred unless the GFR is less than 40 or otherwise contraindicated.  It results in a higher peak serum concentration than traditional multiple daily dosing can achieve, which enhances the concentration-dependent bactericidal killing activity of the compound.  If GFR <40, can give one dose only.
  • Once a day dose for gentamycin or tobramycin in life-threatening patients is 7 mg/kg (Qdaily for GFR>60, Q36 hrs for GFR 45-60 and Q48 hrs for GFR 30-45). Maintain a peak level >25 and trough <2.
  • Once a day dose for amikacin is 15mg/kg (Qdaily for GFR>60, Q36 hrs for GFR 45-60 and Q48 hrs for GFR 30-45). Maintain a peak level <40 and trough <4.
For extended release dosing, check peak levels after 8-12 hours. For traditional dosing, check peak levels 30 mins after 3 rd dose. For trough, check 30 mins before next dose in extended interval dosing and 30 mins before the 4th dose in traditional dosing. Once a day dosing usually doesn’t need monitoring of peaks and trough unless renal function is changing. 
 
 
TETRACYCLINES (DOXYCYCLINE)
 
Bacteriostatic against gram positive/negative and atypicals. Also has activity against MRSA. Used mainly in urethritis and skin infections.
 
 
BACTRIM
 
Active against some gram positive/negatives except pseudomonas. Also has activity against MRSA. Used mainly in UTI, bronchitis, sinusitis and skin . Can cause leucopenia, thrombocytopenia and megaloblastic anemia due to anti-folate properties. 
 
 
TIGECYCLINE:
 
Has broad activity against resistant gram positives such as MRSA and VRE, CRE, Acineobacter, anaerobes, gram negatives but not pseudomonas, proteus or serratia. Used mainly for skin/soft tissue infections and intra-abdominal infections. 
  • Tigecycline doesn’t cover 4P’s: Pee (Urine), pseudomonas, proteus, providentia
  • Higher dose tigecycline (200mg loading dose followed by 100mg Q12) may improve clinical cure rates in VAP due to MDR gram negative organisms. However, there was no significant mortality benefit. Also, in this study, tigecycline was added as a second antibiotic.
  • FDA released a warning in September 2010, citing an increased mortality risk associated with tigecycline, compared with active comparator antibiotics. Clearly, tigecycline should be used only when no other effective antimicrobial agents are available. 
 
 
DAPTOMYCIN:
 
Very broad bactericidal activity against all gram positives including resistant MRSA and VRE. However, it is deactivated by surfactant in lungs and hence, not used for pneumonias. Used mainly for MRSA bacteremia and skin infections.
 
It can cause elevated CPK and LFT’s. Check cpk levels once a week to prevent myopathy. 
 
 
ANTIFUNGALS
 
Risk factors for fungal infections: Neutropenia, Immunosuppressed, organ transplants, TPN, Central venous catheters, Steroids, Mechanical Ventilation, Burns, Diabetes, Acute renal failure, Hemodialysis, use of broad spectrum antibiotics, prolonged stay in ICU and chemotherapy.
1. Azoles. Eg: fluconazole, voriconazole, Itraconazole, miconazole, 
Fluconazole and voriconazole are well absorbed orally but itraconazole is not. Fluconazole is eliminated in urine (mainly unchanged) and removed during haemodialysis. Voriconazole is eliminated in urine and extensively metabolized by liver. Itraconazole is mainly metabolized by liver and excreted in bile. Itraconazole is absorbed well in acidic pH.
2. Echinocandins. Eg: Micafungin, capsofungin. 
Capsofungin is metabolized by liver and not cleared by hemodialysis. 
3. Polyenes. Eg: Amphotericin and Nystatin. Generally, Amphotericin is the first-line therapy for invasive fungal and mold infections with a broad spectrum of activity including Candida spp., Aspergillus, Coccidioides immitis, Histoplasma capsulatum, Blastomyces , Cryptococcus, Zygomycetes, and Sporotrix spp.
Liposomal Amphotericin is Ampho attached to lipid molecules. It is associated with less renal toxicity. It also causes Hypokalemia and hypomagnesemia. 
4. Flucytosine. It has inferior activity to Ampho and should never be used as a lone choice. 
 
  • Drug of choice for invasive mycoses is Amphotericin, voriconazole, Posiconazole, Micafungin and Fluconazole. Choice of agents depends on whether the patient on previous azole prophylaxis, culture results, local fungal sensitivity, colonization, renal or liver disease, presence of drug-drug interactions, presence of hardware, immuno -suppresion, site of disease.
  • In ocular, urine or CNS infections, avoid echinocandins like micafungin. Instead use fluconazole which has high urine and CSF penetration. Oral fluconazole can be given as prophylaxis in organ transplant patients. Fluconazole is active against candida, Cryptococcus, histoplasma, Blastomyces, and coccidodes.
  • Itraconazole has wider spectrum than fluconazole but poor CSF penetration.
  • Drug of choice for candidiasis are fluconazole, micafungin, voriconazole and Amphotericin.  Drug of choice for aspergillosis are voriconazole, amphotericin and capsofungin. Drug of choice for cryptococcal meningitis is amphotericin, other Cryptococcus infections are fluconazole or itraconazole, and for ABPA is itraconazole/voriconazole/amphotericin. 
  • Duration of treatment for fungal infections is usually 14 days from negative cultures and 4 weeks for disseminated disease.
 
Pearls: 
  • Drugs active against MRSA are Bactrim, Vanco, Linezolid, Daptomycin, Tigecycline, telavancin, Clindamycin and Quinupristin.
  • In aspiration PNA, usually ceftriaxone or levaquin is sufficient as they have some anerobic activity. No need to routinely add flagyl or Clindamycin.
  • Drugs active against pseudomonas are Cipro, zosyn, gentamycin, amikacin,tobramycin, cefpime, ceftazidime, Imipenem, Meropenem, aztreonam and colistin. 
  • Drugs active against ESBL producing E.Coli and Klebsiella are carbapenems. 
  • Drugs for carbapenemase producing Klebsiella (KPC) are colistin and tigecycline. 
  • Drugs active against Acinetobacter are Meropenem, Unasyn, tigecycline, colistin, polymyxin, cefepime and amikacin.
  • Drugs for VRE are linezolid, daptomycin, tigecycline and Quinupristin.
  • Aztreonam cover pseudomonas but not anaerobes but tigecycline covers anaerobes but not pseudomonas.
  • Invasive aspergillosis can be diagnosed by Galactomannan assay. However, Zosyn can give false positive test results.
  • All patients with candidemia should have an eye exam to rule out endopthalmitis. 
  • Beta –D-Glucan assay ( Fungitell assay) is useful in detection of aspergillus, candida, histoplasma and pneumocystis jiroveci.
  • If patient has a h/o recent exposure to antifungals, try to avoid the same class.
  • Due to increase in incidence of C.glabrata, empiric antifungal therapy shouldn’t be started with fluconazole.
  • Based upon the pharmacokinetic and pharmacodynamic properties of each agent, optimization of antimicrobial effect can be achieved with increased doses (for concentration-dependent antibiotics such as aminoglycosides and fluoroquinolones) or with prolonged or continuous infusions (for time- dependent antibiotics such as beta-lactams). An extended infusion of imipenem is not appropriate, since it does not remain stable for prolonged periods. 
  • Bad Bugs (MDR organisms) are ESCAPE; Enterococcus, S.Aureus, C.Diff, Acinetobacter, Pesudomonas and Enterobacteriaceae.
  • Bacteremia which is most likely contaminated are coagulase negative staph, corynebacterium, diptheroids, bacillus species and propionibacterium.
  • Candida in sputum is usually colonized unless immunocompromised.
  • Fungemia, Staph.Aureus and pseudomonas in blood is always real and never contaminated. 
  • Treatment for ABPA is itraconazole and steroids.
  • Telavancin can be used for MRSA ventilator associated pneumonia.
  • Doribax (Doripenem) carries an increased risk of death and lower clinical cure rates compared to use of Imipenem for VAP.
  • In septic shock, there is capillary leak and third spacing. Hence, the doses of hydrophilic drugs like Betalactams and aminoglycosides should be on the higher side. 
  • Concentration based antibiotics are fluoroquinolones and aminoglycosides. Their efficacy is based on peak concentration.
  • In septic pts, GFR may be raised due to CO and inotropes, especially in the young. They may need higher beta-lactam dosing, probable aminoglycosides as well. 
  • Time dependent antibiotics include Betalactams and vancomycin. Killing of bacteria depends on the amount of time the tissue levels are above the minimum inhibitory concentration (MIC).
  • Drugs that require adjustment in renal or hepatic impairment :
a) Contraindicated in renal failure: Doxycycline
b) No dose change needed in renal failure: ceftriaxone, nafcillin, azithromycin, amphotericin, Clindamycin, flagyl and linezolid.
c) Need adjustment with moderate renal failure: Vancomycin, aminoglycosides, fluconazole, PCN.
d) Need adjustment only in severe renal failure: Zosyn, Imipenem, fluoroquinolones, Bactrim.
e) Need adjustment in hepatic failure: ceftriaxone, Clindamycin, voriconazole and nafcillin. 
  • Cephalosporin use is contraindicated in penicillin-allergic patients only if an IgE-mediated reaction such as urticaria, angioedema, or anaphylaxis occurs.
  • When patients with a history of PCN allergy receive 1st generation cephalosporins – which share a side chain similar to penicillin – they may exhibit an increased risk of an allergic reaction. However, 2nd and 3rd generations cephalosporins are different enough structurally from PCN that they do not increase the risk of allergic cross-reactivity.
  • For bacteremia/endocarditis: if the S. aureus MIC ≥ 1.5 mcg/mL, don’t use vancomycin. For MRSA infections: if the S. aureus MIC ≥ 2 mcg/mL, don’t use vancomycin. 
  • If E coli is reported as resistant to ceftazidime or the MIC is 2 or more, you should assume the organism has ESBLs. 
  • Bactericidal antibiotics are penicillins, cephalosporins, carbapenems, aminoglycosides, and fluoroquinolones.
  • Fluconazole pretty much covers everything except aspergillosis and candida.
  • Main side effect of inhaled colistin is bronchoconstriction. 
 
Infections