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Pulmonary & Critical Care Bulletin
Vol. VII, No. 3, July 15, 2001
In this issue :

From Editor's Desk

(Dr. Uma Maheswari,)

(R. S. Bedi & U.S. Bedi)

16th Annual Meeting on Pulmonary and Critical Care Medicine
(Dr. S. K. Jindal)

Publihed under the auspices of:
Pulmonary C. M. E. Programme

Editorial Board :

Department of Pulmonary Medecine
Post Graduate Institute of Medical Education & Research (PGIMER) Chandigarh. INDIA-160012

Subscription :

Newer Antimicrobials - Antifungals and Antibacterials

A. Antibacterials :

I. New fluoroquinolones
II. Glycoprotein antibiotics
III. Beta -Lactam antibiotics -

a. Extended spectrum penicillins
b. Carbapenems
c. Cephalosporins
d. Monobactams

B. Newer Antifungals

I. Lipid formulation of ambphotericin -B
II. New azoles
III. Invstigational agnts

I. New Fluoroquinolones (FQ)

Basic structure of quinolones involves 4-quinolone nucleus. It is by modifications of the basic nucleus by which we get various generations of flouroquinolones

First generation
Ist generation
(Nalidixic acid).
Structural modification
4 quinolone
i. Spectrum narrow : cover only enterobacteriacease.
ii. Poor tissue plasma concentration; so used for treatment of urinary tract infections (UTI)
IInd generation
Gr. I Norfloxacin
F' atom at position 6 & piperqzine at 7 Spectrum improved but still low plasma/tissue concentration
Gr.II Ofloxacin, Ciprofloxacin Substitution of cyclopropyl Spectrum improved but still low plasma/tissue concentration
IIIrd generation
Some modification of Piperazine at C7 i. Streptococci are covered
ii. Half life increased
iii. Neurological side effects decreased
iv. Drug interactions decreased
IVth generation
Some reconfiguration at position 8 of 4 Quinolone i. Anaerobic cover
ii. Extensive hepatic metabolism instead of renal (Pseudomonas cover is not authenticated)

Therapeutic uses of 3rd & 4th Generation - FQs

1. Role in Community Acquired Pneumonia: 3rd and 4th generations FQs because of their spectrum include almost all the organisms causing community acquired pneumonia - so they are agents of choice for treatment of community acquired pneumonias. But it is strongly recommended that their use should be limited to those 20% cases of community acquired pneumonia who are acutely and severely ill requiring hospitalization. Rest of 80% of patients being treated as outdoor patients should be given some less potent agents. This is because of concerns regarding emergence of drug resistance strains if these agents are indiscriminately used.

2. Role in Nosocomial Pneumonia: Because pseudomonas are not included in spectrum so they cannot be relied upon as single agents for treatment of nosocomial pneumonia.

3. Role as antimycobacterial : Levofloxacin has been used in dosage ranging from 500 mg to 1000 mg as an anti TB agent and has been found to be superior to ofloxacin.

4. Role in transitional therapy: (Change from parenteral to enteral) Third and 4th generation FQs form excellent agents for transitional therapy because of the following : (I) Both oral / parenteral forms are available (ii) Bioavailability after oral route is high and high concentration in plasma/tissue/body fluids is achieved (iii) Rapid bactericidal action.

5. Role in combination chemotherapy: Antipseudomonas beta lactam combined with aminoglycosides produce more frequently synergistic action against pseudomonas than fluoroquinolones combined with aminoglycosides.

Side effects :

i. Phototoxicity - Decreasing order of phototoxicity with Sport. >Lomef >Clinaf. > Trovaf. Not reported with Gatiflox and Trovafloxacin.
II. GIT toxicity - Grepaf > Trovf. > Sparf > Levof.
iii. Cardiotoxicity - Increased Q-Tc interval seen with Grepafloxacin, sparfloxacin
iv. CNS toxicity - 1-2%

None of the 4th generation FQs are available in India at present.

II. Glycoprotein Antibiotics: include vancomycin and teichoplanin

Advantages of Teichoplanin over vancomycin :

i. Half life long so single daily dose possible/vancomycin has to be given bid/quid.
ii. Both i.m. and i.v. preparations are available and can be given as i.v. bolus while in case of vancomycin only i.v. preparation is available and has to be given as slow i.v. infusion over one hour.
iii. Adverse actions like ototoxicity/nephrotoxicity/Redman syndrome are more often seen with vancomycin than Teichoplanin.
iv. There are reports from Japan and North America of isolates which are resistant to vancomycin (called V.I. MRSA i.e. Vancomycin Insensitive Methicillin Resistant Staphylococcus Aureus while no such reports are available with teichoplanin.

Disadvantages of Teichoplanin

i. No oral formulation is available so vancomycin is drug of choice for pseudomembranous colitis.
ii. High cost of Teichoplanin

Availability : Inj. Targocid (Teichoplanin) 200 mg @ Rs. 675/-
400 mg @ Rs. 1100/-
In. Vancomycin 500 mg @ Rs. 160/-

III. Beta Lactams:

(a) Extended Spectrum Penicillins:

Piperacillin and Tazobactam Sodium is an injectable antibacterial combination of piperacillin sodium and tazobactum sodium (Beta Lactamase inhibitor)

Indications are very specific -

i. Community acquired pneumonias caused by piperacillin resistant beta lactamase producing strains of H. influenzae.

ii. Nosocomial pneumonias caused by beta lactamase producing strains of Staph. aureus

For nosocomial pneumonias - caused by pseudomonas, it must be combined with aminoglycoside because tazobactam sodium inhibits only plasmid mediated beta lactamase products while beta lactamase producing isolates of pseudomonas are chromosomally derived and are not sensitive.

Dosage:                            Daily adult dose is 12 g/1.5 g by slow i.v., 4 divided dosages.
Availability and cost :      Inj. Zosyn 4 g/0.5 g Rs. 760/-
Daily cost of therapy :     Approx. Rs. 3000/-

b) Carbapenems : Include Cilstatin Imepenem combination and Meropenem. Carbapenems are broad spectrum antibacterials covering against : i. Gram +ve including staph (except MRSA), ii. Gram neg. aerobes including pseudomonas, iii. Gram +ve and neg. anaerobes.

Indications :

i. LRTI caused by staph (Penicillinase + ve), E. coli, klebsiella, enterobecter sp, H. influenzae;
ii. Bacterial septicemia caused by Staph aureus, E. facalis, P. aeurginosa, anaerobes etc.

Menopenems - Advantages over cilstatin - Imipenam combination

i. No drug interaction with ganciclovir
ii. Cilstatin combination not required
iii. Safe in children after the age of 3 months
iv. Relatively less unsafe in pregnancy (category C drug compared to Imepenem which is category B drug).
v. Can be given as i.v. bolus also.

c) Cephalosporins - i. Cefpodoxime proxetil (3rd gen.; oral)

Cefpodoxime proxetil is a prodrug, absorption increases when taken with food. Spectrum is broad, includes gram, neg. organism including moderate activity against Staph aureus.

Clinical use - comparative studies have shown it to be a good agent for mild to moderate cases of community acquired pneumonia and acute exacerbation of chronic bronchitis.

ii. Cefepime - 4th generation broad spectrum parenteral compound approved by FDA in 1996.

Indications :

1. Moderate to severe pneumonia caused by gram neg. organisms including Ps. aeruginosa (1-2 g i.v. 12 hourly)

2. Empiric therapy for febrile neutropenic patients (2 g. i.v. 8 hrly) for seven days or till neutropenia persist.

Availability - Not available in India.

d) Monobactams - Aztreonam belong to the group. It has two peculiar features.
i. Narrow spectrum - covering gram neg. aerobes only.
ii. It can be used with impunity among patients who are hypersonsitive to penicillin.

Availability - Not available in India.

New antifungals

i. Lipid formulations for ambphotericin B (Am B) - Lipsosomal technology was introduced in the late 1970s with the purpose of increasing drug delivery at the site of action. But when applied to polyene antifungals it was found to decrease nephrotoxicity appreciably.

Currently, 3 lipid forms are available depending upon the type of lipid and their arrangement.

a. ABLC (AmB Lipid complex)
b. ABCD (AmB Colloid dispersion)
c. Ambisome (Liposome AmB)

Clinical use - indicated in patients who have renal toxicity due to conventional AmB therapy or who fail to conventional AmB.

Availability : Ambisome and ABCD are available in India. Cost of treatment is very high - Rs. 35000 - Rs. 45000/- per day

ii. News Azoles - include         - ZD 0870
-     Voriconazole                      - SCH 56592
-     ER 30346

Voriconazole is a derivative of fluconazole. It is 4-16 times more active than fluconazole and 2-8 fold more active than itraconazole againt candida cruzei and glabrata. It is 160 times more potent than fluconazole in inhibiting cell membrane enzymes of Aspergillus fumigatus. It has good in vitro activity against isolates of aspergillus which are resistant to AmB.

Current status : Voriconazole is in phase III trials while other azoles are in phase I and phase II trials.

Investigational antifungals include :

- Echinocardins and related peptides - Cyclic depsipeptides
- Benzo - (alpha) Naphthacene -quinones - Polyoxins and nikomycins

Dr. Surinder Mahajan, Senior Resident,
Dept. of Pulmonary Medicine,
PGI, Chandigarh

Dr. Surinder Mahajan, Senior Resident

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