Emerging Antibiotics Antifungals

Emerging Antibiotics:

Emerging Antibiotics Dr. Shrikant S. Somani 2 nd Year Resident , Dr. A N Shah Unit, Medicine Dept., B.J.Medical College

Super bug:

Super bug Times of India reports – A new highly resistant bacteria Circulating in Indian, Asian hospitals in ICU International concern over its spread Control measures include screening and isolation of travellers “Lancet” reports Emergence of NDM 1 in strains of enterobacteriacea NDM 1 resistance plasmid mediated Most patients had travel history to India.

NDM 1:

NDM 1 The well known journal “Lancet”- infectious diseases, August issue reports regarding emergence of new strain of enterobacteriacea , especially E.coli , K.pneumoni , A.baumanii , that are resistant to carbapenems , aminoglycosides , floroquinolones and most other antibiotics except the tigecyclin and colistin . The resistance is plasmid acquired. They all tend to produce the enzyme NDM 1 i.e New Delhi Metallo B lactamase 1 . The origin of the NDM 1 is considered to have taken place in India and then has spread to other countries and most patients, in Europe and US, in whom it was isolated have some travel or exposure history with India.

Slide 4:

Indian medical fraternity strongly condemned such publications and naming of the resistance with the Indian capital saying that they were far too stretched and articulated. And findings were actually to disrepute India as a global medical tourism hub. Also the studies were actually funded by the manufacturer of the sensitive antibiotics. Just four days before on 12 th January,2011 Lancet publicly apologizes for naming of the superbug with Indian capital. However, continues to support the truth behind the report.

Slide 5:

MRSA Methicillin resistant Staph. Aureus : Discovered in 1960 in UK. Its major emergence was in 1980’s and since then it has been a menace in hospitals and ICU’s. It is resistant to commonly used B- lactams , cephalosporins , floroquinolones and macrolides . Many clinical microbiologists refer to it as a SUPERBUG.

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According to JAMA Oct. 2007 issue, about 94,000 serious infections and 18,000 hospital stay related deaths per year were due to MRSA infection. The drug of choice for treating MRSA is now believed to be Vancomycin according to a Henry Ford Hospital Study presented at the 48th annual meeting of the Infectious Diseases Society of America in Vancouver in October 2010. However, VISA ( Vancomycin Intermediate Sensitive Staph Aureus ) have been reported at many centres ie . resistant to even vancomycin

Why New antibiotics ?:

Why New antibiotics ? The problem with the antibiotics is - The better an antibiotic is, the more extensively it is used, the more resistant bacteria emerges against it. With emergence of such highly resistant bacterias like MRSA, VISA, VRE, ESBL, NDM 1 we are in need of upgradation of our armentarium of antibiotics. Here comes the newer emerging antibiotics…..

COLISTIN:

COLISTIN Group: Polypeptide, polymyxin History: Developed in 1950 as Polymyxin E, went into disrepute due to its toxicity. Reemerged in 1990 against MDR Gram negative organisms. Analogues- Polymyxin B, not used systemically because of its toxicity. Available as Colistin sulfate and CMS - colistimethate sodium ( prodrug of colistin ).

Pharmacokinetics:

Pharmacokinetics Poor oral absorption. Colistin is metabolised by still unknown mechanisms. CMS excretion is by kidneys. Mechanism of action: Primarily bactericidal; kills by increasing membrane permeability. Routes: Intravenous, Intrathecal , topical, Inhalational, oral.

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Its spectrum include most Gram negative organisms E.coli , klebsiella , pseudomonas, enterobacter , shigella , acinetobacter . Also effective against NDM 1. Microbiology

Clinical Uses:

Clinical Uses Clinical Uses include: (1) Ventilator associated Pneumonia (VAP) (2) Complicated pneumonias (3) Gram negative bacteremia /sepsis (4) Meningitis (5) Complicated Urinary Tract Infections

Clinical Study :

Clinical Study A 50% cure rate was noted with IV colistin when used alone for Gram Negative MDR Ventilator Asso . Pneumonias. No significant difference in cure rates and side effects in colistin group when compared to carbapenem group when given for pseudomonas in ICU. Equal efficacy of IV colistin given along with carbapenems for Gram Negative MDR VAP.

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Aerosolised colistin can be used as a beneficial adjunctive therapy in the treatment of MDR VAP. 70 to 75% cure rates in Gram Negative sepsis and bacteriamia with IV colistin . 90% cure rate in meningitis caused by resistant Gram Negative organisms by using 1,25,000 IU every 12 hrly intrathecally . Some trials report high cure rates with IV + intrathecal route.

Dosage:

Dosage Dosage: Not standardized. Most recommended regimen is colistin given as 50,000 to 75,000 IU/kg/day dose in 3-4 divided doses. Colymycin M given as 2.5 to 5 mg/kg/day of ‘ colistin base’ in 3-4 divided doses. Inhalational dose is 1 million U given as nebulisation every 8 hrly .

Adverse Effects:

Adverse Effects Adverse effects: With IV form- mainly nephrotoxicity and neurotoxicity. Most papers suggest that at currently recommended doses colistin is safer than aminoglycosides . Others include hypersensitivity reactions, ototoxicity , vertigo, ataxia, paresthesias , visual disturbances. Inhalational forms- bronchospasm and chest tightness.

Special categories:

Special categories Pregnacy category C drug. Renal impairment – dose modification needed Availability in India: Xylistin Inj. ½ to 1 million units vial (Rs.650/ vial).

LINEZOLID:

LINEZOLID Group: Oxazolidinone History: US FDA approval in 2000. Mechanism of action: Protein synthesis inhibitor by novel mechanism; primarily Bacteriostatic

Pharmacokinetics:

Pharmacokinetics Routes: Oral and Intravenous. Bioavailability is 100% by oral route. So switch over to oral therapy is easy and early. Reaches in high concentrations in lower respiratory tract. Penetration across BBB is slow but reaches in sufficient concentration in CSF. Metabolized in liver. Half life is about 4-5 hours.

Microbiology:

Microbiology Its spectrum includes Gram positive organisms - MRSA, resistant enterococci , all streptococcal strains including viridians group, listeria , corynebacteria . No clinically significant effect on most Gram Negative organisms or Anaerobes.

Clinical Uses :

Clinical Uses US FDA approved indications are:- (1) Complicated skin and soft tissue infections ( cSSTI ) including diabetic foot, without osteomyelitis (2) Vancomycin Resistant Enterococcus infections with or without bacteremia (3) Community acquired Pneumonias caused by sensitive organisms.

Clinical Study:

Clinical Study A meta analysis of no. of Randomized control trials found linezolid to be more effective and a cheaper alternative compared to glycopeptides and beta lactams in treatment of SSTI’s, including diabetic foot. Community Acquired Pneumonias – Both British Thoracic Society and American Thoracic Society recommend Linezolid to be used as a reserve drug after vancomycin and beta lactams .

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For nosocomial pneumonias both BTS and ATS recommend linezolid has usage advantages over vancomycin , particularly the VAP as there is better concentration of linezolid in bronchial secretions and also these patients usually have renal impairment for which linezolid is safe enough. Economic Consideration: Several studies, involving health care system models and cost effectiveness models, have found linezolid to be much more cheaper to health system compared to other comparable antibiotics either due to higher cure rates or early switch over to oral therapy (with same efficacy) reducing the overall hospital stay.

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Endocarditis: Oxford Journals, Sept. 2006 reports -Though Linezolid is bacteriostatic antibiotic, limited available evidence suggests that it can be effective therapeutic option in treatment of bacterial endocarditis caused by MDR Gram Positive cocci – 63% of the patients treated with linezolid of the total of 56 patients were cured. CNS infections: The guidelines of the Infectious Diseases Society of America recommend linezolid as the first-line drug of choice for VRE meningitis, and as an alternative to vancomycin for MRSA meningitis. Febrile Neutropenia : As an alternative to vancomycin in cancer and transplant patients with febrile neutropenia when Gram Positive infection is suspected.

Adverse Effects :

Adverse Effects Adverse Effects: Relatively safe drug. Most common are nausea, vomiting, diarrhoea, rashes. Serious ones are pancreatitis, elevation of hepatic enzymes. After long term use, bone marrow suppression, especially thrombocytopenias is common. Others are peripheral neuropathy, optic neuropathy and lactic acidosis. Drug Interactions: Linezolid is weak MAOI. So should not be combined with serotonergic drugs, tyramine rich food, pethidine and other MAOI’s for fear of serotonin syndrome.

Dosage:

Dosage Dosage: 600mg oral or IV given 12 hrly in adults and 8 hrly in children <12 yrs.

Special Categories:

Special Categories Pregnancy category C drug. Renal Impairment – No dose modification required. No dose modification in mild to moderate liver diseases. Secreted in breast milk but without clinical significance.

Availability in India:

Availability in India Inj. Linospan (Rs.350/infusion), Inj. Lizolid (Rs.330/infusion), Tab. Lizolid (Rs.304/4 tab), Tab. Linospan (Rs.290/4 tab). Other brands are linox , lizoforce , alzolid , linid , zolid - infusion and tablets.

Daptomycin:

Daptomycin Group: Cyclic Lipopeptide History: US FDA approval in 2003. Mechanism of action: Primarily bactericidal; causes membrane depolarization and inhibit synthesis of protein, DNA and RNA.

Pharmacokinetics:

Pharmacokinetics Complete evaluation is still going on. Half life is about 10 hours. Metabolism is, at least partially, by renal mechanism. Route: only Intravenous

Microbiology:

Microbiology It is active against Gram Positive organisms only. In vitro studies show good activity against Staph. aureus including MRSA and VISA, Streptococci, Enterococci including VRE.

Clinical Study:

Clinical Study A study published in NEJM reports the pooled analysis of two randomised phase III trials which showed that daptomycin is “non-inferior” to vancomycin and semi- synthethic penicillins . The studies involved 1,092 patients with a complicated skin and skin structure infection( cSSSI ). The success rates were 71.5% and 71.1% respectively.

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According to study done in USA, published in NEJM august 2006 - They randomly assigned 250 patients with Staph. aureus bacteremia with or without endocarditis to either daptomycin or standard Gram Positive endocarditis treatment. Patients were evaluated after 42 days. The study concluded that Daptomycin is not inferior to standard therapy for Staph. aureus bacteremia and right-sided endocarditis .

Clinical Use:

Clinical Use US FDA approved indications are – (1) Complicated skin and soft tissue infections (2) Bacteremia and Rt. Sided endocarditis caused by susceptible organisms.

Adverse Effects:

Adverse Effects Most common are nausea, vomiting, diarrhoea , dyspepsia, hypotension, thrombocytopenia, rash, hypersensitivity reactions, myalgias , arthalgias . Elevation of CPK levels and hepatic enzymes is seen. US FDA issued warning that daptomycin therapy has been asso . with life threatening eosinophilic pneumonia. Drug Interactions: Statins should be temporarily stopped during daptomycin therapy. Cautious use with other neuromuscular blocking agents

Dosage:

Dosage Dosage: (1) Skin and soft tissue infections - 4 mg/kg IV once every 24 hours for 7-14 days. (2) Bacteremia and Endocarditis – 6mg/kg IV once every 24 hours. The infusion is given over a period of 30 minutes.

Special Categories:

Special Categories Pregnancy category B drug. Renal Impairment: Dose reduction required. No available data for use in children. Availability in India: Inj. Cubicin (Rs.3500/vial)

Quinopristin/Dalfopristin:

Quinopristin / Dalfopristin Group: Streptogramin Mechanism of action: While each of the two are only bacteriostatic , the combination shows bactericidal activity, thus protein synthesis inhibitor in synergistic manner.

Pharmacokinetics:

Pharmacokinetics Metabolised in liver. Half life is about 3 hours. Available formulations contain 30% quinupristin and 70% dalfopristin . Only given by Intravenous route.

Microbiology:

Microbiology Good activity is seen against Gram Positive cocci like Streptococcus Pyogenes , Methicillin Sensitive S. Aureus and Vancomycin resistant Enterococcus faecium (VREF). Moderate activity is seen against MRSA.

Clinical Study:

Clinical Study The journal Clinical Therapeutics Jan 2007 issue, published an article from School of Health Sciences, University of Montana, U.S.A. – it reviewed all the articles in MEDLINE search from 1960 to 2000 on the drug and gave conclusion that quinupristin / dalfopristin has the potential to play an important role in the treatment of bacteremia , complicated skin and skin-structure infections, and nosocomial pneumonia caused by VREF. Other articles suggest that it has its role in complicated skin and soft tissue infections caused by resistant strains of Staph Aureus .

Dosage :

Dosage Dosage: 7.5mg/kg every 8 or 12 hrly The drug is to be given as IV infusion over 1 hour diluted in 250 ml 5% Dextrose solution.

Adverse Effects:

Adverse Effects Most common include – injection site reactions (>50%), nausea, diarrhoea, rash, headache, vomiting, arthralgias , myalgia . Most frequent laboratory change was rise in total bilirubin and hepatic enzymes.

Special Categories:

Special Categories Pregnancy category B drug. No available data for lactating mothers. Renal Impairment – No dose modification needed Hepatic impairment – Sufficient data not available Brand name – Synercid (MRP not available)

Telavancin:

Telavancin Group: Lipoglycopeptide It is actually a synthetic derivative of Vancomycin History: US FDA approval came in Sept. 2009. Mechanism of action: Primarily bactericidal. It inhibits bacterial cell wall synthesis as well as disrupts the cell membrane function.

Pharmacokinetics:

Pharmacokinetics Half life is about 9 hours. Exact metabolic pathway has not been elucidated Excretion in mainly by renal mechanism (80%). Route: only Intravenous

Microbiology:

Microbiology Its spectrum includes Gram positive organisms including Staph Aureus (MSSA and MRSA), Streptococci spp. , Pneumococci and Enterococcus faecalis .

Clinical Use :

Clinical Use It has been licensed for use only in complicated skin and soft tissue infections ( cSSTIs ). Another off label use is in Hospital acquired pneumonias. Dosage: 10mg/kg IV over 1 hour once every 24hours for 7- 14 days.

Clinical Study:

Clinical Study ATLAS I and ATLAS II are two large phase III randomized controlled trials that compared telavancin with vancomycin for cSSTIs . Trials included 1,410 patients. Analysis showed that cure rates were 86.6% and 86.3% respectively. However, in elderly vancomycin showed better results than telavancin . ATTAIN 1 and ATTAIN 2 are two large phase III randomized controlled trials that compared telavancin with vancomycin for hospital acquired pneumonias. Trials included 1,500 patients. Clinical cure rates were 82.7% and 80.9% respectively.

Adverse Effects:

Adverse Effects Taste disturbances, nausea, vomiting, diarrhoea, rash, pruritus and foamy urine are the most common. Rarely, Red man syndrome type infusion reactions, worsening of renal functions. Monitoring of RFTs is required. Caution when used with other drugs that cause QTc prolongation.

Special Categories:

Special Categories Pregnancy category C drug. Dose modification is required when CrCl <50ml/min. No dose modification for moderate hepatic insufficiency. Availability: Vibativ Inj. (MRP not available)

Dalbavancin:

Dalbavancin History: US FDA issued approvable letter in 2007. Still not approved. The manufacturer is performing further clinical trials.

Pharmacokinetics:

Pharmacokinetics A unique attribute of dalbavancin is its long half-life of 120 to 210 hours, which supports a once-weekly dosing regimen. Single doses ≥ 500 mg provided plasma concentrations above the minimum bactericidal level for MRSA for at least 7 days. Metabolism is by renal(30%) and non renal(70%) mechanisms.

Clinical Study:

Clinical Study Clinical Studies: In phase III randomized control trials dalbavancin was evaluated for SSTIs against linezolid , vancomycin , cefazolin . In linezolid study of 850 patients, clinical cure rates were 88% vs 90% with linezolid . In vancomycin study of 156 patients, clinical cure rates were 89% vs 86% with vancomycin . In all studies the drug was very well tolerated. Status: very promising drug with once a week dosing and high efficacy with minimal side effects.

Oritavancin:

Oritavancin Status: Completed phase III trials and under review committee of US FDA and EU for approval.

Ramoplanin:

Ramoplanin Group: Glycolipodepsipeptide Route: Oral Status: Phase III trials have been complete with excellent efficacy of the drug. Under fast track approval by US FDA for multi-resistant clostridium difficile infections of gi tract.

Iclaprim:

Iclaprim Group: Diaminopyridine Mechanism of action: Dihydrofolate reductase inhibitor, similar to trimethoprim High efficacy against MRSA, VISA , pneumococci and some gram negative organisms. Status: Completed phase III trials for use in complicated SSTIs and resistant pneumonias. US FDA given the drug status of fast track approval.

Tigecycline:

Tigecycline Group: Glycylcycline; related to tetracyclines History: US FDA approval came in 2005. Mechanism of action: Primarily Bacteriostatic; protein synthesis inhibitor.

Pharmacokinetics:

Pharmacokinetics Not metabolised in the body. Excretion is by biliary route 60% and renal 40%. Half life is about 42 hours. Route: Given only by Intravenous route

Microbiology:

Microbiology It has high efficacy against resistant Gram Positive organisms (MRSA, VISA, VRE), Gram Negative (Acinetobacter, ESBL and NDM 1) bacteria and anaerobic organisms – acc. to study done at AIIMS, dept. of microbiology in April 2009.

Clinical Study:

Clinical Study Tigecycline has been evaluated in four large-scale, phase III, double-blind, randomized, multicenter, active-comparator clinical studies in hospitalized patients with complicated skin and soft tissue infection ( cSSTI ) and complicated intraabdominal infection ( cIAI ). In the cSSTI trials, tigecycline monotherapy was shown to be as effective as the combination of vancomycin plus aztreonam . ( 87% vs 89% respectively) Similarly, tigecycline was shown to be as effective as imipenem / cilastatin in treating cIAI .

Clinical Uses:

Clinical Uses The drug is licensed for use in the treatment of complicated skin and soft tissue infections( cSSTI ) as well as complicated intra-abdominal infections( cIAI ), surgical wound infections, particularly following abdominal surgery, where the likely pathogens include MRSA as well as Enterobacteriaceae , streptococci and anaerobes. No other single agent covers this spectrum. Because of its biliary excretion, it is not recommended for use in urinary tract infections.

Adverse Effects:

Adverse Effects The most common are g.i . effects nausea(35%), vomiting(20%), diarrhoea(10%), dyspepsia(5%). Others include headache, injection site reactions, rash and hypersensitivity allergic reactions, elevations of hepatic enzymes and amylase levels.

Dosage:

Dosage A single dose of 100mg is given first followed by 50mg every 12 hourly. IV infusion is to be given over a period of 30 to 60 minutes

Special Categories:

Special Categories Pregnancy category D drug. Renal impairment - no dose modification required. Liver impairment - Lower dose need to be given for those with moderate to severely impaired liver function. Not recommended for use in children due to its effect on teeth and bones. Availability in India: Inj. Tigez (50mg/vial) Rs.2800, Inj. Tygacil (50mg/vial) Rs. 2700.

Cefepirome:

Cefepirome Group: B lactams ; 4 th generation Cephalosporin History: Successfully completed phase III trials and is now under review of approval committee of US FDA and EU. Mechanism of action: Bactericidal; Cell wall synthesis inhibitor

Pharmacokinetics:

Pharmacokinetics Bioavailability by IM injection is 100%. 15% of the drug metabolised in liver. Half life is about 2 hours. Most of the drug is removed unchanged by renal pathway. Routes: IM, IV infusion.

Microbiology:

Microbiology Its spectrum includes Gram Positive cocci – all Streptococcal strains including resistant Pneumococci , Sensitive Staph Aureus . Gram negative bacteria include sensitive as well multi resistant Enterobacteriacea , Pseudomonas, Neisseria , Enterobacter species. Not effective against MRSA, enterococci and anaerobes.

Clinical Study:

Clinical Study Numerous trials have shown its invitro efficacy and clinical safety and efficacy in ICU patients and neutropenic patients. A no. of other phase III trials are going on.

Adverse Effects:

Adverse Effects In comparative trials about 20% patients experienced an adverse event. G.i . symptoms, including nausea (1.8%), diarrhoea (1.7%), vomiting (1.5%) and constipation (1.2%), and headache (3.2%) and rash (1.8%) were the most common. Rarely, skin reactions like S J syndrome, TEN, pancytopenias , superinfection . Contraindicated in those with hypersensitivity reactions to other cephalosporins .

Cefazopran:

Cefazopran Another 4 th generation cephalosporin in phase III clinical trials

Ceftobiprole:

Ceftobiprole Group: B lactams ; 5 th generation cephalosporin History- Discovered in 2000. Approved for use in Canada and Switzerland. Under review of regulatory authorities by US FDA and EU. Spectrum of activity: Extended activity onto resistant gram positive and gram negative organisms including MRSA, pneumococci , enterococci , pseudomonas and enterobacteriacea . Has been shown as statistically non-inferior to combination of ceftazidime and vancomycin .

Ceftaroline:

Ceftaroline Another 5 th generation cephalosporin. Has received US FDA approval just recently October 2010 for use in community acquired pneumonias and complicated SSTIs. Spectrum includes most resistant gram positive organisms including MRSA as well as gram negative organisms.

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Metabolism is by renal mechanism. Routes: IV and IM Phase III trials have shown efficacy equals to vancomycin plus aztreonam and very good tolerability. Pregnancy category B drug. Dose modification in renal impaired.

Prulifloxacin:

Prulifloxacin Group: 4 th generation Fluoroquinolones History: Approved for use in Japan in 1997 and in Italy and few other European countries in 2007. However, still not approved for use by US FDA. Mechanism of action: Inhibits bacterial DNA gyrase enzyme and thus inhibits DNA replication and transcription.

Pharmacokinetics:

Pharmacokinetics Oral bioavailability is high. After gi absorption, undergoes high first pass metabolism in liver to its active form ulifloxacin . It reaches in high concentration in body fluids and tissues like respiratory tract, prostate, urinary tract. Ulifloxacin half life is about 10-12 hours. Unchanged ulifloxacin is predominantly excreted by renal pathway. Routes: Only oral.

Microbiology:

Microbiology Ulifloxacin is generally more active invitro than any other fluoroquinolones against a variety of clinical isolates of Gram-negative bacteria, including community and nosocomial isolates of E. coli, Klebsiella spp., Proteus, Providencia and Morganella spp., Moraxella , Haemophilus spp., Pseudomonas. Gram-positive organisms, including MSSA, Enterococcus spp. and S. pneumoniae are susceptible to ulifloxacin . Does not show good activity against MRSA.

Clinical Uses:

Clinical Uses Prulifloxacin has been approved for: Acute uncomplicated lower urinary tract infections (simple cystitis) Complicated lower urinary tract infections Acute exacerbation of chronic bronchitis Gastroenteritis, including infectious diarrheas Other Uses: Prostatitis

Clinical Study:

Clinical Study According to study published in Int J Chron Obstruct Pulmon Dis 2007, March issue- Grassi et al studied the activity of prulifloxacin in AECB. This double-blind, randomized study compared prulifloxacin 600 mg once daily with ciprofloxacin 500 mg twice daily for 10 days. A total of 235 patients were studied. Clinical cure/improvement was seen in 85.3% and 85% of patients respectively. Bacterial eradication was seen in 88% and 92% patients respectively. Prulifloxacin showed no better results than ciprofloxacin.

Slide 79:

In 2007 a Phase III clinical study was done comparing prulifloxacin to levofloxacin to treat bacterial prostatitis . Within this study prulifloxacin was found to be as effective as levofloxacin , but not superior. This study also indicated that prulifloxacin had a reported adverse drug reaction rate in excess of 18%. In 1996 a Phase III clinical study was completed involving prulifloxacin and gastroenteritis. Within this study prulifloxacin was compared to ciprofloxacin, ofloxacin , tosufloxacin and nalidixic acid. According to the results of this study prulifloxacin performed no better than ciprofloxacin or tosufloxacin as the MIC90 rates were found to be equivalent.

Adverse Effects:

Adverse Effects Gastric pain - the most common Others being nausea, skin rashes, photo toxicity. Worsening of psychiatric disorders was noted. Two clinical trials ( Lacroix et al 2003, Akita et al 2004) suggest very low probability of QTc prolongation by the drug. Still US FDA has asked the manufacturers of the drug in US to conduct trials to further confirm that there is no QTc prolongation by the drug.

Contraindictaions :

Contraindictaions Tendon diseases History of hypersensitivity to Prulifloxacin , any member of the quinolone class of antimicrobial agents Celiac disease Pediatric population, pregnancy, nursing mothers Patients with seizure disorder.

Dosage:

Dosage Available as 250mg, 450mg, 600mg once a day dosing. Availability in India: Tab Pruflox 600mg (Rs. 350/5 tab.), Tab Percin 600mg (58 US $/l0 tab)

Balofloxacin:

Balofloxacin Group: 3 rd generation Fluoroquinolone History: Korean FDA approved drug for UTI in 2001. Currently the drug is marketed in Korea, Japan and few other Asian countries including India. US FDA website do not recognize any drug like Balofloxacin . Routes: Oral Pharmacokinetics: Excreted by renal mechanism

Clinical Study:

Clinical Study Drugs,1995 issue reports a trial done in Japan regarding the clinical efficacy and safety of Balofloxacin in UTI. It reports high efficacy >90% cure rate and good tolerability of the drug. Curr Opio Investig Drugs, 2003 issue reports that the drug is undergoing phase III trials for use in RTI. Another Japanese journal Kansenshogaku Zasshi . 1995 Sept issue reports a trial of Balofloxacin in enteritis. It reports very high efficacy (95%) both clinically and bacteriologically in Shigella , salmonella, cholera and E.coli asso . enteritis.

Newer 3rd Genera FQ:

Newer 3 rd Genera FQ Grepafloxacin was withdrawn from US markets due to QTc prolongation risks in 1999. Pazufloxacin , Tosufloxacin , Olamufloxacin have entered phase III trials in Japan. However, these drugs are not found on US FDA website.

Newer 4th Genera FQ:

Newer 4 th Genera FQ Gatifloxacin has been available in Indian markets for few years now in both oral and eye drops form. NEJM in March 2006 published a report regarding Gatifloxacin asso . with life threatening side effects including serious diabetes. May 2006 oral form of the drug was withdrawn from US markets. Trovafloxacin which was once the highest selling FQ in US markets, has been withdrawn due to its asso . with serious hepatic damage in 1999.

Moxifloxacin:

Moxifloxacin 4 th generation FQ. History: Approved by US FDA since 1999. Route: Both IV and oral.

Clinical Uses :

Clinical Uses Acute Exacerbations of Chronic Bronchitis (AECB) (restricted use) Acute Bacterial Sinusitis (ABS) (restricted use) Community Acquired Pneumonia (CAP)(restricted use) Complicated Skin and Skin Structure Infections ( cSSSI ) Complicated Intra-Abdominal Infections ( cIAI ).

Caution :

Caution However, there have been several reports of Moxifloxacin been associated with QTc prolongation and fatalities. Marketed in India in both oral and Intravenous forms. Availability in India: Inj. And tab. MOXIF

Imipenem-Cilastatin:

Imipenem-Cilastatin Group: B lactams ; Carbapenem group History: FDA approval came in early 1990s. Mechanism of action: Primarily bactericidal; Cell wall synthesis inhibitor. Role of Cilastatin : Imipenem given alone is rapidly degraded by renal enzyme dehydropeptidase 1, so it is always given in combination with cilastatin , which perfectly matches its pharmacokinetics and is also inhibitor of dehydropeptidase enzyme.

Pharmacokinetics:

Pharmacokinetics Bioavailability is high with IM injection. Metabolised and excreted by kidneys. Half life is about 1 hour. Routes: IM and IV

Microbiology:

Microbiology Its spectrum includes most Gram Positive and Gram Negative organisms as well as anaerobic organisms. Most multi- resistant enterobacteriacea , pseudomonas, gram positive cocci , enterococci are sensitive to imipenem except MRSA. It remains very stable in the presence of beta- lactamases produced by some bacteria, and is a strong inhibitor of beta- lactamases from some gram-negative bacteria that are resistant to most beta- lactam .

Dosage:

Dosage Adults - Usually 1gm to 4gm/day given in 3-4 divided doses. The dosage recommendations represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present in the solution. Each 125 mg, 250 mg, or 500 mg dose should be infused over 30 min. and 750mg or 1000mg over period of 60 minutes. It is recommended that the maximum total daily dosage should not exceed 50 mg/kg/day or 4.0 g/day, whichever is lower.

Clinical Uses:

Clinical Uses These include - complicated lower respiratory tract infections complicated urinary tract infections gynaecological infections complicated intra abdominal infections bone and joint infections complicated skin and soft tissue infections

Slide 95:

Resistant bacterial septicaemia Bacterial endocarditis Polymicrobial infections Febrile Neutropenia associated with haematological malignancies and transplantation. Not recommended for use in meningitis as safety and efficacy has not been validated.

Adverse Effects:

Adverse Effects The most frequently reported are nausea (2.0%), diarrhea (1.8%), vomiting (1.5%), rash (0.9%), fever (0.5%), hypotension (0.4%), seizures (0.4%). Rarely severe skin reactions like TEN, S J syndrome, hypersensitivity reactions can occur. Precautions: CNS adverse events like seizures, myoclonus have been reported when doses higher than recommended were given or even at low doses in presence of CNS disorder or renal impairment.

Special Categories:

Special Categories Pregnancy category C drug. Cautious use in lactating mothers. Renal Impairment - Total daily dose is reduced. However, a Korean study has quoted in its national medical journal on emergence of IRPA ( Imipenem resistant Pseudomonas Aeruginosa ). Availability in India: Inj. Cilaspene (500mg) Rs.1100, I- Nem Inj.(500mg) Rs.1200, Inj. Mpenex (500mg) Rs.590

Faropenem:

Faropenem Group: Carbapenem History: Marketed in Japan since 1997. Submitted for approval in US FDA in 2005. Still not approved by US FDA. Pharmacokinetics: Orally active drug of carbapenem group

Clinical Uses:

Clinical Uses Proposed indications are – acute bacterial sinusitis community acquired pneumonia acute exacerbations of chronic bronchitis uncomplicated skin and skin structure infections.

Meropenem:

Meropenem Group: Carbapenem History: First marketed in Japan. US FDA approval came in 1996. Mechanism of action: Bactericidal; Cell wall synthesis inhibitor. Unlike imipenem , it is stable to dehydropeptidase-1 and can therefore be given without cilastatin .

Pharmacokinetics:

Pharmacokinetics Given as IV injection, half life is about 1 hr. It is excreted unchanged by renal mechanism. It penetrates well into all tissues and body fluids including CSF, heart valves, bile, peritoneal fluid, lungs.

Microbiology:

Microbiology Spectrum is similar to that of imipenem including gram positive, gram negative and anaerobic organisms. However, it is more active against Enterobacteriacea and poor response to MRSA. In contrast to other beta- lactams , it is highly resistant to degradation by beta- lactamases or cephalosporinases .

Clinical Study And Uses:

Clinical Study And Uses In a Study published in 2005 in Curr Med Resp Opin . – Meta-analyses of 27 trials was carried out. Results demonstrated that when compared to imipenem plus cilastatin , meropenem is associated with a significantly greater clinical response, a significantly greater bacteriologic response, a non-significant reduction in mortality and a significantly lower adverse event rate.

Clinical Uses:

Clinical Uses Indications include same as that of imipenem particularly as a single agent in complicated intra abdominal infections, febrile neutropenia in the transplantation and haematological malignancy patients. Added indication is that of bacterial meningitis.

Adverse Effects:

Adverse Effects Most common are diarrhoea, nausea, vomiting, rash, thrombophlebitis . Low potential for causing seizures compared to imipenem .

Dosage:

Dosage It is given as 1 gram IV infusion over 15 to 30 minutes or by rapid intravenous injection over three to five minutes, every 8 hourly.

Special Categories:

Special Categories Pregnancy Category B drug. It is excreted in milk so cautious use in lactating mothers. Its safety and efficacy has been established in the children >3 months age. Renal Impairment: Dose modification is needed Availability in India: Inj. Meropenem 1gm as - Maxopen Inj. (Rs.2100), Meplife Inj. (Rs.2290), Merocrit Inj. (Rs. 2000), Morepenam Inj. (Rs.2190), Rescue Inj. (Rs. 2200), Merathon Inj. (Rs. 600)

Ertapenem:

Ertapenem History: US FDA approved in 2001. Microbiology: Spectrum is same as that of Meropenem and includes most resistant gram positive and negative bacteria and the anaerobes. No effective activity against pseudomonas.

Pharmacokinetics:

Pharmacokinetics Highly protein bound. Half life is about 4 hours. Primarily excreted by kidneys (80%). Route: IV and IM

Dosage:

Dosage It is given as 1g intravenous injection over 30 minutes, or 1g diluted with1% lidocaine given intramuscularly. Ertapenem cannot be mixed with glucose. The marketing slogan for ertapenem is "The Power of One", because the dose is one gram, once a day.

Newer Carbapenems:

Newer Carbapenems Panipenem / betamipron has been marketed in Japan since 1995. US FDA do not show any information on its website. Doripenem has been approved by US FDA in 2007 for treatment of complicated, life threatening infections. Spectrum is same as that of Imipenem . However, claimed to be having better pharmacokinetic profile and lesser microbilogical resistance.

VORICONAZOLE:

VORICONAZOLE Group: Triazole antifungal History: Developed in late 1980’s. US FDA approved the drug for use in 2002. Mechanism of action: Inhibits enzyme involved in sterol synthesis; disrupts fungal cell membrane synthesis and halts fungal cell growth. Routes: Oral and Intravenous.

Pharmacokinetics:

Pharmacokinetics Oral bioavailability is high so switch to oral therapy is easy. Metabolised by cytochrome P450 enzyme system and hence results in lot of drug interaction. Administration is contraindicated with some drugs such as sirolimus , rifampicin , rifabutin and ergot alkaloids and dose adjustments and/or monitoring when coadministered with others (cyclosporine, tacrolimus , omeprazole and phenytoin ). However, Voriconazole may be safely administered with cimetidine , ranitidine, indinavir , macrolide antibiotics, mycophenolate and prednisolone .

Microbiology:

Microbiology It has broad-spectrum activity against pathogenic yeasts, dimorphic fungi and opportunistic moulds. Unlike fluconazole , voriconazole has potent in vitro activity against Aspergillus spp., Fusarium spp. and Scedosporium apiospermum . In Phase II/III trials, voriconazole was well-tolerated and had excellent clinical efficacy in patients with fluconazole -sensitive as well as resistant candida infections, aspergillosis , and various resistant fungal infections.

Clinical Uses:

Clinical Uses US FDA approved indications are - Invasive Aspergillosis - Voriconazole has become the new standard of care in the treatment of invasive aspergillosis which may occur in immunocompromised patients including HIV, haematological malignancies and transplant patients. This is based on the results of a large, randomized, non blinded study involving 392 patients in which voriconazole proved superior to amphotericin B with 52.8% complete or partial response, compared with 31.5% for amphotericin B. Voriconazole also offered a 22% greater survival benefit over amphotericin B.

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Serious invasive infections caused by Fusarium and Scedosporium apiospermum spp. – including serious nosocomial fungal infections, fluconazole resistant fungal infections. Invasive Candidiasis : Voriconazole has proven to be as effective as a regimen of IV amphotericin B followed by oral fluconazole in patients with culture-proven candidemia , esophageal candidiasis and disseminated candidial infections in non- neutropenic patients as well as fluconazole resistant candidiasis . Voriconazole was also much better tolerated than amphotericin B – study published in NEJM august 2002

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Other Off label uses are: Empirical antifungal therapy - A large randomized, international, multicentric study involving >800 patients compared Voriconazole to that of liposomal amphotericin B in the treatment of patients with neutropenia and unresolved fever despite broad-spectrum antibiotic therapy who are at risk for breakthrough fungal infections. There were significantly fewer breakthrough infections with voriconazole . Voriconazole group had fewer severe infusion related reactions and nephrotoxicity but more transient visual disturbances and hallucinations. Voriconazole was also associated with a shorter duration of hospitalization as early switch over to oral therapy was possible – a study published in NEJM January 2002.

Dosage:

Dosage Voriconazole is given as 6 mg/kg IV every 12 hrly on day 1 followed by 4 mg/kg every 12 hrly . For switching to oral therapy, dose is 200mg 12 hrly for pt. >40 kg weight or 100 mg for <40 kg weight. Infusion should be given slowly over 2-3 hours.

Adverse Effects:

Adverse Effects The most common include transient visual disturbances, rash, nausea, vomiting, diarrhea , headache, abdominal pain. Visual disturbances (such as blurred vision) and hallucinations have been reported by more than 30% of patients in clinical trials. They generally occur approximately one-half hour after administration and last approximately 30 minutes. Studies have shown that there is no damage to the eye or long-term effect on vision. Rarely, serious hepatic reactions have occurred. LFT’s need to be monitored.

Special Categories:

Special Categories Pregnancy Category D drug. Renal Impairment: No dose modification is required. Hepatic dysfunction: Dose modification is required for mild to mod. dysfunction. Contraindicated in severe hepatic dysfunction. Lactation is another contraindication.

Availability:

Availability Tab. Vfend 200mg (Rs.17,000/10 tab.), Inj. Vfend 200mg (Rs. 6000/vial) Other brands are Voritrol , Voriz and Vonaz Injections and tablets.

Caspofungin:

Caspofungin Group: Echinocandins anti- fungals History: US FDA approval came in 2001. Mechanism of action: Echinocandins inhibit the synthesis of B(1,3)-D Glucans – an essential component of fungal cell wall and halt their growth

Pharmacokinetics:

Pharmacokinetics Given by IV route it is 97% plasma protein bound. Very slowly metabolised in liver. Redistribution in body tissues plays important role in influencing plasma levels. Effective half life of the drug is about 10 hours. Metabolites are excreted via urine and faeces.

Microbiology:

Microbiology Fungicidal activity is seen against majority of Candida spp. including non- albicantes . Fungistatic activity against most Aspergillus spp. They also show their clinical efficacy in azole resistant fungal infections.

Clinical Uses:

Clinical Uses Empirical therapy for presumed fungal infections in febrile, neutropenic patients Treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis and pleural space infections. It has not been studied in endocarditis , osteomyelitis , and meningitis due to Candida. Treatment of esophageal candidiasis Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (e.g., amphotericin B, lipid formulations of amphotericin B, itraconazole ). It has not been studied as initial therapy for invasive aspergillosis .

Clinical Study:

Clinical Study NEJM, 2002 Dec issue published a trial regarding comparison between caspofungin and Ampho B in invasive candidiasis – analysis showed that the efficacy of caspofungin was similar to that of amphotericin B, with successful outcomes in patients in 73.4% and in 61.7% respectively. There were significantly fewer drug-related adverse events in the caspofungin group than in the amphotericin B group. Am J Med, 2002 Sep issue published a trial of comparison of caspofungin and fluconazole in treatment of esophageal candidiasis – results showed that symptoms had resolved in >50% patients by fifth day of therapy in both groups. Favorable response rates were achieved in 81% and in 85% patients respectively.

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NEJM, 2004 Sept. Issue published a trial of comparison of caspofungin and Liposomal Ampho B as empirical antifungal therapy in persistent fever and neutropenia – study included more than 1000 patients and analysis showed that caspofungin was as efficacious as Liposomal Ampho B and much better tolerated. Drugs, 2003 issue published a review of use of caspofungin in invasive candidiasis and aspergillosis . In that it cites a no. of randomized controlled trials and analyses that caspofungin was as effective as fluconazole or Ampho B in above indications and much better tolerated than Ampho B.

Adverse Effects:

Adverse Effects In most clinical trials, caspofungin has been shown good tolerability. Most common are nausea, vomiting, abd . Pain, headache, skin rashes and hypersensitivity reactions, bronchospams , pruritus . Elevations in liver enzymes is seen and hence LFT monitoring is required. Drug Interactions: Cyclosporin and tacrolimus and P450 enzyme inducers. Contraindications: known hypersensitivity to echinocandins

Dosage:

Dosage An initial dose of 70 mg by i.v. -infusion is given followed by 50 mg i.v . daily. An infusion should take approximately 1 hour. Duration of therapy: Patients found to have a fungal infection should be treated for a minimum of 14 days; treatment should continue for at least 7 days after both neutropenia and clinical symptoms are resolved.

Special Categories:

Special Categories Pregnancy category C drug. No studies in lactating women so should be avoided. No dose modification in renal impairment. Dose modification required in moderate liver impairment. No studies done in severe liver impairment.

Mikafungin:

Mikafungin History: US FDA approval came in 2005. Routes: Intravenous only Clinical Uses: Micafungin is indicated for the treatment of all systemic candidial infections. In 2008, micafungin has been approved for the prophylaxis of candida infections in patients undergoing haematopoietic stem cell transplantation. Dosage: For treatment it is 100-150 mg daily and for prophylaxis it is 50mg daily. Minimal drug interactions.

Anidulafungin:

Anidulafungin History: US FDA approval came in 2006. Routes: Intravenous only Pharmacokinetics: As it does not depend on renal or hepatic mechanism for metabolism, it can be safely given in renal or hepatic impairment. Dosage: 50-100mg/day for 10-14 days. Clinical Uses: At present only approved for use in invasive candidiasis , oesophageal candidiasis and disseminated candidemia , peritonitis and intraabdominal abscesses.