- Email: [email protected]
Meropenem
Antimicrobials in clinical practice Meropenem Dr. Bakul Parekh, Dr. Sneha Desai Introduction â lactam antibiotics is a family of cell wall active agents and include penicillins, cephalosporins, carbapenems and monobactams. Meropenem is an ultra-broad spectrum injectable antibiotic of the carbapenem group. It is a derivative of Theinamycin, a compound produced by soil organism, Sreptomyces cattleya. The other members of this group are Imipenem/Cilastatin, Ertapenem, Faropenem etc. Unlike imipenem, it is stable to dehydropeptidase-1 of the renal tubules and can therefore be given without concomittant addition of cilastatin. Mechanism of action The structural formula of meropenem is:
R1 CH 2
OH CH 3 CH O
R2
CH
CH
C
C
N
CH
â lactam ring
COOH
The shaded circles indicate the differences from the penicillin core structure Although the main carbapenem nucleus has a betalactam ring, unlike the penicillins and cephalosporins, the sulphur in the side chain is replaced by methylene group and the ring contains a double bond. These two important differences confer on the carbapenems a resistance to degradation by the usual beta-lactamases as well as the extended s p e c t r u m beta-lactamases ( E S B L s ) a n d chromosomally produced AmpC beta-lactamases. Like other beta lactam antibiotics, the bactericidal activity of Meropenem results from the inhibition of Correspondence : Dr. Bakul Parekh, Bakul Parekh Children Hospital & Multispecialist Center, 4th Floor, Jayant Arcade, M.G. Road, Ghatkopar (E), Mumbai - 400 077. E mail : [email protected] Pediatric Infectious Disease, Vol.1- Apr - June 2009
peptidoglycan cell wall synthesis by binding to specific Penicillin Binding Proteins (PBPs) and inactivating the enzymes responsible for cell wall synthesis 1 There are three properties of carbapenems that account for their incredibly broad spectra of activity. First, the molecule is quite small and have the charge characteristics that allow them to utilize special porins in the outer membrane of Gram-negative bacteria to gain access to to the PBP. Second, the structure makes them resistant to cleavage by most beta lactamases. Third, carbapenems have affinity for a broad range of PBPs from many different kinds of bacteria. As a result of these three properties, the carbapenems are adept at getting acess to the periplasm, resisting destruction by â lactamases that reside there and binding to PBPs to cause bacterial cell death. Bactericidal concentrations (defined as a 3 log10 reduction in cell counts within 12 to 24 hours) are typically 1-2 times the bacteriostatic concentrations of meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed, and it is only bacteriostatic. Spectrum of action Meropenem has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the Use in clinical practice section. Aerobic and facultative gram-positive microorganisms Enterococcus faecalis (excluding vancomycinresistant isolates) Staphylococcus aureus (modest activity against â-lactamase and non â-lactamase producing, methicillin susceptible isolates only) Streptococcus agalactiae Streptococcus pneumoniae (penicillin-susceptible isolates only) (Note: Penicillin-resistant isolates had meropenem MIC90 values of 1 or 2 μg/mL, which is above the 0.12 μg/mL susceptible breakpoint for this species.) Streptococcus pyogenes Viridans group streptococci
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Aerobic and facultative gram-negative microorganisms Escherichia coli, Haemophilus influenzae â-lactamase and non-â-lactamase producing Klebsiella pneumoniae Neisseria meningitidis Pseudomonas aeruginosa (carbapenem resistance in pseudomonas is on the rise) Proteus mirabilis Anaerobic micro-organisms Bacteroides fragilis, Bacteroides spp., Peptostreptococcus spp. Resistance Organisms that often display resistance to carbapenems are Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii. Various other bacteria like Citrobacter species, Enterobacter species, Proteus mirabilis, Salmonella enterica and most alarmingly, E.Coli are now showing resistance to this group of antibiotics2. Mechanism of resistance There are several mechanisms of resistance to carbapenems: Changes in outer membrane proteins. The predominant mechanism contributing to meropenem resistance is change in OprD protein (previously refered to as D2.), an outer membrane porin. OprD serves as a carbapenem conduit without affecting other B-lactam antibiotics. This mechanism is seen in P. aeruginosa, Acinetobacter, and other gram negative organisms. Carbapenem hydrolyzing enzymes. Carbamases are defined as â-lactamases that significantly hydrolyze at least Imipenem and/or meropenem3. Over expression of drug efflux pumps. This mechanism involves the up-regulation of the MexAB-OprM efflux system. The Opr designation refers to the outer membrane portal. The Mex components consists of an inner membrane embedded pump and linker elements that connect the pump to the outer membrane. The MexAB-OprM efflux system when upregulated is responsible for resistance to many antibiotics including Pediatric Infectious Disease, Vol.1- Apr - June 2009
Meropenem. Modification of penicillin binding proteins. This mechanism appears to be of little consequence compared with impermeability and B-lactamase. e.g. MRSA and Enterococcus faecium Use in clinical practice Carbapenams have broad spectrum anti bacterial activity against Gram-positive, Gram-negative and Anaerobes and are therefore useful agents for treatment of nosocomial infections, infections in immunocompromised, polymicrobial infections and presumptive therapy in serious bacterial infections before identification of infecting organism. Meropenem is used as empirical monotherapy for treatment of febrile neutropenia in various malignancies 4,5. In neonates with sepsis due to multi drug resistant gram negative organisms, Meropenem gives excellent results6 (100% cure rates for sepsis, and 87.5% for nosocomial pneumonia.) Meropenem may also be used for treatment of infections of urinary tract, the skin, septicemia, meningitis, and intra abdominal infections7. Intra-abdominal infections Complicated appendicitis and peritonitis caused by polymicrobial infections including viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, and Peptostreptococcus species. Good results have been documented in pelvic and hepatic abscesses also. Early antibiotic treatment is associated with a significant improvement in the prognosis of necrotizing acute pancreatitis, because of a reduction in the occurrence of septic complications. Bacterial meningitis (pediatric patients ≥ 3 months only) Meropenem is effective in treatment of bacterial meningitis caused by Streptococcus pneumoniae‡, Haemophilus influenzae (â-lactamase and non-âlactamase-producing isolates), and Neisseria meningitidis8,9 Howewer the efficacy of meropenem
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as monotherapy in the treatment of meningitis caused by penicillin nonsusceptible isolates of Streptococcus pneumoniae has not been established. Skin and skin structure infections10,11 Meropenem has excellent activity against many pathogens associated with complicated skin and soft tissue infections (cSSTIs). Complicated skin and soft tissue infections (cSSTIs) are those which involve abnormal skin or wounds, occur in a compromised host, or require substantial surgical intervention.
Clinical pearls Meropenem has significant stability to hydrolysis by â-lactamases of most categories, there is stability against both penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria. Meropenem is effective against most strains of penicillin resistant S. pneumoniae at concentrations usually reached in serum and soft tissues. Meropenem should not be used to treat MethicillinResistant Staphylococci (MRSA).
cSSTIs often involve deeper skin structures such as fascia or muscle layers and require surgical intervention for effective management . Examples of complicated infections include more complex cellulitis and abscesses, perirectal abscesses, posttraumatic or surgical site infections, myositis, necrotizing fasciitis, and infected diabetic and vascular ischemic ulcers. Based on available data, meropenem should be considered relatively interchangeable with Imipenem/Cilastatin for treatment of cSSTIs and would be preferred over Ertapenem for certain patients who are at high risk of infection with P. aeruginosa. Mycobacterium TB â-lactam antibiotics are ineffective against Mycobacterium tuberculosis, being rapidly hydrolyzed by the chromosomally encoded BlaC gene product. When meropenem was combined with the â-lactamase inhibitor clavulanate, potent activity against laboratory strains of M. tuberculosis was observed [MIC < 1 microgram per milliliter], and sterilization of aerobically grown cultures was
In vitro tests show meropenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa. Meropenem is more active against Gram negative and less active against Gram positive in comparison to Imipenem. Meropenem shows incomplete crossresistance with imipenem/cilastatin and slightly greater activity against P. aeruginosa; potentially decreased CNS toxicity compared with imipenem/cilastatin; and potential cost advantages. Conversely, potential disadvantages of meropenem use include an excessively broad spectrum of activity for treatment of many infections in which P. aeruginosa, anaerobes, and/or multidrug-resistant pathogens are not likely to be present. This too broad spectrum of activity may increase selective pressure for development of resistance among organisms such as P. aeruginosa. Other disadvantages are the need for addition of another agent when MRSA is possibly present in; the need for three-times-daily dosing; and potentially higher costs relative to some alternative agents.
observed within 14 days. In addition, this combination exhibited inhibitory activity against anaerobically grown cultures that mimic the "persistent" state and inhibited the growth of 13 extensively drug-resistant strains of M. tuberculosis at the same levels seen for drug-susceptible strains. This combination could potentially be used to treat patients with currently untreatable MDRTB disease12.
Pediatric Infectious Disease, Vol.1- Apr - June 2009
Need for meropenem With widespread use of third generation cephalosporins, there has been emergence of strains of bacteria that produce Extended Spectrum Beta Lactamases (ESBLs). These are usually plasmid mediated beta lactamases that are capable of hydrolyzing third generation cephalosporins, penicillins and aztreonam. Additionally the same
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plasmid usually also carries the resistance genes for aminoglycosides,trimethoprim sulphamethoxazole and fluroquinolones. In addition to ESBLs, gram negative bacteria such as Pseudomonas, Serratia, Citrobacter and Enterobacter produce chromosomally mediated AmpC beta lactamases. These hydrolyse penicillins and cephalosporins and are not inhibited by beta lactamase inhibitors. Potential agents for use in such infections caused by ESBL producing infections are betalactam betalactam inhibitor(BLI) combinations like piperacillin-tazobactam but as the BLI does not penetrate the CSF, they are unsuitable for use in neonates or in cases with meningitis. Fourth generation cephalosporins have not shown adequate effectiveness in such cases because they suffer from the innoculum effect of high bacterial load. Many of these organisms show simultaneous resistance precluding the use of aminoglycosides and fluoroquinolones; besides the latter are not freely usable in children because of potential cartilage toxicity. In such cases, Meropenem is invaluable and less toxic than other alternatives like colistin and tigecycline. Pharmacokinetics Meropenem is acid labile and hence needs to be given parenterally. It should be given as intravenous infusion over approximately 15 to 30 minutes or as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes. Meropenem unlike imipenem does not require the use of Dehydropeptidase-1 (DHP-1) as it has a Methyl group at C1 position, which confers resistance to hydrolysis by DHP-1 present in the brush border of proximal renal tubular cells. Meropenem is excreted by glomerular filteration and with some active tubular secretion as well. Meropenem is eliminated unchanged in urine , accounting for 58%–83% of total systemic clearance of the drug and up to 98% of each dose is eventually
Pediatric Infectious Disease, Vol.1- Apr - June 2009
excreted in the urine as unchanged meropenem. The elimination half-life of meropenem is approximately one hour in patients with normal renal function. The elimination half life is longest in preterm neonates and decreases as age advances. It appears that meropenem pharmacokinetics in children ≥ 6 months of age are very similar to those seen in adults. Plasma protein binding of meropenem is approximately 2%. Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid in presence of inflamed meninges, achieving concentrations matching or exceeding those required to inhibit most susceptible bacteria. The volume of distribution is greater in infants than children in view of their reduced renal functioning capacity and increased extra cellular volume. The plasma half life of meropenem is approx 1 hour and peak plasma levels attained after intravenous dose decline to less than 1 micro gm after 4-6 hrs , hence the usual dosing interval is 6 hrs for patients with normal renal function. Plasma trough concentrations on an 8 hour dosing schedule are well above the MIC values for most of the organisms. Meropenem requires modification in patients with renal insufficiency although detailed studies in pediatric age group are pending. Modes of administration Intravenous bolus administration Injection vials constituted with sterile water for injection for bolus administration (up to 50 mg/mL) may be stored for up to 2 hours at controlled room temperature 15-25°C or for up to 12 hours at 4°C Intravenous infusion administration Infusion vials constituted with Sodium chloride injection 0.9% (concentrations ranging from 2.5 to 50 mg/mL) are stable for up to 2 hours at controlled room temperature 15-25°C or for up to 18 hours at 4°C. Infusion vials constituted with Dextrose injection 5% (concentrations ranging from 2.5 to 50 mg/mL) are stable for up to 1 hour at controlled room temperature 15-25°C or for up to 8 hours at 4°C.
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Meropenem should not be mixed with or physically added to solutions containing other drugs. Pharmacodynamics The activity of meropenem is dependent on the time for which the drug levels remain above the Minimum Inhibitory Concentration (MIC) for the organism. Studies of carbapenems indicate that the percentage of the dosing interval during which concentrations of free (i.e., not protein bound) drug
Common adverse reactions seen with different studies on pediatric patients (515 pediatric patients (≥ 3 months to <13 years of age) with serious bacterial infections at dosages of 10 to 20 mg/kg every 8 hours and 321 pediatric patients (≥3 months to < 17 years of age) with meningitis at a dosage of 40 mg/kg every 8 hour) are diarrhea, rash, nausea and vomiting, but all these occur in less than 5% of cases.
Table 1 : Recommended. meropenem dosage schedule for pediatrics with normal renal function
Category of Infection Complicated skin and skin structure Intra-abdominal and sepsis Meningitis
Dose (mg/kg) 10
Maximum Dose 500 mg
Dosing Interval Every 8 hours
20 40
1 Gm 2 Gm
Every 8 hours Every 8 hours
remain above the MIC of the pathogen (referred to as the percent time above MIC, or % T>MIC) is the key pharmacodynamic parameter which is related to clinical and microbiological efficacy of the drugs. A ≥ 30% T>MIC is associated with bacteriostatic activity of the carbapenems, while a ≥ 40% T>MIC is more predictably bactericidal and associated with prevention of the development of resistance Meropenem also exhibits a Post Antibiotic Effect (PAE) against both gram positive and negative organisms, so their effect may last even longer than that predicted by their half life. Meropenem provides a significant advantage in treating ESBL producing strains since they do not exhibit the “INNOCULUM EFFECT” which is reduced efficacy in relation to size of innoculum. Its MIC for a bacterial load of 107 CFU is not much higher as compared to that of MIC of 105 CFU13,14. Plasma trough concentrations on an 8 hours dosing schedule are well above the MIC valves for most of the organisms. Adverse reactions Clinical Adverse Reactions Local adverse reactions such as pain, inflammation, edema at the injection site may be seen in a small percentage of patients administered meropenem. Pediatric Infectious Disease, Vol.1- Apr - June 2009
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including meropenem, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. Although carbapenems have been associated with seizures and other central nervous system (CNS) toxicities, the rate of meropenem-associated CNS toxicity appears to be less than that of imipenem/ cilastatin and probably similar to ertapenem15 . The incidence of seizures during meropenem therapy is very low and appears to be 0.05% to 0.08% This potential difference in CNS toxicities between meropenem and imipenem / cilastatin may be most relevant in higher-risk patients such as those with head trauma, seizure disorders, or other underlying CNS pathology. The pathogenesis of neurotoxity is by virtue of its interaction with GABA receptor and this interaction depends on the side chain of the second carbon atom in the carbapenem nucleus16. The more basic the side chain is, the better is the binding of the GABA receptor, and this results in higher convulsant activity. Imipenem and Panipenem have basic C-2 side chain whereas Meropenem's side chain is not basic, hence meropenem is approved by FDA for use in meningitis in children greater than 3 months of age.
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Adverse laboratory changes Adverse laboratory changes that were reported occurring in greater than 0.2% of the patients were as follows: Hepatic: increased SGPT (ALT), SGOT (AST), alkaline phosphatase, LDH, and bilirubin Hematologic: increased platelets, increased eosinophils, decreased platelets, decreased hemoglobin, decreased hematocrit, decreased WBC, shortened prothrombin time and shortened partial thromboplastin time, leukocytosis, hypokalemia Renal: increased creatinine and increased BUN While Meropenem possesses the characteristic low toxicity of the beta-lactam group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. Drug interactions Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. This led to statistically significant increases in the elimination half-life (38%) and in the extent of systemic exposure (56%). Therefore, the co-administration of probenecid with meropenem is not recommended. A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics and may result in loss of seizure control. Although the mechanism of this interaction is not fully understood, data from in vitro and animal studies suggest that carbapenem antibiotics may inhibit valproic acid glucuronide hydrolysis. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop below the therapeutic range or a seizure occurs Carcinogenesis, mutagenesis, impairment of fertility Carcinogenesis studies have not been performed. Genetic toxicity studies were performed with meropenem using various tests in animal models Pediatric Infectious Disease, Vol.1- Apr - June 2009
showed no evidence of mutagenic potential in any of these tests. Reproductive studies were performed with meropenem in rats at doses up to 1000 mg/kg/day, and cynomolgus monkeys at doses up to 360 mg/kg/day (on the basis of AUC comparisons, approximately 1.8 times and 3.7 times, respectively, to the human exposure at the usual dose of 1 g every 8 hours). There was no reproductive toxicity seen. There are, however, no adequate and wellcontrolled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. (Pregnancy Category B) Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Meropenem. is administered to a nursing woman. Contraindications Meropenem is contraindicted in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to âlactams. Recent data indicate a low rate of cross-reactivity between penicillins and meropenem. Therefore, the practice of avoiding meropenem therapy in penicillin-allergic patients should be reconsidered. In patients who especially require meropenem treatment, pretreatment skin tests should be carried out because negative results indicate tolerability. Conclusions Meropenem is possibly our last line of defence against multi drug resistant gram negative infections. It is therefore extremaly important that we use it with caution and discretion especially as there are not many drugs in the pipeline in the near future. Refrences 1) Ayalew K, Nambiar S, Yasinskaya Y, Jantausch BA, Carbapenems in Pediatrics. Ther Drug Monit. 2003;25: 593-9. 2) Livermore DM. Of Pseudomonas, porins, pumps and carbapenems. J Antimicrob Chemother 2001; 47: 247 – 250.
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3) Nordmann P, Poirel L. Emerging Carbapene-mases in gramnegative aerobes. Clin Microbiol Infect 2002; 8: 321-31. 4) Fleischhack G, Hartmann C, Simon A et al. Meropenem versus Ceftazidime as empirical monotherapy in febrile neutropenia of pediatric patients with cancer. J Antimicrob Chemother 2001; 47: 841 – 853. 5) Duzova A, Kutluk T, Kanra G, Buyukpamukcu M, Akyuz C, Secmeer G, Ceyhan M. Monotherapy with meropenem versus combination therapy with piperacillin plus amikacin as empiric therapy for neutropenic fever in children with lymphoma and solid tumors. Turk J Pediatr 2001; 43: 105 – 9. 6) Koksal N, Hacimustafaoglu M, Bagci S, Celebi S. Meropenem in neonatal severe infections due to multiresistant gram – negative bacteria. Indian J Pediatr 2001; 68: 15 – 9. 7) Hsu HL, Lu CY, Tseng HY, Lee PI, Lai HP, Lin WC, Hsieh YC, Lee CY, Huang LM. Empirical monotherapy with meropenem in serious bacterial infections in children. J Microbiol Immunol Infect. 2001; 34: 275 – 80. 8) Lopez E and the Meropenem Meningitis Study Group. Poster presented at 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy. New Orleans, USA, 17 – 20 October 1993, Abstract 638. 9) Schmutzhard E, Williams KJ, Vukmirovits G, Chmelik V, Pfausler B, Featherstone A. A randomized comparison of meropenem with cefotaxime or ceftriaxone for the treatment of bacterial meningitis in adults. Meropenem Meningitis Study Group. J 10) Antimicr Ther Clin Risk Manag. 2006 December; 2(4): 401–415. Meropenem in the treatment of complicated skin and soft tissue infections Douglas N Fish 11) A post hoc subgroup analysis of meropenem versus imipenem / cilastatin in a multicenter, double-blind, randomized study of complicated skin and skin-structure infections in patients with diabetes mellitus MD John M. Embil, , MD Norberto E. Soto and MD David A. Melnick Prevention and Control Unit, Health Sciences Centre, Winnipeg, Manitoba, Canada2AstraZeneca Pharmaceuticals LP, Wilmington, Delaware, USA Accepted 12 June 2006. 12) Science 27 Feb2009;Vol 323, no. 5918,pp. 1215-1218. Meropenem – Clavulanate is effective Against Extensively Drug Resistant Mycobacterium Tuberculosis. Jean-Emma nuel et al. 13) Lipman J, Wallis SC, Rickard C. Low plasma cefepime levels in critically ill septic patients: pharmacokinetic modeling indicates improved troughs with revised dosing. Antimicrob Agents Chamother 1999; 43: 2559 –61. 14) Thomson K, Moland ES. Cefepime, piperacillin – tazobactam, and the inoculum effect in tests with extended – spectrum beta – lactamase – producing Enterobacteriaceae. Antimicrob Agents Chemother 2001; 45: 3548. 15) Wong VK, Wright HTJr .Imepenem- Cilastin in treatment of bacterial meningitis in children.Pedia Jour Infec Dise 1991;10:122-125. 16) Norrby SR. Neurotoxicity of Carbapenem antibiotics: consequences for their use in bacterial meningitis. J Antimicrob Chemother 2000; 45: 5 – 7.
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FURTHER READING 1) Nechyba C, Gunn VL. Drugs in Renal Failure. In, Nechyba C, Gunn VL (eds). The Harriet Lane Handbook: A manual for Pediatric House Officers. 16th edition, Philadelphia: Mosby; 2002. pp 943. 2) Thauvin – Eliopoulos C, Tripodi MF, Moellering RCJr, Eliopoulos GM. Efficacies of piperacillin – tazobactam and cefepime in rats with experimental intra – abdominal abscesses due to an extended – spectrum beta – lactamase – producing strain of Klebsiella pneumoniae. Antimicrob Agents Chemother 1997 ; 41: 1053 – 7. 3) Kang CI, Pai H, Kim SH, Kim HB, Kim EC, Oh MD, Choe KW. Cefepime and the inoculum effect in tests with Klebsiella pneumoniae producing plasmid – mediated AmpC –type beta – lactamase. J Antimicrob Chemother 2004; 54: 1130 – 3. 4) Alpert G, Dagan R, Connor E, Campos JM, Bloh M, Powell KR, et al. Imipenem / cilastatin for the treatment of infections in hospitalized children. Am J Dis Child 1985; 139; 1153 – 1156. 5) Karadeniz C, Oguz A, Canter B et al. Imipenem – Cilastatin in treatment of bacterial meningitis in children. Pediatr Infect Dis J 1991; 10: 122 – 125. 6) E x t e n s i v e l y D r u g - R e s i s t a n t M y c o b a c t e r i u m tuberculosisMeropenem-Clavulanate Is Effective Against Jean-Emmanuel Hugonnet, 1 Lee W. Tremblay,1 Helena I. Boshoff, 2 Clifton E. Barry, 3rd,2 John S. Blanchard1* 7) Timing of antibiotic prophylaxis in acute pancreatitis: a controlled randomized study with meropenem.Author(s): Manes G, Uomo I, Menchise A, Rabitti PG, Ferrara EC, Uomo GAffiliation(s): Department of Gastroenterology, L. Sacco University Hospital, Milano, Italy.Publication date & source: 2006-06, Am J Gastroenterol., 101(6):1348-53. 8) Comparison of probability of target attainment calculated by Monte Carlo simulation with meropenem clinical and microbiological response for the treatment of complicated skin and skin structure infections.Author(s): Kuti JL, Ong C, Lo M, Melnick D, Soto N, Nicolau DPAffiliation(s): Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.Publication date & source: 2006-07, Int J Antimicrob Agents., 28(1):62-8. Epub 2006 Jun 6. 9) Department of Clinical Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado, USAExperience with cefepime versus meropenem as empiric monotherapy for neutropenia and fever in pediatric patients with solid tumors.Author(s): Oguz A, Karadeniz C, Citak EC, Cil V, Eldes NAffiliation(s): Gazi University, Faculty of Medicine, D e p a r t m e n t o f P e d i a t r i c O n c o l o g y, A n k a r a , Turkey.Publication date & source: 2006-04, Pediatr Hematol Oncol., 23(3):245-53. 10) Pharmacokinetic and Safety Study of Meropenem in Young Infants With Intra-Abdominal InfectionsInformation source: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Information obtained from ClinicalTrials.gov on February 12, 2009
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11) Complicated Skin and Skin Structure InfectionsInformation source : AstraZeneca Information obtained from ClinicalTrials.gov on June 20, 2008 12) AHFS DRUG INFORMATION 2006 (2006 ed ed.). American Society of Health.
13) Mosby's Drug Consult 2006 (16 ed ed.). Mosby, Inc.. 2006. 14) Smith – Moland E, Black JA, Ourada J, Reisbig MD, Hanson ND, Thomson KS. Occurrence of newer Beta – lactamases in Klebsiella pneumoniae isolates from 24 U.S. hospitals. Antimicrob Agents Chemother 2002; 46: 3837-42.
IAP Guidebook on Immunization, 2009 Edition
The 2009 edition of the IAPCOI guidebook has been published by Jaypee Brothers and released at Pedicon 2009. This edition of the book comprehensively discusses basics of immunology, IAP immunization schedule and its rationale, individual vaccines, immunization in special situations, cold chain, adverse effects following immunization, practical aspects of immunization and also includes a ready reckoner for vaccines currently available in the country. This book is available for purchase at all medical book stores at a nominal price of Rs 100.
Pediatric Infectious Disease, Vol.1- Apr - June 2009
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R1 CH 2
OH CH 3 CH O
R2
CH
CH
C
C
N
CH
â lactam ring
COOH
The shaded circles indicate the differences from the penicillin core structure Although the main carbapenem nucleus has a betalactam ring, unlike the penicillins and cephalosporins, the sulphur in the side chain is replaced by methylene group and the ring contains a double bond. These two important differences confer on the carbapenems a resistance to degradation by the usual beta-lactamases as well as the extended s p e c t r u m beta-lactamases ( E S B L s ) a n d chromosomally produced AmpC beta-lactamases. Like other beta lactam antibiotics, the bactericidal activity of Meropenem results from the inhibition of Correspondence : Dr. Bakul Parekh, Bakul Parekh Children Hospital & Multispecialist Center, 4th Floor, Jayant Arcade, M.G. Road, Ghatkopar (E), Mumbai - 400 077. E mail : [email protected] Pediatric Infectious Disease, Vol.1- Apr - June 2009
peptidoglycan cell wall synthesis by binding to specific Penicillin Binding Proteins (PBPs) and inactivating the enzymes responsible for cell wall synthesis 1 There are three properties of carbapenems that account for their incredibly broad spectra of activity. First, the molecule is quite small and have the charge characteristics that allow them to utilize special porins in the outer membrane of Gram-negative bacteria to gain access to to the PBP. Second, the structure makes them resistant to cleavage by most beta lactamases. Third, carbapenems have affinity for a broad range of PBPs from many different kinds of bacteria. As a result of these three properties, the carbapenems are adept at getting acess to the periplasm, resisting destruction by â lactamases that reside there and binding to PBPs to cause bacterial cell death. Bactericidal concentrations (defined as a 3 log10 reduction in cell counts within 12 to 24 hours) are typically 1-2 times the bacteriostatic concentrations of meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed, and it is only bacteriostatic. Spectrum of action Meropenem has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the Use in clinical practice section. Aerobic and facultative gram-positive microorganisms Enterococcus faecalis (excluding vancomycinresistant isolates) Staphylococcus aureus (modest activity against â-lactamase and non â-lactamase producing, methicillin susceptible isolates only) Streptococcus agalactiae Streptococcus pneumoniae (penicillin-susceptible isolates only) (Note: Penicillin-resistant isolates had meropenem MIC90 values of 1 or 2 μg/mL, which is above the 0.12 μg/mL susceptible breakpoint for this species.) Streptococcus pyogenes Viridans group streptococci
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Aerobic and facultative gram-negative microorganisms Escherichia coli, Haemophilus influenzae â-lactamase and non-â-lactamase producing Klebsiella pneumoniae Neisseria meningitidis Pseudomonas aeruginosa (carbapenem resistance in pseudomonas is on the rise) Proteus mirabilis Anaerobic micro-organisms Bacteroides fragilis, Bacteroides spp., Peptostreptococcus spp. Resistance Organisms that often display resistance to carbapenems are Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii. Various other bacteria like Citrobacter species, Enterobacter species, Proteus mirabilis, Salmonella enterica and most alarmingly, E.Coli are now showing resistance to this group of antibiotics2. Mechanism of resistance There are several mechanisms of resistance to carbapenems: Changes in outer membrane proteins. The predominant mechanism contributing to meropenem resistance is change in OprD protein (previously refered to as D2.), an outer membrane porin. OprD serves as a carbapenem conduit without affecting other B-lactam antibiotics. This mechanism is seen in P. aeruginosa, Acinetobacter, and other gram negative organisms. Carbapenem hydrolyzing enzymes. Carbamases are defined as â-lactamases that significantly hydrolyze at least Imipenem and/or meropenem3. Over expression of drug efflux pumps. This mechanism involves the up-regulation of the MexAB-OprM efflux system. The Opr designation refers to the outer membrane portal. The Mex components consists of an inner membrane embedded pump and linker elements that connect the pump to the outer membrane. The MexAB-OprM efflux system when upregulated is responsible for resistance to many antibiotics including Pediatric Infectious Disease, Vol.1- Apr - June 2009
Meropenem. Modification of penicillin binding proteins. This mechanism appears to be of little consequence compared with impermeability and B-lactamase. e.g. MRSA and Enterococcus faecium Use in clinical practice Carbapenams have broad spectrum anti bacterial activity against Gram-positive, Gram-negative and Anaerobes and are therefore useful agents for treatment of nosocomial infections, infections in immunocompromised, polymicrobial infections and presumptive therapy in serious bacterial infections before identification of infecting organism. Meropenem is used as empirical monotherapy for treatment of febrile neutropenia in various malignancies 4,5. In neonates with sepsis due to multi drug resistant gram negative organisms, Meropenem gives excellent results6 (100% cure rates for sepsis, and 87.5% for nosocomial pneumonia.) Meropenem may also be used for treatment of infections of urinary tract, the skin, septicemia, meningitis, and intra abdominal infections7. Intra-abdominal infections Complicated appendicitis and peritonitis caused by polymicrobial infections including viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, and Peptostreptococcus species. Good results have been documented in pelvic and hepatic abscesses also. Early antibiotic treatment is associated with a significant improvement in the prognosis of necrotizing acute pancreatitis, because of a reduction in the occurrence of septic complications. Bacterial meningitis (pediatric patients ≥ 3 months only) Meropenem is effective in treatment of bacterial meningitis caused by Streptococcus pneumoniae‡, Haemophilus influenzae (â-lactamase and non-âlactamase-producing isolates), and Neisseria meningitidis8,9 Howewer the efficacy of meropenem
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as monotherapy in the treatment of meningitis caused by penicillin nonsusceptible isolates of Streptococcus pneumoniae has not been established. Skin and skin structure infections10,11 Meropenem has excellent activity against many pathogens associated with complicated skin and soft tissue infections (cSSTIs). Complicated skin and soft tissue infections (cSSTIs) are those which involve abnormal skin or wounds, occur in a compromised host, or require substantial surgical intervention.
Clinical pearls Meropenem has significant stability to hydrolysis by â-lactamases of most categories, there is stability against both penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria. Meropenem is effective against most strains of penicillin resistant S. pneumoniae at concentrations usually reached in serum and soft tissues. Meropenem should not be used to treat MethicillinResistant Staphylococci (MRSA).
cSSTIs often involve deeper skin structures such as fascia or muscle layers and require surgical intervention for effective management . Examples of complicated infections include more complex cellulitis and abscesses, perirectal abscesses, posttraumatic or surgical site infections, myositis, necrotizing fasciitis, and infected diabetic and vascular ischemic ulcers. Based on available data, meropenem should be considered relatively interchangeable with Imipenem/Cilastatin for treatment of cSSTIs and would be preferred over Ertapenem for certain patients who are at high risk of infection with P. aeruginosa. Mycobacterium TB â-lactam antibiotics are ineffective against Mycobacterium tuberculosis, being rapidly hydrolyzed by the chromosomally encoded BlaC gene product. When meropenem was combined with the â-lactamase inhibitor clavulanate, potent activity against laboratory strains of M. tuberculosis was observed [MIC < 1 microgram per milliliter], and sterilization of aerobically grown cultures was
In vitro tests show meropenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa. Meropenem is more active against Gram negative and less active against Gram positive in comparison to Imipenem. Meropenem shows incomplete crossresistance with imipenem/cilastatin and slightly greater activity against P. aeruginosa; potentially decreased CNS toxicity compared with imipenem/cilastatin; and potential cost advantages. Conversely, potential disadvantages of meropenem use include an excessively broad spectrum of activity for treatment of many infections in which P. aeruginosa, anaerobes, and/or multidrug-resistant pathogens are not likely to be present. This too broad spectrum of activity may increase selective pressure for development of resistance among organisms such as P. aeruginosa. Other disadvantages are the need for addition of another agent when MRSA is possibly present in; the need for three-times-daily dosing; and potentially higher costs relative to some alternative agents.
observed within 14 days. In addition, this combination exhibited inhibitory activity against anaerobically grown cultures that mimic the "persistent" state and inhibited the growth of 13 extensively drug-resistant strains of M. tuberculosis at the same levels seen for drug-susceptible strains. This combination could potentially be used to treat patients with currently untreatable MDRTB disease12.
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Need for meropenem With widespread use of third generation cephalosporins, there has been emergence of strains of bacteria that produce Extended Spectrum Beta Lactamases (ESBLs). These are usually plasmid mediated beta lactamases that are capable of hydrolyzing third generation cephalosporins, penicillins and aztreonam. Additionally the same
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plasmid usually also carries the resistance genes for aminoglycosides,trimethoprim sulphamethoxazole and fluroquinolones. In addition to ESBLs, gram negative bacteria such as Pseudomonas, Serratia, Citrobacter and Enterobacter produce chromosomally mediated AmpC beta lactamases. These hydrolyse penicillins and cephalosporins and are not inhibited by beta lactamase inhibitors. Potential agents for use in such infections caused by ESBL producing infections are betalactam betalactam inhibitor(BLI) combinations like piperacillin-tazobactam but as the BLI does not penetrate the CSF, they are unsuitable for use in neonates or in cases with meningitis. Fourth generation cephalosporins have not shown adequate effectiveness in such cases because they suffer from the innoculum effect of high bacterial load. Many of these organisms show simultaneous resistance precluding the use of aminoglycosides and fluoroquinolones; besides the latter are not freely usable in children because of potential cartilage toxicity. In such cases, Meropenem is invaluable and less toxic than other alternatives like colistin and tigecycline. Pharmacokinetics Meropenem is acid labile and hence needs to be given parenterally. It should be given as intravenous infusion over approximately 15 to 30 minutes or as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes. Meropenem unlike imipenem does not require the use of Dehydropeptidase-1 (DHP-1) as it has a Methyl group at C1 position, which confers resistance to hydrolysis by DHP-1 present in the brush border of proximal renal tubular cells. Meropenem is excreted by glomerular filteration and with some active tubular secretion as well. Meropenem is eliminated unchanged in urine , accounting for 58%–83% of total systemic clearance of the drug and up to 98% of each dose is eventually
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excreted in the urine as unchanged meropenem. The elimination half-life of meropenem is approximately one hour in patients with normal renal function. The elimination half life is longest in preterm neonates and decreases as age advances. It appears that meropenem pharmacokinetics in children ≥ 6 months of age are very similar to those seen in adults. Plasma protein binding of meropenem is approximately 2%. Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid in presence of inflamed meninges, achieving concentrations matching or exceeding those required to inhibit most susceptible bacteria. The volume of distribution is greater in infants than children in view of their reduced renal functioning capacity and increased extra cellular volume. The plasma half life of meropenem is approx 1 hour and peak plasma levels attained after intravenous dose decline to less than 1 micro gm after 4-6 hrs , hence the usual dosing interval is 6 hrs for patients with normal renal function. Plasma trough concentrations on an 8 hour dosing schedule are well above the MIC values for most of the organisms. Meropenem requires modification in patients with renal insufficiency although detailed studies in pediatric age group are pending. Modes of administration Intravenous bolus administration Injection vials constituted with sterile water for injection for bolus administration (up to 50 mg/mL) may be stored for up to 2 hours at controlled room temperature 15-25°C or for up to 12 hours at 4°C Intravenous infusion administration Infusion vials constituted with Sodium chloride injection 0.9% (concentrations ranging from 2.5 to 50 mg/mL) are stable for up to 2 hours at controlled room temperature 15-25°C or for up to 18 hours at 4°C. Infusion vials constituted with Dextrose injection 5% (concentrations ranging from 2.5 to 50 mg/mL) are stable for up to 1 hour at controlled room temperature 15-25°C or for up to 8 hours at 4°C.
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Meropenem should not be mixed with or physically added to solutions containing other drugs. Pharmacodynamics The activity of meropenem is dependent on the time for which the drug levels remain above the Minimum Inhibitory Concentration (MIC) for the organism. Studies of carbapenems indicate that the percentage of the dosing interval during which concentrations of free (i.e., not protein bound) drug
Common adverse reactions seen with different studies on pediatric patients (515 pediatric patients (≥ 3 months to <13 years of age) with serious bacterial infections at dosages of 10 to 20 mg/kg every 8 hours and 321 pediatric patients (≥3 months to < 17 years of age) with meningitis at a dosage of 40 mg/kg every 8 hour) are diarrhea, rash, nausea and vomiting, but all these occur in less than 5% of cases.
Table 1 : Recommended. meropenem dosage schedule for pediatrics with normal renal function
Category of Infection Complicated skin and skin structure Intra-abdominal and sepsis Meningitis
Dose (mg/kg) 10
Maximum Dose 500 mg
Dosing Interval Every 8 hours
20 40
1 Gm 2 Gm
Every 8 hours Every 8 hours
remain above the MIC of the pathogen (referred to as the percent time above MIC, or % T>MIC) is the key pharmacodynamic parameter which is related to clinical and microbiological efficacy of the drugs. A ≥ 30% T>MIC is associated with bacteriostatic activity of the carbapenems, while a ≥ 40% T>MIC is more predictably bactericidal and associated with prevention of the development of resistance Meropenem also exhibits a Post Antibiotic Effect (PAE) against both gram positive and negative organisms, so their effect may last even longer than that predicted by their half life. Meropenem provides a significant advantage in treating ESBL producing strains since they do not exhibit the “INNOCULUM EFFECT” which is reduced efficacy in relation to size of innoculum. Its MIC for a bacterial load of 107 CFU is not much higher as compared to that of MIC of 105 CFU13,14. Plasma trough concentrations on an 8 hours dosing schedule are well above the MIC valves for most of the organisms. Adverse reactions Clinical Adverse Reactions Local adverse reactions such as pain, inflammation, edema at the injection site may be seen in a small percentage of patients administered meropenem. Pediatric Infectious Disease, Vol.1- Apr - June 2009
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including meropenem, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. Although carbapenems have been associated with seizures and other central nervous system (CNS) toxicities, the rate of meropenem-associated CNS toxicity appears to be less than that of imipenem/ cilastatin and probably similar to ertapenem15 . The incidence of seizures during meropenem therapy is very low and appears to be 0.05% to 0.08% This potential difference in CNS toxicities between meropenem and imipenem / cilastatin may be most relevant in higher-risk patients such as those with head trauma, seizure disorders, or other underlying CNS pathology. The pathogenesis of neurotoxity is by virtue of its interaction with GABA receptor and this interaction depends on the side chain of the second carbon atom in the carbapenem nucleus16. The more basic the side chain is, the better is the binding of the GABA receptor, and this results in higher convulsant activity. Imipenem and Panipenem have basic C-2 side chain whereas Meropenem's side chain is not basic, hence meropenem is approved by FDA for use in meningitis in children greater than 3 months of age.
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Adverse laboratory changes Adverse laboratory changes that were reported occurring in greater than 0.2% of the patients were as follows: Hepatic: increased SGPT (ALT), SGOT (AST), alkaline phosphatase, LDH, and bilirubin Hematologic: increased platelets, increased eosinophils, decreased platelets, decreased hemoglobin, decreased hematocrit, decreased WBC, shortened prothrombin time and shortened partial thromboplastin time, leukocytosis, hypokalemia Renal: increased creatinine and increased BUN While Meropenem possesses the characteristic low toxicity of the beta-lactam group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. Drug interactions Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. This led to statistically significant increases in the elimination half-life (38%) and in the extent of systemic exposure (56%). Therefore, the co-administration of probenecid with meropenem is not recommended. A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics and may result in loss of seizure control. Although the mechanism of this interaction is not fully understood, data from in vitro and animal studies suggest that carbapenem antibiotics may inhibit valproic acid glucuronide hydrolysis. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop below the therapeutic range or a seizure occurs Carcinogenesis, mutagenesis, impairment of fertility Carcinogenesis studies have not been performed. Genetic toxicity studies were performed with meropenem using various tests in animal models Pediatric Infectious Disease, Vol.1- Apr - June 2009
showed no evidence of mutagenic potential in any of these tests. Reproductive studies were performed with meropenem in rats at doses up to 1000 mg/kg/day, and cynomolgus monkeys at doses up to 360 mg/kg/day (on the basis of AUC comparisons, approximately 1.8 times and 3.7 times, respectively, to the human exposure at the usual dose of 1 g every 8 hours). There was no reproductive toxicity seen. There are, however, no adequate and wellcontrolled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. (Pregnancy Category B) Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Meropenem. is administered to a nursing woman. Contraindications Meropenem is contraindicted in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to âlactams. Recent data indicate a low rate of cross-reactivity between penicillins and meropenem. Therefore, the practice of avoiding meropenem therapy in penicillin-allergic patients should be reconsidered. In patients who especially require meropenem treatment, pretreatment skin tests should be carried out because negative results indicate tolerability. Conclusions Meropenem is possibly our last line of defence against multi drug resistant gram negative infections. It is therefore extremaly important that we use it with caution and discretion especially as there are not many drugs in the pipeline in the near future. Refrences 1) Ayalew K, Nambiar S, Yasinskaya Y, Jantausch BA, Carbapenems in Pediatrics. Ther Drug Monit. 2003;25: 593-9. 2) Livermore DM. Of Pseudomonas, porins, pumps and carbapenems. J Antimicrob Chemother 2001; 47: 247 – 250.
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3) Nordmann P, Poirel L. Emerging Carbapene-mases in gramnegative aerobes. Clin Microbiol Infect 2002; 8: 321-31. 4) Fleischhack G, Hartmann C, Simon A et al. Meropenem versus Ceftazidime as empirical monotherapy in febrile neutropenia of pediatric patients with cancer. J Antimicrob Chemother 2001; 47: 841 – 853. 5) Duzova A, Kutluk T, Kanra G, Buyukpamukcu M, Akyuz C, Secmeer G, Ceyhan M. Monotherapy with meropenem versus combination therapy with piperacillin plus amikacin as empiric therapy for neutropenic fever in children with lymphoma and solid tumors. Turk J Pediatr 2001; 43: 105 – 9. 6) Koksal N, Hacimustafaoglu M, Bagci S, Celebi S. Meropenem in neonatal severe infections due to multiresistant gram – negative bacteria. Indian J Pediatr 2001; 68: 15 – 9. 7) Hsu HL, Lu CY, Tseng HY, Lee PI, Lai HP, Lin WC, Hsieh YC, Lee CY, Huang LM. Empirical monotherapy with meropenem in serious bacterial infections in children. J Microbiol Immunol Infect. 2001; 34: 275 – 80. 8) Lopez E and the Meropenem Meningitis Study Group. Poster presented at 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy. New Orleans, USA, 17 – 20 October 1993, Abstract 638. 9) Schmutzhard E, Williams KJ, Vukmirovits G, Chmelik V, Pfausler B, Featherstone A. A randomized comparison of meropenem with cefotaxime or ceftriaxone for the treatment of bacterial meningitis in adults. Meropenem Meningitis Study Group. J 10) Antimicr Ther Clin Risk Manag. 2006 December; 2(4): 401–415. Meropenem in the treatment of complicated skin and soft tissue infections Douglas N Fish 11) A post hoc subgroup analysis of meropenem versus imipenem / cilastatin in a multicenter, double-blind, randomized study of complicated skin and skin-structure infections in patients with diabetes mellitus MD John M. Embil, , MD Norberto E. Soto and MD David A. Melnick Prevention and Control Unit, Health Sciences Centre, Winnipeg, Manitoba, Canada2AstraZeneca Pharmaceuticals LP, Wilmington, Delaware, USA Accepted 12 June 2006. 12) Science 27 Feb2009;Vol 323, no. 5918,pp. 1215-1218. Meropenem – Clavulanate is effective Against Extensively Drug Resistant Mycobacterium Tuberculosis. Jean-Emma nuel et al. 13) Lipman J, Wallis SC, Rickard C. Low plasma cefepime levels in critically ill septic patients: pharmacokinetic modeling indicates improved troughs with revised dosing. Antimicrob Agents Chamother 1999; 43: 2559 –61. 14) Thomson K, Moland ES. Cefepime, piperacillin – tazobactam, and the inoculum effect in tests with extended – spectrum beta – lactamase – producing Enterobacteriaceae. Antimicrob Agents Chemother 2001; 45: 3548. 15) Wong VK, Wright HTJr .Imepenem- Cilastin in treatment of bacterial meningitis in children.Pedia Jour Infec Dise 1991;10:122-125. 16) Norrby SR. Neurotoxicity of Carbapenem antibiotics: consequences for their use in bacterial meningitis. J Antimicrob Chemother 2000; 45: 5 – 7.
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FURTHER READING 1) Nechyba C, Gunn VL. Drugs in Renal Failure. In, Nechyba C, Gunn VL (eds). The Harriet Lane Handbook: A manual for Pediatric House Officers. 16th edition, Philadelphia: Mosby; 2002. pp 943. 2) Thauvin – Eliopoulos C, Tripodi MF, Moellering RCJr, Eliopoulos GM. Efficacies of piperacillin – tazobactam and cefepime in rats with experimental intra – abdominal abscesses due to an extended – spectrum beta – lactamase – producing strain of Klebsiella pneumoniae. Antimicrob Agents Chemother 1997 ; 41: 1053 – 7. 3) Kang CI, Pai H, Kim SH, Kim HB, Kim EC, Oh MD, Choe KW. Cefepime and the inoculum effect in tests with Klebsiella pneumoniae producing plasmid – mediated AmpC –type beta – lactamase. J Antimicrob Chemother 2004; 54: 1130 – 3. 4) Alpert G, Dagan R, Connor E, Campos JM, Bloh M, Powell KR, et al. Imipenem / cilastatin for the treatment of infections in hospitalized children. Am J Dis Child 1985; 139; 1153 – 1156. 5) Karadeniz C, Oguz A, Canter B et al. Imipenem – Cilastatin in treatment of bacterial meningitis in children. Pediatr Infect Dis J 1991; 10: 122 – 125. 6) E x t e n s i v e l y D r u g - R e s i s t a n t M y c o b a c t e r i u m tuberculosisMeropenem-Clavulanate Is Effective Against Jean-Emmanuel Hugonnet, 1 Lee W. Tremblay,1 Helena I. Boshoff, 2 Clifton E. Barry, 3rd,2 John S. Blanchard1* 7) Timing of antibiotic prophylaxis in acute pancreatitis: a controlled randomized study with meropenem.Author(s): Manes G, Uomo I, Menchise A, Rabitti PG, Ferrara EC, Uomo GAffiliation(s): Department of Gastroenterology, L. Sacco University Hospital, Milano, Italy.Publication date & source: 2006-06, Am J Gastroenterol., 101(6):1348-53. 8) Comparison of probability of target attainment calculated by Monte Carlo simulation with meropenem clinical and microbiological response for the treatment of complicated skin and skin structure infections.Author(s): Kuti JL, Ong C, Lo M, Melnick D, Soto N, Nicolau DPAffiliation(s): Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.Publication date & source: 2006-07, Int J Antimicrob Agents., 28(1):62-8. Epub 2006 Jun 6. 9) Department of Clinical Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado, USAExperience with cefepime versus meropenem as empiric monotherapy for neutropenia and fever in pediatric patients with solid tumors.Author(s): Oguz A, Karadeniz C, Citak EC, Cil V, Eldes NAffiliation(s): Gazi University, Faculty of Medicine, D e p a r t m e n t o f P e d i a t r i c O n c o l o g y, A n k a r a , Turkey.Publication date & source: 2006-04, Pediatr Hematol Oncol., 23(3):245-53. 10) Pharmacokinetic and Safety Study of Meropenem in Young Infants With Intra-Abdominal InfectionsInformation source: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Information obtained from ClinicalTrials.gov on February 12, 2009
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11) Complicated Skin and Skin Structure InfectionsInformation source : AstraZeneca Information obtained from ClinicalTrials.gov on June 20, 2008 12) AHFS DRUG INFORMATION 2006 (2006 ed ed.). American Society of Health.
13) Mosby's Drug Consult 2006 (16 ed ed.). Mosby, Inc.. 2006. 14) Smith – Moland E, Black JA, Ourada J, Reisbig MD, Hanson ND, Thomson KS. Occurrence of newer Beta – lactamases in Klebsiella pneumoniae isolates from 24 U.S. hospitals. Antimicrob Agents Chemother 2002; 46: 3837-42.
IAP Guidebook on Immunization, 2009 Edition
The 2009 edition of the IAPCOI guidebook has been published by Jaypee Brothers and released at Pedicon 2009. This edition of the book comprehensively discusses basics of immunology, IAP immunization schedule and its rationale, individual vaccines, immunization in special situations, cold chain, adverse effects following immunization, practical aspects of immunization and also includes a ready reckoner for vaccines currently available in the country. This book is available for purchase at all medical book stores at a nominal price of Rs 100.
Pediatric Infectious Disease, Vol.1- Apr - June 2009
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