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ORIGINAL CONTRIBUTION AND CLINICAL INVESTIGATION n; number of patients. Table 2: The mean plasma and tissue concentrations of meropenem after the last intravenous infusion of 1000 mg every eight hours to diabetic patients Table 3: Pharmacokinetic parameters of meropenem in ten diabetic patients after intravenous infusion of meropenem at 1000 mg over 30 minutes every eight hours The mean plasma concentration of meropenem declined from 72.87±12.02 to 0.42±0.31 µg/ml after 1 and 8 hours of administration of the last dose following first-order kinetics (Figure 1). Tissue concentrations were highly comparable after IV infusion of meropenem with the highest concentration 32.00±11.03µg/ g obtained 2 hours after the last administered dose (Table 2). The pharmacokinetic parameters for meropenem in plasma (Table 3) showed that the mean plasma t ½ , volume of distribution (Vd), total clearance and the area under the plasma curve (AUC) of meropenem in these patients were 0.91±0.1h, 31.41±7.44 (L/Kg), 23.8±6 (L/h) and 156.27±39 (mg. h /l) respectively. The percent of T>MIC for the isolated bacteria from each patient ranged from 29.7 to 98.1% (Mean 77.5±19.45%); with the lowest percent for Enterococcus faecalis while the highest value was for the Kocurea rosea (Table 1). Discussion The most important criterion of antimicrobial activity is the actual tissue concentration at the site of infection (1, 11). The high concentrations of meropenem achieved in foot tissues 38 of the diabetic patients shown in this study, exhibits its good penetration. Numerous studies have shown that meropenem penetration to different organs provides adequate tissue concentrations for the treatment of various infections caused by susceptible bacteria (19, 21, 22, 23, 24, 25). Sustained meropenem levels higher than the MIC90 were observed in the colon, gall bladder, fascia, muscle, omentum, and skin (11, 26, 27, 28). Meropenem exhibited an adequate spectrum of in vitro activity against all the bacterial isolates from the diabetic patients which coincide with those reported by numerous authors (29, 30, 31). Although anaerobes may accompany skin and soft tissue infections (2, 9) however in these patients, no anaerobic bacterium was isolated. The MIC values obtained for the isolated bacteria indicates that they were sensitive since their MIC values were close to those published for sensitive bacteria by many authors (32, 33,34,35) . Although different species of enterococci are shown to have higher MICs than enterobacteriace, nevertheless it was also close to those meropenem MIC values reported for this bacteria (36) MIDDLE EAST JOURNAL OF FAMILY MEDICINE VOLUME 10 ISSUE 6 MIDDLE EAST JOURNAL OF FAMILY MEDICINE • VOLUME 7, ISSUE 10 Meropenem is considered to exhibit time-dependent killing activity (37, 38) , this means that the antibacterial efficacy necessitates concentrations to be maintained at a certain minimal level for sufficient period of time. Indeed the levels of meropenem in the foot tissues in this study were above MIC90 for susceptible bacteria (4µg/ml) isolated from the patients and since that T> MIC of 20%- 40% is a good prognostic indicator for successful bacteriostatic and bactericidal responses of carbapenems(11,40) so the range of T> MIC (29.7-98 %) determined for meropenem indicates its effective antibacterial activity in diabetic foot infected patients. Suggesting effective dosing regimen for time-dependent antibiotics requires drug concentrations to exceed the MIC of the causative pathogen for at least 40% to 50% of the dosing interval (39, 40) therefore, for instance in the present study, klebsiella pneumonia (MIC 0.12µg/ml) produced a T> MIC% of about 86.76 % which means that meropenem will be effective for a period of 6.9 hours and for Pseudomonas aeuroginosa (MIC 0.06µg/ml) activity cover about 7.76 hours for each dosing intervals (8 hourly) which indicates a good efficacy in such a clinical condition. However, for enteroccocus faecalis
ORIGINAL CONTRIBUTION AND CLINICAL INVESTIGATION and enterococcus raffinosus with a T> MIC% of 29.7% and 38.14% respectively and considering less than 40% of the dosing intervals for good efficacy, meropenem will remain effective only for less than 3.2 hours, therefore requires optimizing dosing strategies to maximize the duration of drug exposure as administering the drug at longer intravenous infusions or by continuous intravenous infusion (41, 42). However, since these agents show some degree of post antibiotic effect (PAE) in spite of short duration (43, 44, 45, 46), then this persistent effect would allow a longer effective dosing interval. Indeed, twice-daily administration of meropenem has been shown to be as effective as 3- times daily administration in patients with bacterial infections. (11, 47, 48) In conclusion, this study has shown that meropenem reaches sufficient concentrations in infected wound tissue of diabetic foot tissues and with debridement might cover an adequate spectrum well suited for the treatment of skin structure infections of diabetics, caused by susceptible organisms. References 1- Mueller M, Dela Pen A and Derendorf H. Issues in Pharmacokinetics and pharmacodynamics of anti-infective agents: Kill curves versus MIC: Minireview. Antimicrob Agents Chemother. 2004; 48 (2): 369-77. 2- Lipsky BA. Medical treatment of diabetic foot infections. Clin Infect Dis 2004; 39 Suppl (2): S104-14. 3- FarnsworthJ and Paulman P. Diabetic foot ulcer and poor compliance: how would you treat J Farm. Pract. 2005; 54(9):768-76. 4- Fung HB, Chang JY and Kuczynski S. A practical guide to the treatment of complicated skin and soft tissue infections. Drugs 2003; 63:1459-80. 5- Boulton AJM, Kirsner RS and Vileikyte L. Neuropathic diabetic foot ulcers. The New England J Medicine 2004; 351:48-55. 6- Hena JV and Growther L. Studies on bacterial infections of diabetic foot ulcers. African J. Clin. Exper. Microbilogy 2010; 11(3): 146-9. 7- Alavi SM, Khosravi AD, Sarami A, Dashtebozorg A and Montazeri EA. Bacteriologic study of diabetic foot ulcer. Pak J Med Sci. 2007; 23 (5): 681-4. 8- Timothy K. Fisher, Randall Wolcott, Donna M. Wolk, Manish Bharara, Heather R, Kimbriel, V. and Armstrong G. Diabetic foot infections: A Need for innovative assessments. The Inter. J Lower Extremity Wounds 2010; 9 (1):31-6. 9- Fish DN. Meropenem in the treatment of complicated skin and soft tissue infections. Therapeutics and Clinical Risk Management 2006; 2(4): 401-15. 10- Drusano, G. L. Prevention of resistance: a goal for dose selection for antimicrobial agents. Clin. Infect. Dis.2003; 36(Suppl. 1):S42-S50. 11- Nicolau DP. Pharmacokinetic and pharmacodynamic properties of meropenem. Clin Infect Dis. 2008; 47:S32-40. 12- Tomaselli F, Maier A, Matzi V, Smolle-Jüttner FM, Dittrich P. Penetration of meropenem into pneumonic human lung tissue as measured by in vivo microdialysis. Antimicrob Agents Chemother 2004; 48:2228-32. 13- Drusano GL, Lodise TP, Liu W, oliver AM, Van Scoy B, and Louie A. Meropenem penetration into epithelial lining fluid in mice and humans and delineation of exposure targets. Antimicrob Agents Chemother 2011; 55(7): 3406-12. 14- Kitzes-Cohen R. Pharmacokinetics and pharmacodynamics of meropenem in critically ill patients. Inter J Antimicrob Agents 2003; 19(2):105. 15- Krueger, W. A., G. Neeser, H. Schuster, T. H. Schroeder, E. Hoffmann, A. Heininger, H. J. Dieterich, H. Forst, and K. E. Unertl. Correlation of meropenem plasma levels with pharmacodynamic requirements in critically ill patients receiving continuous veno-venous hemofiltration. Chemotherap. 2003; 49:280-6. 16- Ariano, RE, Nyhlen A, Donnelly JP, Sitar DS, Harding GK, and Zelenitsky SA. Pharmacokinetics and pharmacodynamics of meropenem in febrile neutropenic patients with bacteremia. Ann. Pharmacotherap. 2005; 39: 32- 8. 17- National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M07- A6. National Committee for Clinical Laboratory Standards 2003. Wayne, Pennsylvania. 18- Farin D, Kitsez-cohen R, Piva G and Gozlan I. High performance liquid chromatography for the determination of meropenem in the human plasma. Chromatographia 1999; 49(5): 253-5. 19- Byl B, Jacobs F, Roucloux I, De Franquen P, Cappello M and Thys JP. Penetration of meropenem in lung, bronchial mucosa, and pleural tissues. Antimicrob Agents Chemother 1999; 43:681-2. 20 - Burton ME, Show LM and Schentag JL. Applied pharmacokinetics and pharmacodynamics: principles of therapeutic drug monitoring. 4th edition. Lippincott Williams 2005; ISBN: 0-7817-4413-8. 21- Wise R, Logan M, Cooper M, Ashby JP and Andrews JM. Meropenem pharmacokinetics and penetration into an inflammatory exudate. Antimicrob Agents Chemother. 1990; 34(8): 1515-17. 22- Newsom SWB, Palsingh J, Wells FC and Kelly HC. Penetration of meropenem into heart valve tissue. J Antimicrob. Chemother 1995; 36, 57-62. 23- Gall S, Hemsell DL, McGregor JA, Martens MG, Pitkin D and Allen S. Tissue penetration of meropenem in patients undergoing gynecologic surgery. Clin Infect Dis. 1997; 24 (Supplement 2): S178-S180. 24- Manav Ay G, Akhan SC, Akhan S, Akhan ES, Ozkara S and Caglar Y. Comparison of intravitreal ceftazidime and meropenem in treatment of experimental pseudomonal posttraumatic endophthalmitis in a rabbit model. J Appl. Research 2004; 4(2): 336- 45. 25- Drusano GL, Lodise TP, Liu W, Oliver AM, Van Scoy B, and Louie A. Meropenem penetration into epithelial lining fluid in mice and humans and delineation of exposure targets. Antimicrob Agents Chemother. 2011; 55(7): 3406-12. MIDDLE EAST JOURNAL OF FAMILY MEDICINE VOLUME 10 ISSUE 6 MIDDLE EAST JOURNAL OF FAMILY MEDICINE • VOLUME 7, ISSUE 10 39
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