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Topics in Clinical Pharmacology: Imipenem, A New Broad Spectrum Antibiotic
Topics in Clinical Pharmacology: lmipenem, A New Broad Spectrum Antibiotic BY GAIL MAY, MD
I
mipenem/cilastatin (Primaxin®, Merck Sharp & Dohme, West Point, P A) is a recently released broad spectrum antibiotic used to treat serious infections. This combination drug was introduced for its wide spectrum of activity, low reported incidence of side effects, and potential for cost effectiveness. Microbiologic Activity
Imipenem inhibits cell wall synthesis by binding to penicillin binding proteins (PEPs). It has high affinity for all of the PEPs but has greatest affinity for PEP-2, a critical protein for the enterococcus and for most gram-negative organisms. Imipenem is stable against most f}-lactamases, and its penetration is not hampered by a permeability barrier. 1 Imipenem has the widest in vitro spectrum of activity of any available f}-lactam antibiotic. Most of the commonly encountered aerobic organisms show in vitro sensitivity (MIC < 4 ~g/ml). 2 - 4 In vitro data suggest that imipenem is equal to metronidazole and superior to clindamycin, moxalactam, and cefoxitin for coverage of anaerobic organisms. 5- 7 Routinely resistant organisms include Pseudomonas maltophilia, Pseudomonas cepacia, Streptococcus faecium, Rickettsiaceae, Flavobacterium, Mycobacteria and Chlamydia. Organisms requiring relatively high serum concentrations include Morganella, Proteus, coagulase (-) methicillin-sensitive Staphylococcus and Streptococcus faecalis. Although some strains of Pseudomonas aeruginosa may be resistant, the majority initially are susceptible (MIC 50 = 1.5 ~g/ml). 7 Eightyfive percent of methicillin-resistant Staphylococci are susceptible under routine laboratory testing conditions, but this decreases to about 50% with extended incubation times. 8 In vitro data suggest tolerance (increase in MEC over MIC) for Pseudomonas aeruginosa, Morganella, Listeria, Serratia, Enterobacter and Streptococcus fecal is. 4 Synergy against the enterococ-
From Vanderbilt University Medical Center, Pharmacy and Therapeutics Committee, Nashville, Tennessee. Reprint requests: Dr. Robert Branch, Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
cus and Listeria has been demonstrated with imipenem and the aminoglycosides. 9·10 Emerging resistance is a problem only with single drug therapy of Pseudomonas (18%-36%). Despite imipenem being an antagonist of other f}-lactam antibiotics in vitro, cross resistance is not a significant problem. 11 Indications
Imipenem is useful in the treatment of pneumonia, septicemia, complicated urinary tract infections, bone and joint infections (including post traumatic osteomyelitis), intra-abdominal infections, post partum and gynecological infections, and skin and soft tissue infections. 12- 24 Efficacy in endocarditis has been demonstrated only for S. aureus. 25 Coverage for polymicrobial infections, including anaerobes, is excellent.19·20 Comparative trials show imipenem as efficacious as cefotaxime and cefazolin in treating aerobic infections and as efficacious as clindamycin and gentamicin for treatment of intra-abdominal polymicrobial (including anaerobic) infections. 26-34 Efficacy has not been determined in neutropenic patients and in patients with meningitis; however, animal data suggest the drug may be useful in these areas. 35 ·36 Toxicity
Seizures are the most worrisome side effect and have been reported in 1.5% of patients treated with imipenem. 37 This incidence figure was generated from the first 2516 patients treated. Many of the early clinical trials consisted of patients who were not seriously ill; thus, this incidence figure may be low. Although not proven, seizures may be related to renal insufficiency and predisposing central nervous system conditions; thus seizure incidence may increase as the majority of patients appropriate to receive imipenem have multisystem disease and are acutely ill. Following the addition of imipenem to the Vanderbilt formulary, tracking of all patients treated with imipenem was started to evaluate the incidence ofimipenem-related seizures in seriously ill patients. Of the initial21 patients followed, two patients (9%) had tonic clonic seizures during treatment with 1m1-
289
Review of lmipenem
penem. One patient with Guillain-Barre syndrome developed seizures on imipenem, and the drug was discontinued. Subsequently, during the same hospitalization, imipenem was restarted and seizures recurred. Although the patient experienced a volatile course in the intensive care unit between the two rounds of imipenem, the time relationship between the medication and seizures suggests causality. The second patient with seizures on imipenem had a history of seizure disorder and multiple complicating diagnoses, making a relationship less clear. The most common side effects noted with imipenem are nausea and vomiting (2.2%) and diarrhea ( 1.1%). 37 Allergic reactions have been rare in clinical trials (2. 7% ), but the drug is contraindicated in patients with a history of hypersensitivity to other {3lactam drugs. Mild, transient, liver enzyme elevation, thrombocytosis, and positive Coombs reactions without hemolysis are the most common laboratory findings with imipenem therapy. Superinfection is documented with Candida (1.5%), susceptible bacteria (2.4%), and resistant bacteria (1.6%). Pseudomonas accounts for the majority of bacterial superinfection. 37 Kinetics and Metabolism
Both components of Primaxin® (imipenem/cilastatin) are primariiy excreted by the kidney. 38 lmipenem undergoes both glomerular filtration and secretion. If imipenem is given alone, a renal brush border enzyme, dehydropeptidase-1, hydrolyzes the {3lactam ring, making the drug ineffective in sterilizing the urinary tract. The selective inhibition of this enzyme by cilastatin allows about 70% of imipenem to be excreted unchanged in urine. 39 Cilastatin is excreted predominantly (77%) as the parent drug. 38 The usual daily dose for imipenem is 1-4 grams intravenously, divided every 6 hours. In healthy volunteers, peak imipenem concentrations following a 1 gram intravenous dose are 50-70 !lg/ml, and the halflives of both imipenem and cilastatin are about 1 hour. 40- 42 In renal failure, the half-lives of both drugs become prolonged when creatinine clearance falls below 30 ml/min. If the creatinine clearance is between 10 and 30 ml/min, the dose should be decreased by half, and if the creatinine clearance is less than 10 ml/min, the recommended dose is 500 mg every 12 hours. 43 •44 Cost
The major advantage of imipenem is its usefulness in polymicrobial infections. Daily costs are comparable to other broad spectrum antibiotics such as the third generation cephalosporins. In a comparative, prospective, randomized trial with clindamycin and gentamicin, imipenem has been shown to significantly shorten the duration of therapy and the dura-
290
tion of hospitalization, thereby significantly reducing hospitalization costs. 15 Conclusions
lmipenem's excellent coverage of most anaerobes and gram-positive and gram-negative aerobes makes it useful as single drug therapy for complicated urinary tract infections, bone and joint infections, intraabdominal infections, gynecological and post partum infections and skin and soft tissue infections. Hospital acquired infections or those in which Pseudomonas is a suspected pathogen require combination with an aminoglycoside to diminish emerging resistance. Empiric therapy in acutely ill patients also would require the use of combination therapy until culture information is available. Imipenem as monotherapy in immunocompromised patients or in patients with central nervous system infections may be ill-advised as adequate data are lacking in these areas. All patients receiving imipenem, especially those with pre-existing central nervous system disease or renal disease should be observed closely for seizure activity. Appropriate dosage reductions must be made in patients with renal insufficiency. References 1. Neu HC: Carbapenems: Special properties contributing to their activity. Am J Med 78[6A):33- 40, 1985. 2. Kropp H, Gerckens L, Sundelof JG , Kahan FM : Antibacterial activity of imipenem: The first thienamycin antibiotic. Rev Infect Dis 7[Suppl3]:S389- S410, 1985. 3. Jones RN: Review of the in vitro spectrum of activity of imipenem. Am J Med 78[6A):22-32, 1985. 4. Acar JF, Goldstein FW, Kitzis MD, Gutmann L: Activity of imipenem on aerobic bacteria. J Antimicrob Chemother 12:3745, 1985. 5. Wexler HM, Finegold SM: In vitro activity of imipenem against anaerobic bacteria. Rev /nfec Dis 7[Suppl2]:S417- 425, 1985. 6. Tally FP, Jacobus NV: Susceptibility of anaerobic bacteria to imipenem. J Antimicrob Chemother 12[Suppl D]:47-51, 1983. 7. Williams JD: Activity of imipenem against Pseudomonas and Bacteroides species. Rev lnfec Dis 7[Suppl3]:S411- S415, 1985. 8. Fan W, Del Busto R , Love M, Markowitz N, Cendrowski C, Cardenas J , Quinn E, Saravolatz L: Imipenem-cilastatin in the treatment of methicillin-sensitive and methicillin-resistant staphylococcus aureus infections. Antimicrob Agents Chemother 29:26- 29, 1986. 9. Kim KS: In vitro and in vivo studies of imipenem-cilastatin alone and in combination with gentamicin against Listeria monocytogenes. Antimicrob Agents Chemother 29:289- 293, 1986. 10. Indrelie JA, Wilson WR, Matsumoto JY, Geraci JE, Washington JA II: Synergy of imipenem or penicillin G and aminoglycosides against enterococci isolated from patients with infective endocarditis. Antimicrob Agents Chemother 26(6):909912, 1984. 11. Calandra G, Ricci F, Wang C, Brown K: Cross resistance and imipenem. Lancet 2:3401 , 1986. 12. Beasley CRW, Humbel MW, O'Donnell TV: Treatment of pneumonia with imipenem/cilastatin. NZ Med J 98:494- 497, 1985. 13. Salata RA, Gebhart RL, Palmer DL, Wade BH, Scheid WM, Groschel DH, Wenzel RP, Mandell GL, Duma RJ: Pneumonia October 1988 Volume 296 Number 4
May
14.
15.
16.
17.
18. 19.
20.
21.
22 .
23. 24. 25.
26.
27.
28.
29.
30.
31.
treated with imipenem/cilastatin. Am J Med 78[6A]:104-109, 1985. Acar JF: Therapy for lower respiratory tract infections with imipenem/cilastatin: A review of worldwide experience. Rev Infect Dis 7[Suppl3]:S513- S517, 1985. Brooks RG, McCabe RE, Vosti KL, Remington JS: Open trial of imipenem/cilastatin therapy for serious bacterial infections. Rev Infect Dis 7[Suppl3] :S496- S505, 1985. Zajac BA, Fisher MA, Gibson GA, MacGregor RR: Safety and efficacy of high -dose treatment with imipenem -cilastatin in seriously ill patients. Antimicrob Agents Chemother 27:745-748, 1985. Cox CE, Corrado ML: Safety and efficacy of imipenem/cilastatin in treatment of complicated urinary tract infections. Am J Med 78[6A]:92- 94, 1985. MacGregor RR, Gentry LO: lmipenem/cilastatin in the treatment of osteomyelitis. Am J Med 78(6A]:100-103, 1985. Tally FP, Gorbach SL: Therapy of mixed anaerobic-aerobic infections: Lessons from studies of intra-abdominal sepsis. Am J Med 78[6A]:145- 153, 1985. Kager L, Nord CE: Imipenem/cilastatin in the treatment of intra-abdominal infections: A review of worldwide experience. Rev Infect Dis 7[Suppl3]:S518-S521, 1985. Berkeley AS, Freedman K, Hirsch J, Ledger WJ: Imipenem/ cilastatin in the treatment of obstetric and gynecologic infections. Am J Med 78(6A]:79- 84, 1985. Sweet RL: Imipenem/cilastatin in the treatment of obstetric and gynecologic infections: A review of worldwide experience. Rev Infec Dis 7[Suppl3] :S522- S527, 1985. Marier RL: Role of imipenem/cilastatin in the treatment of soft tissue infections. Am J Med 78[6A] :140-144, 1985. Eron LJ: lmipenem/cilastatin therapy ofbactermia. AmJ Med 78[6A]:95- 99, 1985. Dickinson G, Rodriguez K, Arcey S, Alea A, Greenman R: Efficacy of imipenem/cilastatin in endocarditis. Am J Med 78[6A]:ll7- 121,1985. Diaz-Mitoma G, HardingGKM, LouieTJ, Thomson M,James M, Ronald AR: Prospective randomized comparison of imipenem/cilastatin and cefotaxime for treatment of lung, soft tissue, and renal infections. Rev Infect Dis 7[Suppl 3]:S452S457, 1985. Stamboulian D, Arguello EA, Jasovich A, Villar 0, Maglio F: Comparative clinical evaluation of imipenem/cilastatin vs. cefotaxime in treatment of severe bacterial infections. Rev In fect Dis 7[Suppl 3]:S458- S462, 1985. Fass RJ, Freimer EH, McCloskey RV: Treatment of skin and soft tissue infections with imnipenem/cilastatin. Am J Med 78[6A] :ll0- 112, 1985. Report from a Scandinavian Study Group. Imipenem/cilastatin versus gentamicin/clindamycin for treatment of seriousbacterial infections. Lancet 1:868- 871, 1984. Solomkin JS , Fant WK , Rivera JO, Alexander JW: Randomized trial of imipenem/cilastatin versus gentamicin and clindamycin in mixed flora infections. Am J Med 78[6A]:85-91, 1985. Guerra JG, Casalino E, Palomino JC , Barboza E , del Castillo
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
32.
33.
34.
35.
36.
37.
38.
39. 40.
41.
42.
43.
44.
M, Gonzalea del Riego M, Huapaya VM, Antunez de Mayolo E: Imipenem/cilastatin vs. gentamicin/clindamycin for the treatment of moderate to severe infections in hospitalized patients. Rev Infect Dis 7[Suppl3]:S463-S470, 1985. Ribner BS, Raeder R, Hollstein M, Frimer EH: A randomized study comparing clinical efficacy and safety of thienamycin formamidine (MK0787)/renal dipeptidase inhibitor (MK0791) and cefazolin. J Antimicrob Chemother 12[Suppl D]:387- 391, 1983. Marier RL, McCloskey RV, Dickenson G, Sanders CV, Aldridge KE, Hoffman T, Gutterman D, Janney A: Comparative clinical trial of imipenem-cilastatin (N-formimidoyl-thienamycin-dehydropeptidase inhibitor) and cefazolin. J Antimicrob Chemother 12[Suppl D]:133- 139, 1983. Baumgartner JD, Glauser MP: Comparative study of imipenem in severe infections. J Antimicrob Chemother 12[Suppl D]:141-148, 1983. Wade JC, Standiford HC, Drusano GL, Hohnson DE, Moody MR, Bustamante Cl, Joshi JH, deJongh C, Schimpff SC: Potential of imipenem as single-agent empiric antibiotic therapy febrile neutropenic patients with cancer. Am J Med 78[5A]: 62- 72, 1985. Kim KS: Comparison of cefotaxime, imipenem-cilastatin, ampicillin-gentamicin, and ampicillin-chloramphenical in the treatment of experimental Escherichia coli bacteremia and meningitis. Antimicrob Agents Chemother 28:433- 436, 1985. Calandra GB, Brown KR, Grad CL, Ahonkhai VI, Wang C, Aziz MA: Review of adverse experiences and tolerability in the first 2,516 patients treated with imipenem/cilastatin. Am J Med 78[6A]:73- 78, 1985. Norrby SR, Rogers JD, Ferber F, Jones KH, Zacchei AG, Weidner LL, Demetriades JL, Gravallese DA, Hsieh JYK: Disposition of radio labelled imipenem and cilastatin in normal human volunteers. Antimicrob Agents Chemother 26:707-714, 1984. Norrby SR: Imipenem/cilastatin: Rationale for a fixed combination. Rev Infect Dis 7[Suppl3]:S447- S451, 1985. Drusano GL, Standiford HC: Pharmacokinetic profile of imipenem/cilastatin in normal volunteers. Am J Med 78[6A]:4753, 1985. Rogers JD, Meisinger AP, Ferber F, Calandra GB, Demetriades JL, Bland JA: Pharmacokinetics of imipenem and cilastatin in volunteers. Rev Infec Dis 7 [Suppl3]:S435-S446, 1985. Drusano GL, Standiford HC, Bustamente C, Forrest A, Rivera G, Leslie J, Tatem B, Delaportas D, MacGregor RR, Schimpff SC: Multiple-dose pharmacokinetics of imipenem-cilastatin . Antimicrob Agents Chemother 26:715- 721, 1984. Gibson TP, Demetriades JL, Bland JA: Imipenem/cilastatin: pharmacokinetic profile in renal insufficiency. Am J Med 78[6A]:54-61, 1985. Verbooten GA, Verbist L, Buntinx AP, Entwistle LA, Jones KH, Deb roe ME: The pharmacokinetics of imipenem (theinamycin-formamidine) and the renal dehydropeptidase inhibitor cilastatin sodium in normal subjects and patients with renal failure. Br J Clin Pharmacol18:183-193, 1984.
291
I
mipenem/cilastatin (Primaxin®, Merck Sharp & Dohme, West Point, P A) is a recently released broad spectrum antibiotic used to treat serious infections. This combination drug was introduced for its wide spectrum of activity, low reported incidence of side effects, and potential for cost effectiveness. Microbiologic Activity
Imipenem inhibits cell wall synthesis by binding to penicillin binding proteins (PEPs). It has high affinity for all of the PEPs but has greatest affinity for PEP-2, a critical protein for the enterococcus and for most gram-negative organisms. Imipenem is stable against most f}-lactamases, and its penetration is not hampered by a permeability barrier. 1 Imipenem has the widest in vitro spectrum of activity of any available f}-lactam antibiotic. Most of the commonly encountered aerobic organisms show in vitro sensitivity (MIC < 4 ~g/ml). 2 - 4 In vitro data suggest that imipenem is equal to metronidazole and superior to clindamycin, moxalactam, and cefoxitin for coverage of anaerobic organisms. 5- 7 Routinely resistant organisms include Pseudomonas maltophilia, Pseudomonas cepacia, Streptococcus faecium, Rickettsiaceae, Flavobacterium, Mycobacteria and Chlamydia. Organisms requiring relatively high serum concentrations include Morganella, Proteus, coagulase (-) methicillin-sensitive Staphylococcus and Streptococcus faecalis. Although some strains of Pseudomonas aeruginosa may be resistant, the majority initially are susceptible (MIC 50 = 1.5 ~g/ml). 7 Eightyfive percent of methicillin-resistant Staphylococci are susceptible under routine laboratory testing conditions, but this decreases to about 50% with extended incubation times. 8 In vitro data suggest tolerance (increase in MEC over MIC) for Pseudomonas aeruginosa, Morganella, Listeria, Serratia, Enterobacter and Streptococcus fecal is. 4 Synergy against the enterococ-
From Vanderbilt University Medical Center, Pharmacy and Therapeutics Committee, Nashville, Tennessee. Reprint requests: Dr. Robert Branch, Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
cus and Listeria has been demonstrated with imipenem and the aminoglycosides. 9·10 Emerging resistance is a problem only with single drug therapy of Pseudomonas (18%-36%). Despite imipenem being an antagonist of other f}-lactam antibiotics in vitro, cross resistance is not a significant problem. 11 Indications
Imipenem is useful in the treatment of pneumonia, septicemia, complicated urinary tract infections, bone and joint infections (including post traumatic osteomyelitis), intra-abdominal infections, post partum and gynecological infections, and skin and soft tissue infections. 12- 24 Efficacy in endocarditis has been demonstrated only for S. aureus. 25 Coverage for polymicrobial infections, including anaerobes, is excellent.19·20 Comparative trials show imipenem as efficacious as cefotaxime and cefazolin in treating aerobic infections and as efficacious as clindamycin and gentamicin for treatment of intra-abdominal polymicrobial (including anaerobic) infections. 26-34 Efficacy has not been determined in neutropenic patients and in patients with meningitis; however, animal data suggest the drug may be useful in these areas. 35 ·36 Toxicity
Seizures are the most worrisome side effect and have been reported in 1.5% of patients treated with imipenem. 37 This incidence figure was generated from the first 2516 patients treated. Many of the early clinical trials consisted of patients who were not seriously ill; thus, this incidence figure may be low. Although not proven, seizures may be related to renal insufficiency and predisposing central nervous system conditions; thus seizure incidence may increase as the majority of patients appropriate to receive imipenem have multisystem disease and are acutely ill. Following the addition of imipenem to the Vanderbilt formulary, tracking of all patients treated with imipenem was started to evaluate the incidence ofimipenem-related seizures in seriously ill patients. Of the initial21 patients followed, two patients (9%) had tonic clonic seizures during treatment with 1m1-
289
Review of lmipenem
penem. One patient with Guillain-Barre syndrome developed seizures on imipenem, and the drug was discontinued. Subsequently, during the same hospitalization, imipenem was restarted and seizures recurred. Although the patient experienced a volatile course in the intensive care unit between the two rounds of imipenem, the time relationship between the medication and seizures suggests causality. The second patient with seizures on imipenem had a history of seizure disorder and multiple complicating diagnoses, making a relationship less clear. The most common side effects noted with imipenem are nausea and vomiting (2.2%) and diarrhea ( 1.1%). 37 Allergic reactions have been rare in clinical trials (2. 7% ), but the drug is contraindicated in patients with a history of hypersensitivity to other {3lactam drugs. Mild, transient, liver enzyme elevation, thrombocytosis, and positive Coombs reactions without hemolysis are the most common laboratory findings with imipenem therapy. Superinfection is documented with Candida (1.5%), susceptible bacteria (2.4%), and resistant bacteria (1.6%). Pseudomonas accounts for the majority of bacterial superinfection. 37 Kinetics and Metabolism
Both components of Primaxin® (imipenem/cilastatin) are primariiy excreted by the kidney. 38 lmipenem undergoes both glomerular filtration and secretion. If imipenem is given alone, a renal brush border enzyme, dehydropeptidase-1, hydrolyzes the {3lactam ring, making the drug ineffective in sterilizing the urinary tract. The selective inhibition of this enzyme by cilastatin allows about 70% of imipenem to be excreted unchanged in urine. 39 Cilastatin is excreted predominantly (77%) as the parent drug. 38 The usual daily dose for imipenem is 1-4 grams intravenously, divided every 6 hours. In healthy volunteers, peak imipenem concentrations following a 1 gram intravenous dose are 50-70 !lg/ml, and the halflives of both imipenem and cilastatin are about 1 hour. 40- 42 In renal failure, the half-lives of both drugs become prolonged when creatinine clearance falls below 30 ml/min. If the creatinine clearance is between 10 and 30 ml/min, the dose should be decreased by half, and if the creatinine clearance is less than 10 ml/min, the recommended dose is 500 mg every 12 hours. 43 •44 Cost
The major advantage of imipenem is its usefulness in polymicrobial infections. Daily costs are comparable to other broad spectrum antibiotics such as the third generation cephalosporins. In a comparative, prospective, randomized trial with clindamycin and gentamicin, imipenem has been shown to significantly shorten the duration of therapy and the dura-
290
tion of hospitalization, thereby significantly reducing hospitalization costs. 15 Conclusions
lmipenem's excellent coverage of most anaerobes and gram-positive and gram-negative aerobes makes it useful as single drug therapy for complicated urinary tract infections, bone and joint infections, intraabdominal infections, gynecological and post partum infections and skin and soft tissue infections. Hospital acquired infections or those in which Pseudomonas is a suspected pathogen require combination with an aminoglycoside to diminish emerging resistance. Empiric therapy in acutely ill patients also would require the use of combination therapy until culture information is available. Imipenem as monotherapy in immunocompromised patients or in patients with central nervous system infections may be ill-advised as adequate data are lacking in these areas. All patients receiving imipenem, especially those with pre-existing central nervous system disease or renal disease should be observed closely for seizure activity. Appropriate dosage reductions must be made in patients with renal insufficiency. References 1. Neu HC: Carbapenems: Special properties contributing to their activity. Am J Med 78[6A):33- 40, 1985. 2. Kropp H, Gerckens L, Sundelof JG , Kahan FM : Antibacterial activity of imipenem: The first thienamycin antibiotic. Rev Infect Dis 7[Suppl3]:S389- S410, 1985. 3. Jones RN: Review of the in vitro spectrum of activity of imipenem. Am J Med 78[6A):22-32, 1985. 4. Acar JF, Goldstein FW, Kitzis MD, Gutmann L: Activity of imipenem on aerobic bacteria. J Antimicrob Chemother 12:3745, 1985. 5. Wexler HM, Finegold SM: In vitro activity of imipenem against anaerobic bacteria. Rev /nfec Dis 7[Suppl2]:S417- 425, 1985. 6. Tally FP, Jacobus NV: Susceptibility of anaerobic bacteria to imipenem. J Antimicrob Chemother 12[Suppl D]:47-51, 1983. 7. Williams JD: Activity of imipenem against Pseudomonas and Bacteroides species. Rev lnfec Dis 7[Suppl3]:S411- S415, 1985. 8. Fan W, Del Busto R , Love M, Markowitz N, Cendrowski C, Cardenas J , Quinn E, Saravolatz L: Imipenem-cilastatin in the treatment of methicillin-sensitive and methicillin-resistant staphylococcus aureus infections. Antimicrob Agents Chemother 29:26- 29, 1986. 9. Kim KS: In vitro and in vivo studies of imipenem-cilastatin alone and in combination with gentamicin against Listeria monocytogenes. Antimicrob Agents Chemother 29:289- 293, 1986. 10. Indrelie JA, Wilson WR, Matsumoto JY, Geraci JE, Washington JA II: Synergy of imipenem or penicillin G and aminoglycosides against enterococci isolated from patients with infective endocarditis. Antimicrob Agents Chemother 26(6):909912, 1984. 11. Calandra G, Ricci F, Wang C, Brown K: Cross resistance and imipenem. Lancet 2:3401 , 1986. 12. Beasley CRW, Humbel MW, O'Donnell TV: Treatment of pneumonia with imipenem/cilastatin. NZ Med J 98:494- 497, 1985. 13. Salata RA, Gebhart RL, Palmer DL, Wade BH, Scheid WM, Groschel DH, Wenzel RP, Mandell GL, Duma RJ: Pneumonia October 1988 Volume 296 Number 4
May
14.
15.
16.
17.
18. 19.
20.
21.
22 .
23. 24. 25.
26.
27.
28.
29.
30.
31.
treated with imipenem/cilastatin. Am J Med 78[6A]:104-109, 1985. Acar JF: Therapy for lower respiratory tract infections with imipenem/cilastatin: A review of worldwide experience. Rev Infect Dis 7[Suppl3]:S513- S517, 1985. Brooks RG, McCabe RE, Vosti KL, Remington JS: Open trial of imipenem/cilastatin therapy for serious bacterial infections. Rev Infect Dis 7[Suppl3] :S496- S505, 1985. Zajac BA, Fisher MA, Gibson GA, MacGregor RR: Safety and efficacy of high -dose treatment with imipenem -cilastatin in seriously ill patients. Antimicrob Agents Chemother 27:745-748, 1985. Cox CE, Corrado ML: Safety and efficacy of imipenem/cilastatin in treatment of complicated urinary tract infections. Am J Med 78[6A]:92- 94, 1985. MacGregor RR, Gentry LO: lmipenem/cilastatin in the treatment of osteomyelitis. Am J Med 78(6A]:100-103, 1985. Tally FP, Gorbach SL: Therapy of mixed anaerobic-aerobic infections: Lessons from studies of intra-abdominal sepsis. Am J Med 78[6A]:145- 153, 1985. Kager L, Nord CE: Imipenem/cilastatin in the treatment of intra-abdominal infections: A review of worldwide experience. Rev Infect Dis 7[Suppl3]:S518-S521, 1985. Berkeley AS, Freedman K, Hirsch J, Ledger WJ: Imipenem/ cilastatin in the treatment of obstetric and gynecologic infections. Am J Med 78(6A]:79- 84, 1985. Sweet RL: Imipenem/cilastatin in the treatment of obstetric and gynecologic infections: A review of worldwide experience. Rev Infec Dis 7[Suppl3] :S522- S527, 1985. Marier RL: Role of imipenem/cilastatin in the treatment of soft tissue infections. Am J Med 78[6A] :140-144, 1985. Eron LJ: lmipenem/cilastatin therapy ofbactermia. AmJ Med 78[6A]:95- 99, 1985. Dickinson G, Rodriguez K, Arcey S, Alea A, Greenman R: Efficacy of imipenem/cilastatin in endocarditis. Am J Med 78[6A]:ll7- 121,1985. Diaz-Mitoma G, HardingGKM, LouieTJ, Thomson M,James M, Ronald AR: Prospective randomized comparison of imipenem/cilastatin and cefotaxime for treatment of lung, soft tissue, and renal infections. Rev Infect Dis 7[Suppl 3]:S452S457, 1985. Stamboulian D, Arguello EA, Jasovich A, Villar 0, Maglio F: Comparative clinical evaluation of imipenem/cilastatin vs. cefotaxime in treatment of severe bacterial infections. Rev In fect Dis 7[Suppl 3]:S458- S462, 1985. Fass RJ, Freimer EH, McCloskey RV: Treatment of skin and soft tissue infections with imnipenem/cilastatin. Am J Med 78[6A] :ll0- 112, 1985. Report from a Scandinavian Study Group. Imipenem/cilastatin versus gentamicin/clindamycin for treatment of seriousbacterial infections. Lancet 1:868- 871, 1984. Solomkin JS , Fant WK , Rivera JO, Alexander JW: Randomized trial of imipenem/cilastatin versus gentamicin and clindamycin in mixed flora infections. Am J Med 78[6A]:85-91, 1985. Guerra JG, Casalino E, Palomino JC , Barboza E , del Castillo
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
32.
33.
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35.
36.
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39. 40.
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