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Imipenem and Cilastatin

Class: Carbapenems
Chemical Name: [5R-[5α,6α(R*)]]-6-(1-Hydroxyethyl)-3-[[2-(iminomethyl)amino]ethyl]thio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2carboxylic acid monohydrate mixt. with [R-[R*,S*-(Z)]]-7-[(2-Amino-2-carboxyethyl)thio]-2-[[(2,2-dimethylcyclopropyl) carbonyl]amino]-2-heptenoic acid monosodium salt
Molecular Formula: C12H17N3O4S•H2
CAS Number: 92309-29-0
Brands: Primaxin I.M.

Medically reviewed on July 10, 2018

Introduction

Antibacterial; fixed combination of imipenem (a carbapenem β-lactam antibiotic)2 4 5 6 148 196 197 198 and cilastatin1 35 (prevents renal metabolism of imipenem by dehydropeptidase I [DHP I]).1 2 101 113 125 137 140 141 145 148 196 198

Uses for Imipenem and Cilastatin

Bone and Joint Infections

Treatment of serious bone and joint infections caused by susceptible Staphylococcus aureus (penicillinase-producing strains), S. epidermidis, Enterobacter, or Pseudomonas aeruginosa.1 146 164 167 182 256

Endocarditis

Treatment of endocarditis caused by susceptible S. aureus (penicillinase-producing strains).1 146 186 Not considered a preferred or alternative drug for staphylococcal endocarditis.a b

Should not be used for treatment of enterococcal endocarditis.103 198 199 210

Gynecologic Infections

Treatment of gynecologic infections (including mixed aerobic-anaerobic infections) caused by susceptible Enterococcus faecalis, S. aureus (penicillinase-producing strains), S. epidermidis, S. agalactiae (group B streptococci), Enterobacter, E. coli, Gardnerella vaginalis, Klebsiella, Proteus, Bacteroides (including B. fragilis), Bifidobacterium, Peptococcus, Peptostreptococcus, and Propionibacterium.1 146 176 178

Intra-abdominal Infections

Treatment of intra-abdominal infections (including mixed aerobic-anaerobic infections) caused by susceptible E. faecalis, S. aureus (penicillinase-producing strains), S. epidermidis, Citrobacter, Enterobacter, E. coli, Klebsiella, Morganella morganii, Proteus, Ps. aeruginosa, Bacteroides (including B. fragilis), Bifidobacterium, Clostridium, Eubacterium, Fusobacterium, Peptococcus, Peptostreptococcus, or Propionibacterium.1 164 172 179 256 .

Respiratory Tract Infections

Treatment of lower respiratory tract infections caused by susceptible S. aureus (penicillinase-producing strains), S. pneumoniae, Haemophilus influenzae, H. parainfluenzae, Acinetobacter, Enterobacter, E. coli, Klebsiella, or Serratia marcescens.1 164 167 170 172 183 256

Treatment of pneumonia and bronchitis (as an exacerbation of COPD) caused by susceptible S. pneumoniae.256 Indicated for polymicrobial infections when S. pneumoniae may be involved, but not usually indicated for monobacterial pneumococcal infections.1 Not considered a drug of first choice for empiric treatment of community-acquired pneumonia (CAP);147 193 usually reserved for use in patients with pneumonia who are at risk for Ps. aeruginosa and when anaerobes may be involved.147 193 261

Has been used for treatment of Legionella pneumophila respiratory tract infections.152 154 171 215 Other anti-infectives (e.g., a macrolide or a fluoroquinolone with or without rifampin) generally preferred.76 261 304

Septicemia

Treatment of septicemia caused by susceptible E. faecalis, S. aureus (penicillinase-producing strains), Enterobacter, E. coli, Klebsiella, Ps. aeruginosa, Serratia, or Bacteroides (including B. fragilis).1 146 164 167 170 172 181 261

Skin and Skin Structure Infections

Treatment of serious skin and skin structure infections caused by susceptible S. aureus (penicillinase-producing strains), S. epidermidis, E. faecalis, Acinetobacter, Citrobacter, Enterobacter, E. coli, Klebsiella, M. morganii, P. vulgaris, P. rettgeri, Ps. aeruginosa, or Serratia.1 146 164 167 170 172 179 184

Treatment of serious skin and skin structure infections caused by susceptible Bacteroides (including B. fragilis), Fusobacterium, Peptococcus, or Peptostreptococcus.1 179 184

Urinary Tract Infections (UTIs)

Treatment of complicated and uncomplicated UTIs caused by susceptible E. faecalis, S. aureus (penicillinase-producing strains) , Enterobacter, E. coli, Klebsiella, M. morganii, P. vulgaris, Providencia rettgeri, or Ps. aeruginosa.1 146 158 164 167 168 170 172 173 180 261

Actinomycosis

Has been used for treatment of thoracic actinomycosis.291 Not considered a drug of choice; penicillin G generally preferred for initial treatment of all forms of actinomycosis, including thoracic, abdominal, CNS, and cervicofacial infections.76 261 292

Bacillus Infections

Treatment of invasive infections caused by Bacillus cereus.76 261 Vancomycin considered drug of choice; carbapenems (imipenem or meropenem) or clindamycin are alternatives.261

Burkholderia Infections

Treatment of localized or septicemic melioidosis,261 280 281 282 283 284 a potentially life-threatening disease caused by Burkholderia pseudomallei.280 282 283 A drug of choice.261 280 281 282 283 284 285 B. pseudomallei is difficult to eradicate (relapse of melioidosis is common).280 281 283 285

Alternative for treatment of glanders caused by B. mallei.261

Alternative for treatment of infections caused by B. cepacia.261

Campylobacter Infections

Treatment of systemic infections caused by Campylobacter fetus;261 286 a drug of choice.261 286

Capnocytophaga Infections

Treatment of infections caused by Capnocytophaga canimorsus.261

Optimum regimens for treatment of infections caused by Capnocytophaga have not been identified; some clinicians recommend use of penicillin G261 290 or, alternatively, a third generation cephalosporin (cefotaxime, ceftizoxime, ceftriaxone), a carbapenem (imipenem or meropenem), vancomycin, a fluoroquinolone, or clindamycin.261

Nocardia Infections

Treatment of infections caused by Nocardia, including pulmonary nocardiosis caused by N. asteroides and primary cutaneous nocardiosis.261 293 294 295 Co-trimoxazole considered drug of first choice for Nocardia infections;76 147 261 alternatives include a sulfonamide (e.g., sulfisoxazole) with or without minocycline or amikacin; a tetracycline (e.g., doxycycline, minocycline); a carbapenem (imipenem or meropenem) with or without amikacin; amoxicillin and clavulanate; cycloserine; or linezolid.76 147 261

Rhodococcus Infections

Treatment of infections caused by Rhodococcus equi; used in conjunction with vancomycin.261 Optimum regimens have not been identified;298 combination regimens usually are recommended, including vancomycin given with a fluoroquinolone, rifampin, a carbapenem (imipenem or meropenem), or amikacin.261 297 298 299

Empiric Therapy in Febrile Neutropenic Patients

Empiric anti-infective therapy of presumed bacterial infections in febrile neutropenic patients.265 266 267 268 269 270 271 Used alone or in conjunction with other anti-infectives.268 269 271

Consult published protocols for the treatment of infections in febrile neutropenic patients for specific recommendations regarding selection of the initial empiric regimen, when to change the initial regimen, possible subsequent regimens, and duration of therapy in these patients.14 Consultation with an infectious disease expert knowledgeable about infections in immunocompromised patients also is advised.14

Imipenem and Cilastatin Dosage and Administration

Administration

Administer by intermittent IV infusion1 and by deep IM injection.256

IM route should only be used for mild to moderately severe infections;256 257 258 259 it is not intended for use in severe and/or life-threatening infections (e.g., sepsis, endocarditis) or in patients with major physiologic impairment (e.g., shock).256 Patients for whom IM therapy is being considered should be selected carefully256 257 258 259 since some reported treatment failures and/or recurrences may have been related to the route of administration.257 258 259

The IM suspension should not be given IV.256

ADD-Vantage vials should be used only for IV infusion.1

For solution and drug compatibility information, see Compatibility under Stability.

IV Infusion

Imipenem solutions for IV infusion should have concentrations ≤5 mg/mL since physical and chemical stability of the drug may be adversely affected at higher concentrations.219

If an aminoglycoside is administered concomitantly, the drugs should not be admixed but may be administered from separate containers through the same IV tubing.219

Reconstitution and Dilution

Reconstitute infusion bottles containing 250 mg of imipenem and 250 mg of cilastatin or 500 mg of imipenem and 500 mg of cilastatin with 100 mL of a compatible IV solution1 to provide solutions containing 2.5 or 5 mg/mL of each drug, respectively.219 Shake until a clear solution is obtained.1

Alternatively, vials containing 250 mg of imipenem and 250 mg of cilastatin or 500 mg of imipenem and 500 mg of cilastatin may be initially suspended with a portion of a compatible IV solution and then the resulting suspension of drug added to the remaining IV solution to a volume of 100 mL.1 A suggested procedure for preparing an initial suspension is to add approximately 10 mL from a 100-mL container of the IV solution to the vial of drug.1 The resulting initial suspension should be shaken well and then transferred to the IV solution container.1 To ensure complete transfer of the vial contents, an additional 10 mL from the IV solution container should be added to the vial and transferred back to the IV solution container.1

ADD-Vantage vials should be reconstituted according to the manufacturer’s directions with the diluent provided.1

Rate of Administration

The rate of IV infusion depends on the dose.1 164 If nausea and/or vomiting occur during administration, the rate of IV infusion may be decreased.1 164

In adults, each 125-, 250- or 500-mg dose of imipenem should be infused over 20–30 minutes and each 1-g dose should be infused over 40–60 minutes.1 164

In pediatric patients, doses of ≤500 mg should be given by IV infusion over 15–30 minutes and doses >500 mg should be given by IV infusion over 40–60 minutes.1

IM Administration

IM suspensions are administered by deep IM injection into a large muscle mass (such as the gluteal muscle or lateral aspect of the thigh) with a 21-gauge, 2-inch needle.256 Use aspiration to avoid inadvertent injection into a blood vessel.256

Reconstitution and Dilution

IM injections are reconstituted with lidocaine hydrochloride 1% injection (without epinephrine).256 Add 2 or 3 mL of the diluent to a vial containing 500 or 750 mg of imipenem, respectively.256 The vial should be agitated well to form a suspension and the entire contents of the vial withdrawn for IM injection.256

Dosage

Available as fixed-combination containing imipenem monohydrate and cilastatin sodium; dosage generally expressed in terms of the imipenem content (as anhydrous imipenem).1 35 256

To minimize risk of seizures, closely adhere to dosage recommendations, especially in patients with factors known to predispose to seizure activity; dosage adjustment recommended for patients with advanced age and/or renal impairment.1 Anticonvulsant therapy should be continued in patients with existing seizure disorders.1 (See CNS Effects under Cautions.)

Duration of therapy depends on type and severity of infection.256 Safety and efficacy of the IM route for >14 days have not been established.256

Pediatric Patients

General Dosage for Neonates
IV

Neonates <1 week of age weighing ≥1.5 kg: 25 mg/kg every 12 hours.1

Neonates 1–4 weeks of age weighing ≥1.5 kg: 25 mg/kg every 8 hours.1

General Dosage for Infants and Children
IV

Children 1–3 months of age weighing ≥1.5 kg: 25 mg every 6 hours.1

Children ≥3 months of age: 15–25 mg/kg every 6 hours.1

Mild to Moderately Severe Infections
Gynecologic, Lower Respiratory Tract, or Skin and Skin Structure Infections
IM

Children ≥12 years of age: 500 or 750 mg every 12 hours.256

Intra-abdominal Infections
IM

Children ≥12 years of age: 750 mg every 12 hours.256

Adults

Recommended IV adult dosages are for adults weighing ≥70 kg.1 Modification of dosage is recommended for patients weighing <70 kg.1 (See Adults with Low Body Weight under Dosage and Administration.)

Mild Infections
Fully Susceptible Aerobic or Anaerobic Bacteria
IV

Adults weighing ≥70 kg: 250 mg every 6 hours (1 g daily).1

Moderately Susceptible Aerobic or Anaerobic Bacteria
IV

Adults weighing ≥70 kg: 500 mg every 6 hours (2 g daily).1

Moderately Severe Infections
Fully Susceptible Aerobic or Anaerobic Bacteria
IV

Adults weighing ≥70 kg: 500 mg every 8 hours (1.5 g daily) or 500 mg every 6 hours (2 g daily).1

Moderately Susceptible Aerobic or Anaerobic Bacteria
IV

Adults weighing ≥70 kg: 500 mg every 6 hours (2 g daily) or 1 g every 8 hours (3 g daily).1

Severe, Life-threatening Infections
Fully Susceptible Aerobic or Anaerobic Bacteria
IV

Adults weighing ≥70 kg: 500 mg every 6 hours (2 g daily).1

Moderately Susceptible Aerobic or Anaerobic Bacteria
IV

Adults weighing ≥70 kg: 1 g every 6 hours (4 g daily) or 1 g every 8 hours (3 g daily).1

Urinary Tract Infections (UTIs)
Uncomplicated UTIs
IV

Adults weighing ≥70 kg: 250 mg every 6 hours (1 g daily)1 .

Complicated UTIs
IV

Adults weighing ≥70 kg: 500 mg every 6 hours (2 g daily).1

Mild to Moderately Severe Infections
Gynecologic, Lower Respiratory Tract, or Skin and Skin Structure Infections
IM

500 or 750 mg every 12 hours.256

Intra-abdominal Infections
IM

750 mg every 12 hours.256

Empiric Therapy in Febrile Neutropenic Patients
IV

500 mg every 6 hours (1 g daily).265 266 268

Prescribing Limits

Pediatric Patients

IV

2 g daily in those with infections caused by fully susceptible bacteria or 4 g daily in those with infections caused by moderately susceptible bacteria (e.g., some strains of Ps. aeruginosa).1 Higher dosage (up to 90 mg/kg daily in older children) has been used in some cystic fibrosis patients.1

Adults

IV

50 mg/kg daily or 4 g daily, whichever is lower.1

IM

1.5 g daily.256

Special Populations

Renal Impairment

Infections in Adults
IV

Dosage adjustments recommended in adults with Clcr <70 mL/minute per 1.73 m2.1 Serum creatinine concentrations alone may not be sufficiently accurate to assess the degree of renal impairment; dosage preferably should be based on the patient’s measured or estimated Clcr.1 256

Manufacturer makes the following recommendations for dosage in adults with Clcr <70 mL/minute per 1.73 m2 and/or body weight <70 kg.1 (See Table 1.)

Table 1. Reduced Intravenous Dosage of Imipenem and Cilastatin Sodium IV in Adult Patients with Impaired Renal Function and/or Body Weight < 70 kg

 

If Total Recommended Daily Dose is:

 

1 g/day

1.5 g/day

2 g/day

 

and creatinine clearance (mL/min/1.73 m2) is:

 

≥71

41–70

21–40

6–20

≥71

41–70

21–40

6–20

≥71

41–70

21–40

6–20

and Body Weight (kg) is:

then the reduced dosage regiment (mg) is:

≥70

250 q6h

250 q8h

250 q12h

250 q12h

500 q8h

250 q6h

250 q8h

250 q12h

500 q6h

500 q8h

250 q6h

250 q12h

60

250 q8h

125 q6h

250 q12h

125 q12h

250 q6h

250 q8h

250 q8h

250 q12h

500 q8h

250 q6h

250 q8h

250 q12h

50

125 q6h

125 q6h

125 q8h

125 q12h

250 q6h

250 q8h

250 q12h

250 q12h

250 q6h

250 q6h

250 q8h

250 q12h

40

125 q6h

125 q8h

125 q12h

125 q12h

250 q8h

125 q6h

125 q8h

125 q12h

250 q6h

250 q8h

250 q12h

250 q12h

30

125 q8h

125 q8h

125 q12h

125 q12h

125 q6h

125 q8h

125 q8h

125 q12h

250 q8h

125 q6h

125 q8h

125 q12h

Table 1. Renal Impairment Dosage (contd.)

 

If Total Recommended Daily Dose is:

 

3 g/day

4 g/day

 

and creatinine clearance (mL/min/1.73 m2) is:

 

≥71

41–70

21–40

6–20

≥71

41–70

21–40

6–20

and Body Weight (kg) is:

then the reduced dosage regiment (mg) is:

≥70

1000 q8h

500 q6h

500 q8h

500 q12h

1000 q6h

750 q8h

500 q6h

500 q12h

60

750 q8h

500 q8h

500 q8h

500 q12h

1000 q8h

750 q8h

500 q8h

500 q12h

50

500 q6h

500 q8h

250 q6h

250 q12h

750 q8h

500 q6h

500 q8h

500 q12h

40

500 q8h

250 q6h

250 q8h

250 q12h

500 q6h

500 q8h

250 q6h

250 q12h

30

250 q6h

250 q8h

250 q8h

250 q12h

500 q8h

250 q6h

250 q8h

250 q12h

Imipenem should be used in patients undergoing hemodialysis only when potential benefits outweigh the potential risk of drug-induced seizures.1 219 If used IV in hemodialysis patients, a supplemental dose of the drug should be given after each dialysis period1 120 126 140 and at 12-hour intervals thereafter.1 In addition, patients should be monitored closely for adverse CNS effects (e.g., confusion, myoclonic activity, seizures), especially those with CNS disease.1

Patients with Clcr ≤5 mL/minute per 1.732 should not receive imipenem and cilastatin sodium IV unless hemodialysis is instituted within 48 hours.1

IM

IM route should not be used in patients with Clcr <20 mL/minute per 1.73 m2.256

Infections in Pediatric Patients
IV

Not recommended in pediatric patients weighing <30 kg with impaired renal function.1

Adults with Low Body Weight

Dosage adjustment recommended when IV imipenem used in adults with body weight <70 kg.1 IV dosage recommended for these adults is the same as that recommended for adults with renal impairment.1 (See Tables.)

Geriatric Patients

No dosage adjustments except those related to renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Cautions for Imipenem and Cilastatin

Contraindications

  • Hypersensitivity to any ingredient in the formulation.1 256

  • IM injections are prepared using lidocaine hydrochloride and are contraindicated in patients with known hypersensitivity to local anesthetics of the amide type and in patients with severe shock or heart block.256

Warnings/Precautions

Warnings

Superinfection/Clostridium difficile-associated Colitis

Possible emergence and overgrowth of nonsusceptible organism.1 256 Careful observation of the patient is essential.1 256 Institute appropriate therapy if superinfection occurs.1 256

Treatment with anti-infectives may permit overgrowth of clostridia.1 256 305 306 307 308 309 Consider Clostridium difficile-associated diarrhea and colitis (antibiotic-associated pseudomembranous colitis) if diarrhea develops and manage accordingly.1 256

Some mild cases of C. difficile-associated diarrhea and colitis may respond to discontinuance alone.1 256 305 306 307 308 309 Manage moderate to severe cases with fluid, electrolyte, and protein supplementation; appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) recommended if colitis is severe.1 256 305 306 307 308 309

CNS Effects

Seizures and other CNS effects (e.g., confusional states, myoclonic activity) have occurred.1 256 Reported most frequently in those with CNS disorders (e.g., brain lesions, history of seizures) and/or renal impairment, but also reported in patients with no recognized or documented underlying CNS disorder or renal impairment.1 256

Do not exceed recommended dosage, especially in those with known factors that predispose to seizures.1 256 Anticonvulsant therapy should be continued in those with known seizure disorders.1 256

Patients with Clcr ≤20 mL/minute per 1.73 m2 (even if undergoing hemodialysis) are at increased risk of seizures if recommended doses are exceeded.1 For patients undergoing hemodialysis, IV imipenem should be used only if benefits outweigh the potential risk of seizures.1

If focal tremors, myoclonus, or seizures occur, evaluate the patient neurologically, initiate anticonvulsant therapy if necessary, and determine whether imipenem dosage should be decreased or the drug discontinued.1 256

Sensitivity Reactions

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity reactions (e.g., anaphylaxis) reported with β-lactams.1 256

If hypersensitivity occurs, discontinue imipenem and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, and maintenance of an adequate airway and oxygen).1 256

Cross-Hypersensitivity

Partial cross-allergenicity among β-lactam antibiotics, including penicillins, cephalosporins, and other β-lactams.1 256

Prior to initiation of therapy, make careful inquiry concerning previous hypersensitivity reactions to imipenem, cephalosporins, penicillins, or other drugs.1 256

General Precautions

Laboratory Monitoring

Periodically assess organ system functions, including renal, hepatic, and hematopoietic, during prolonged therapy.1 256

Sodium Content

IV preparations contain approximately 1.6 mEq (37.5 mg) of sodium per 500 mg of imipenem;1 IM preparations contain approximately 1.4 mEq (32 mg) of sodium per 500 mg of imipenem.1

Ps. aeruginosa Infections

Because resistant strains of Ps. aeruginosa have emerged during imipenem and cilastatin therapy,137 153 157 162 163 164 171 173 183 191 198 222 240 most clinicians recommend that an aminoglycoside be used concomitantly whenever the drug is used in the treatment of serious infections known or suspected to be caused by Ps. aeruginosa.137 146 153 157 162 163 164 173 174 183 191 196 198 210 240

Meningitis and Other CNS Infections

Safety and efficacy for treatment of meningitis has not been established.1 High incidence of seizures reported in children 3 months to 12 years of age who received the drug for empiric treatment of bacterial meningitis.242

Specific Populations

Pregnancy

Category C.1 256

Lactation

Imipenem distributed into milk.219 Use with caution.1 256

Pediatric Use

Safety and efficacy of IM imipenem and cilastatin have not been established in children <12 years of age.256

Adverse effects reported with IV imipenem in neonates and children are similar to those reported in adults.1 Seizures have been reported in neonates and children ≤3 months of age; a high incidence of seizures reported in children 3 months to 12 years of age who received the drug for empiric treatment of bacterial meningitis.1 242 Because of the risk of seizures, imipenem should not be used in pediatric patients with CNS infections.1

Data are insufficient to date regarding use of imipenem in pediatric patients with impaired renal function who weigh <30 kg; the drug should not be used in these children.1

Imipenem solutions that have been reconstituted with bacteriostatic water for injection containing benzyl alcohol should not be used in neonates or children ≤3 months of age.1 272 273 Although a causal relationship not established, injections preserved with benzyl alcohol have been associated with toxicity in neonates.272 273

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1 256

Substantially eliminated by kidneys; risk of toxicity may be greater in patients with impaired renal function.1 256 Select dosage with caution and assess renal function periodically since geriatric patients are more likely to have renal impairment.1 256

No dosage adjustments except those related to renal function.1 256 (See Renal Impairment under Dosage and Administration.)

Renal Impairment

Half-lives of both imipenem and cilastatin prolonged in patients with impaired renal function.120 126 185

Patients with renal impairment are at increased risk for adverse CNS effects (e.g., seizures), especially if usual dosage is exceeded.1 Do not use in patients undergoing hemodialysis unless benefits outweigh the possible risk of drug-induced seizures.1 219 Patients with Clcr ≤5 mL/minute per 1.73 m2 should not receive IV imipenem and cilastatin IV unless hemodialysis is instituted within 48 hours.1 If used IV in hemodialysis patients, a supplemental dose of the drug should be given after each dialysis period1 120 126 140 and at 12-hour intervals thereafter.1 In addition, patients should be monitored closely for adverse CNS effects (e.g., confusion, myoclonic activity, seizures), especially those with CNS disease.1

Dosage adjustment recommended in adults with Clcr ≤70 mL/minute.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

GI effects (nausea, diarrhea, vomiting); CNS effects; eosinophilia; local reactions (phlebitis/thrombophlebitis).1 256

Interactions for Imipenem and Cilastatin

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Aminoglycosides

In vitro evidence of additive or synergistic antibacterial effects against E. faecalis, S. aureus, and Listeria monocytogenes13 19 103 106 109 139

β-Lactam anti-infectives

In vitro evidence of antagonism with other β-lactam anti-infectives against Enterobacteriaceae and Ps. aeruginosa3 13 54 102 107 111 137 198 240 244 247

Clinical importance unclear; probably should not be used in conjunction with other β-lactam anti-infectives54 102 210 240

Chloramphenicol

In vitro evidence of antagonism with chloramphenicol against K. pneumoniae104 111

If used concomitantly, consider administering chloramphenicol a few hours after imipenem104

Co-trimoxazole

In vitro evidence of synergistic antibacterial effect against Nocardia asteroides108

Clinical importance unclear108

Ganciclovir

Seizures reported with concomitant use1 253 254

Use concomitantly only when potential benefits outweigh the possible risks1 253 254

Probenecid

Increased cilastatin concentrations and prolonged half-life125 140

Concomitant use not recommended1 256

Tests for glucose

Possible false-positive reactions in urine glucose tests using Clinitest, Benedict’s solution, or Fehling’s solution132

Use glucose tests based on enzymatic glucose oxidase reactions (e.g., Clinistix, Tes-Tape)132

Imipenem and Cilastatin Pharmacokinetics

Absorption

Bioavailability

Neither imipenem nor cilastatin appreciably absorbed from GI tract; must be given parenterally.125 143

Imipenem incompletely absorbed following IM administration;217 256 peak plasma concentrations of imipenem attained within 2 hours and peak plasma concentrations of cilastatin attained within 1 hour.256 Bioavailabilities of imipenem and cilastatin following IM administration range from 60–75 and 95–100%, respectively.217 256

Following IV administration, plasma imipenem concentrations during the first 2 hours exceed those attained following IM administration of the same doses; however, plasma imipenem concentrations achieved 4–6 hours after an IM dose exceed those after an IV dose and persist longer.256

Distribution

Extent

Following IV administration, imipenem distributed into saliva, 208 sputum, 1 208 215 aqueous humor, 1 215 bone, 1 182 208 215 bile, 1 215 reproductive organs, 1 myometrium, 215 endometrium, 215 heart valve, 215 intestine, 215 and pleural, 1 interstitial, 1 blister, 142 and wound208 215 fluids.

Only low imipenem concentrations distribute into CSF following IV administration.1 117 188 205

Both imipenem and cilastatin cross the placenta and are distributed into cord blood and amniotic fluid.209 251 Imipenem is distributed into milk.219

Plasma Protein Binding

Imipenem is 13–21%1 125 256 and cilastatin is approximately 40%1 256 bound to serum proteins.

Elimination

Metabolism

If imipenem is administered alone, the drug is partially hydrolyzed in kidneys by dehydropeptidase I (DHP I) to a microbiologically inactive metabolite.1 113 125 140 143 148 256 Concurrent administration of cilastatin prevents metabolism of imipenem by DHP I.1 2 113 118 120 125 137 140 141 148 196 197 198 256

Imipenem also is metabolized to some extent by a nonrenal mechanism unrelated to DHP I2 115 140 204 to an inactive metabolite identical to that formed by renal DHP I, this nonspecific hydrolysis is unaffected by concurrent administration of cilastatin.2 140 204

Cilastatin is partially metabolized in the kidneys to N-acetylcilastatin, 2 125 140 148 which also is an effective inhibitor of DHP I.2

Elimination Route

Imipenem, cilastatin, and their metabolites eliminated principally in urine.2 115 123 125 140 148

Half-life

In adults with normal renal function, distribution half-life of IV imipenem averages 0.23–0.31 hours114 122 124 and elimination half-life averages 0.85–1.35 hours.1 114 122 124 125 140 143 IV cilastatin has an elimination half-life of 0.83–1.1 hours in adults with normal renal function1 114 116 125 140

Elimination half-life of IV imipenem averages 1–1.3 hours in children144 and 1.5–2.6 hours in neonates.117 118 Elimination half-life of IV cilastatin is 3.1–8.8 hours in neonates.117 118

The elimination half-life of imipenem following IM administration of imipenem and cilastatin suspension is 2–3 hours.256

Special Populations

Serum half-lives of both imipenem and cilastatin are prolonged in patients with impaired renal function; half-life of cilastatin is prolonged to a greater extent than that of imipenem.120 126 185

In healthy geriatric adults, mean plasma half-lives of imipenem and cilastatin are similar to half-lives expected in individuals with slight renal impairment.1

Stability

Storage

Parenteral

Powder for Injection

<25°C.1 256

Solutions and suspensions may darken (i.e., IV solutions may turn deep yellow or IM suspensions may turn light tan) with time;1 256 this color change does not indicate loss of potency.1 256 However, IV solutions of the drug should be discarded if they become brown.219

IV solutions prepared using 100 mL of 0.9% sodium chloride injection; 5 or 10% dextrose; 5% dextrose and 0.225, 0.45, or 0.9% sodium chloride; 0.15% potassium chloride in 5% dextrose; or 5 or 10% mannitol are stable for 4 hours at room temperature or 24 hours when refrigerated at 5°C.1

Reconstituted ADD-Vantage vials are stable for 4 hours at room temperature.1

IM suspensions prepared using lidocaine hydrochloride 1% injection (without epinephrine) should be used within 1 hour of reconstitution.256

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Incompatible

Dextrose 5% with potassium chloride 0.15%1

Dextrose 5% in Ringer’s injection, lactatedHID

Dextrose 5% in sodium chloride 0.225, 0.45, or 0.9%1 HID

Dextrose 10% in water1 HID

Mannitol 2.5, 5, or 10% in water1 HID

Normosol M in dextrose 5%HID

Ringer’s injection, lactatedHID

Sodium bicarbonate 5%HID

Sodium lactate 1/6 MHID

Variable

Dextrose 5% in waterHID

Sodium chloride 0.9%HID

Drug Compatibility
Y-Site CompatibilityHID

Compatible

Acyclovir sodium

Amifostine

Anidulafungin

Aztreonam

Caspofungin acetate

Cisatracurium besylate

Diltiazem HCl

Docetaxel

Famotidine

Fludarabine phosphate

Foscarnet sodium

Granisetron HCl

Idarubicin HCl

Insulin, regular

Linezolid

Melphalan HCl

Methotrexate sodium

Ondansetron HCl

Propofol

Remifentanil HCl

Tacrolimus

Teniposide

Thiotepa

Tigecycline

Vasopressin

Vinorelbine tartrate

Zidovudine

Incompatible

Allopurinol sodium

Amiodarone HCl

Amphotericin B cholesteryl sulfate complex

Azithromycin

Etoposide phosphate

Fluconazole

Gallium nitrate

Gemcitabine HCl

Lorazepam

Meperidine HCl

Midazolam HCl

Milrinone lactate

Sargramostim

Sodium bicarbonate

Variable

Filgrastim

Telavancin HCl

Actions and Spectrum

  • Fixed combination of imipenem monohydrate and the sodium salt of cilastatin.1 35 256 Imipenem is carbapenem antibiotic2 4 5 6 148 196 197 198 structurally and pharmacologically related to meropenem and ertapenem.1 2 3 Cilastatin is a specific and reversible inhibitor of dehydropeptidase I (DHP I).1 2 101 125 140 141 145 148 196 198 256

  • Concomitant use of cilastatin prevents in vivo metabolism of imipenem by DHP I and results in urinary concentrations of active imipenem that are higher than could be obtained following use of the antibiotic alone.1 2 113 125 137 140 141 148 196 198 256

  • Usually bactericidal in action.1 256

  • Like other β-lactam antibiotics, antibacterial activity results from inhibition of bacterial cell wall synthesis.1 256

  • Spectrum of activity includes many gram-positive and -negative aerobic bacteria and some gram-positive and -negative anaerobic bacteria.1 256 Stable in the presence of a variety of β-lactamases (including penicillinases, cephalosporinases, and extended-spectrum β-lactamases).1 256

  • Gram-positive aerobes: active in vitro and in clinical infections against Enterococcus faecalis, Staphylococcus aureus (including penicillinase-producing strains), S. epidermidis, Streptococcus agalactiae (group B streptococci), S. pneumoniae, and S. pyogenes (group A β-hemolytic streptococci).1 256 Also active in vitro against S, saprophyticus, groups C and G streptococci, viridans streptococci, Bacillus, Listeria monocytogenes, and Nocardia.1 256 Oxacillin-resistant (methicillin-resistant) staphylococci are resistant.1 256

  • Gram-negative aerobes: active in vitro and in clinical infections against Acinetobacter, Citrobacter, Enterobacter, Escherichia coli, Gardnerella vaginalis, Haemophilus influenzae, H. parainfluenzae, Klebsiella, Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa, and Serratia (including S. marcescens).1 256 Also active in vitro against Aeromonas hydrophila, Alcaligenes, Capnocytophaga, H. ducreyi, Neisseria gonorrhoeae, Pasteurella, and P. stuartii.1 256

  • Anaerobes: active in vitro and in clinical infections against Bacteroides (including B. fragilis), Bifidobacterium, Clostridium, Eubacterium, Fusobacterium, Peptococcus, Peptostreptococcus, and Propionibacterium.1 256 Also active in vitro against Prevotella bivia, P. disiens, P. melaninogenica, and Veillonella.1

Advice to Patients

  • Importance of informing clinicians of other medical conditions, including history of seizures.1

  • Importance of discontinuing therapy and informing clinician if an allergic or hypersensitivity reaction occurs.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patient of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Imipenem and Cilastatin Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injectable suspension, for IM use only

500 mg (of anhydrous imipenem) and 500 mg (of cilastatin)

Primaxin I.M.

Merck

750 mg (of anhydrous imipenem) and 750 mg (of cilastatin)

Primaxin I.M.

Merck

For injection, for IV infusion

250 mg (of anhydrous imipenem) and 250 mg (of cilastatin)

Primaxin I.V. (available in infusion bottles and vials)

Merck

Primaxin ADD-Vantage

Merck

500 mg (of anhydrous imipenem) and 500 mg (of cilastatin)

Primaxin I.V. (available in infusion bottles and vials)

Merck

Primaxin ADD-Vantage

Merck

AHFS DI Essentials. © Copyright 2018, Selected Revisions July 10, 2013. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Merck & Co, Inc. Primaxin I.V. (imipenem and cilastatin for injection) prescribing information. West Point, PA; 2001 Nov.

2. Birnbaum J, Kahan FM, Kropp H et al. Carbapenems, a new class of beta-lactam antibiotics. Am J Med. 1985; 78(Suppl 6A):3-21. http://www.ncbi.nlm.nih.gov/pubmed/3859213?dopt=AbstractPlus

3. Neu HC. Carbapenems: special properties contributing to their activity. Am J Med. 1985; 78(Suppl 6A):33-40. http://www.ncbi.nlm.nih.gov/pubmed/3873871?dopt=AbstractPlus

4. Neu HC. Structure-activity relations of new β-lactam compounds and in vitro activity against common bacteria. Rev Infect Dis. 1983; 5(Suppl 2):S319-36. http://www.ncbi.nlm.nih.gov/pubmed/6342103?dopt=AbstractPlus

5. Neu HC. Trends in the development of beta-lactam antibiotics. Scand J Infect Dis. 1984; 42(Suppl):7-16.

6. Ekstrom B. Basic design of beta-lactam antibiotics: penams and analogues and monocyclic beta-lactam. Scand J Infect Dis. 1984; 42(Suppl):38-49.

7. Thompson RL, Fisher KA, Wenzel RP. In vitro activity of N-formimidoyl thienamycin and other β-lactam antibiotics against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 1982; 21:341-3. (IDIS 146667)

8. Enciso MD, Lindemann ML, Altes AG. In vitro evaluation of N-formimidoyl thienamycin (MK0787) combined with amikacin against gram-negative bacilli and Staphylococcus aureus. Antimicrob Agents Chemother. 1982; 22:1064-6. (IDIS 161997)

9. Witte JL, Sapico FL, Canawati HN. In vitro susceptibility of methicillin-resistant and methicillin-susceptible Staphylococcus aureus strains to N-formimidoyl thienamycin. Antimicrob Agents Chemother. 1982; 22:906-8. http://www.ncbi.nlm.nih.gov/pubmed/6960806?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=185682&blobtype=pdf

10. Auckenthaler R, Wilson WR, Wright AJ et al. Lack of in vivo and in vitro bactericidal activity of N-formimidoyl thienamycin against enterococci. Antimicrob Agents Chemother. 1982; 22:448-52. http://www.ncbi.nlm.nih.gov/pubmed/6958215?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=183764&blobtype=pdf

11. Gutmann L, Tomasz A. Penicillin-resistant and penicillin-tolerant mutants of group A streptococci. Antimicrob Agents Chemother. 1982; 22:128-36. http://www.ncbi.nlm.nih.gov/pubmed/6181734?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=183685&blobtype=pdf

12. Ruckdeschel G, Ehret W, Ahl A. Susceptibility of Legionella spp. to imipenem and 27 other beta-lactam antibiotics. Eur J Clin Microbiol. 1984; 3:463-7. http://www.ncbi.nlm.nih.gov/pubmed/6594234?dopt=AbstractPlus

13. Braveny I. In vitro activity of imipenem: a review. Eur J Clin Microbiol. 1984; 3:456-62. http://www.ncbi.nlm.nih.gov/pubmed/6389125?dopt=AbstractPlus

14. Chokkavelu V, Chandrasekar P, Rolston K et al. Activity of eleven antimicrobial agents against methicillin-, methicillin- and rifampin-resistant Staphylococcus aureus. Chemotherapy. 1984; 30:97-101. (IDIS 182282)

15. Eliopoulos GM, Reiszner E, Moellering RC. In vitro activity of Sch 34343 against enterococci and other gram-positive bacteria. Antimicrob Agents Chemother. 1985; 27:28-32. http://www.ncbi.nlm.nih.gov/pubmed/3845792?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=176199&blobtype=pdf

16. Megran D, Carlson C, Chow A. In vitro activity of imipenem against anaerobic bacteria. Eur J Clin Microbiol. 1984; 3:488-9. http://www.ncbi.nlm.nih.gov/pubmed/6594238?dopt=AbstractPlus

17. Larsson S, Walder MH, Cronberg SN et al. Antimicrobial susceptibilities of Listeria monocytogenes strains isolated from 1958 to 1982 in Sweden. Antimicrob Agents Chemother. 1985; 28:12-4. http://www.ncbi.nlm.nih.gov/pubmed/3929675?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=176300&blobtype=pdf

18. Markowitz N, Pohlod DJ, Saravolatz LD et al. In vitro susceptibility patterns of methicillin-resistant and susceptible Staphylococcus aureus strains in a population of parenteral drug abusers from 1972 to 1981. Antimicrob Agents Chemother. 1983; 23:450-7. http://www.ncbi.nlm.nih.gov/pubmed/6552151?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=184668&blobtype=pdf

19. Eliopoulos GM, Moellering RC. Susceptibility of enterococci and Listeria monocytogenes to N-formimidoyl thienamycin alone and in combination with an aminoglycoside. Antimicrob Agents Chemother. 1981; 29:789-93.

20. Cherubin CE, Corrado ML, Sierra MF et al. Susceptibility of gram-positive cocci to various antibiotics, including cefotaxime, moxalactam, and N-formimidoyl thienamycin. Antimicrob Agents Chemother. 1981; 20:553-5. http://www.ncbi.nlm.nih.gov/pubmed/6282200?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=181744&blobtype=pdf

21. Talley FP, Jacobus NV, Gorbach SL. In vitro activity of N-formimidoyl thienamycin (MK0787). Antimicrob Agents Chemother. 1980; 18:642-4. http://www.ncbi.nlm.nih.gov/pubmed/6934708?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=284063&blobtype=pdf

22. Ward JI, Moellering RC. Susceptibility of pneumococci to 14 beta-lactam agents: comparison of strains resistant, intermediate-resistant, and susceptible to penicillin. Antimicrob Agents Chemother. 1981; 20:204-7. http://www.ncbi.nlm.nih.gov/pubmed/6912777?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=181664&blobtype=pdf

23. Jacobs MR, Kelly F, Speck WT. Susceptibility of group B streptococci to 16 β-lactam antibiotics, including new penicillin and cephalosporin derivatives. Antimicrob Agents Chemother. 1982; 22:897-900. http://www.ncbi.nlm.nih.gov/pubmed/6758692?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=185679&blobtype=pdf

24. Wise R, Andrews JM, Danks G. Comparison of in vitro activity of FCE 22101, a new penem, with those of other β-lactam antibiotics. Antimicrob Agents Chemother. 1983; 24:909-14. http://www.ncbi.nlm.nih.gov/pubmed/6607032?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=185406&blobtype=pdf

25. Muytjens HL, van der Ros-van de Repe J. Comparative activities of 13 β-lactam antibiotics. Antimicrob Agents Chemother. 1983; 21:925-34.

26. Verbist L, Verhaegen J. In vitro activity of N-formimidoyl thienamycin in comparison with cefotaxime, moxalactam, and ceftazidime. Antimicrob Agents Chemother. 1983; 19:402-6.

27. Haas H, Zubi R, Sacks TG. Susceptibility of Mycobacterium fallax to imipenem and twenty other antimicrobial agents. Eur J Clin Microbiol. 1984; 3:489-91. http://www.ncbi.nlm.nih.gov/pubmed/6594239?dopt=AbstractPlus

28. Thornsberry C. Review of in vitro activity of third-generation cephalosporins an other newer beta-lactam antibiotics against clinically important bacteria. Am J Med. 1985; 79(Suppl 2A):14-20. http://www.ncbi.nlm.nih.gov/pubmed/3927723?dopt=AbstractPlus

29. Tutlane VA, McCloskey RV, Trent JA. In vitro comparison of N-formimidoyl thienamycin, piperacillin, cefotaxime, and cefoperazone. Antimicrob Agents Chemother. 1981; 20:140-3. http://www.ncbi.nlm.nih.gov/pubmed/6269481?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=181646&blobtype=pdf

30. Shadomy S, May RS. N-formimidoyl thienamycin (MK0787): in vitro study. Antimicrob Agents Chemother. 1981; 19:201-4. http://www.ncbi.nlm.nih.gov/pubmed/6941741?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=181385&blobtype=pdf

31. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing; twelfth informational supplement. NCCLS document M100-S12. Wayne, PA: NCCLS; 2002 Jan.

32. Henry D, Skidmore AG, Ngui-Yen J et al. In vitro activities of enoxacin, ticarcillin plus clavulanic acid, aztreonam, piperacillin, and imipenem and comparison with commonly used antimicrobial agents. Antimicrob Agents Chemother. 1985; 28:259-64. http://www.ncbi.nlm.nih.gov/pubmed/3869433?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=180229&blobtype=pdf

33. Fass RJ. In vitro activity of ciprofloxacin (Bay o 9867). Antimicrob Agents Chemother. 1983; 24:568-74. http://www.ncbi.nlm.nih.gov/pubmed/6228192?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=185375&blobtype=pdf

34. Cullmann W, Opferkuch W, Stieglitz M et al. A comparison of the antibacterial activities of N-formimidoyl thienamycin (MK0787) with those of other recently developed β-lactam derivatives. Antimicrob Agents Chemother. 1982; 22:302-7. http://www.ncbi.nlm.nih.gov/pubmed/6821459?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=183729&blobtype=pdf

35. US Food and Drug Administration. Antibiotic drugs; imipenem monohydrate-cilastatin sodium for injection (Docket No. 86N-0070). Fed Regist. 1986; 51:11571-6.

36. Gutierrez-Nunez J, Harrington PT, Ramirez-Ronda CH. Activity of N-formimidoyl thienamycin and cephalosporins against isolates from nosocomially acquired bacteremia. Antimicrob Agents Chemother. 1982; 21:509-12. http://www.ncbi.nlm.nih.gov/pubmed/6954876?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=181925&blobtype=pdf

37. O’Donnell ED, Freimer EH, Gilardi GL et al. Comparative in vitro activities of N-formimidoyl thienamycin and moxalactam against nonfermentative aerobic gram-negative rods. Antimicrob Agents Chemother. 1982; 21:673-5. http://www.ncbi.nlm.nih.gov/pubmed/6211143?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=181966&blobtype=pdf

38. Garcia I, Fainstein V, LeBlanc B et al. In vitro activities of new β-lactam antibiotics against Acinetobacter spp. Antimicrob Agents Chemother. 1983; 24:297-9. http://www.ncbi.nlm.nih.gov/pubmed/6638992?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=185157&blobtype=pdf

39. Dudek EJ, Stephenson JD, Bohnhoff M et al. Susceptibility of Neisseria meningitidis and Neisseria gonorrhoeae isolates to N-formimidoyl thienamycin. Antimicrob Agents Chemother. 1982; 22:926-9. http://www.ncbi.nlm.nih.gov/pubmed/6817708?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=185689&blobtype=pdf

40. Melby K, Storvold G, Leinslie T et al. Activity of nine antibacterial agents on penicillinase- and nonpenicillinase-producing Neisseria gonorrhoeae isolated from clinical specimens obtained in northern Norway. Chemotherapy. 1985; 31:346-50. http://www.ncbi.nlm.nih.gov/pubmed/3931991?dopt=AbstractPlus

41. Vuye A, Pijck J. In vitro antibacterial activity of BMY-28142, a new extended-spectrum cephalosporin. Antimicrob Agents Chemother. 1985; 27:574-7. http://www.ncbi.nlm.nih.gov/pubmed/3859244?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=180098&blobtype=pdf

42. Pierson CL, Schaberg DR, Fekety FR et al. In-vitro activity of Sch 29482, MK 0787, ceftriaxone and seven other antimicrobials against 840 separate clinical isolates. J Antimicrob Chemother. 1982; 9(Suppl C):79-89. http://www.ncbi.nlm.nih.gov/pubmed/6277844?dopt=AbstractPlus

43. Bremner DA. Azthreonam activity against gram-negative bacilli. Chemotherapy. 1984; 30:44-8. http://www.ncbi.nlm.nih.gov/pubmed/6537908?dopt=AbstractPlus

44. Livingston WK, Elliott AM, Cobbs CG. In vitro activity of N-formimidoyl thienamycin (MK0787) against resistant strains of Pseudomonas aeruginosa, Staphylococcus epidermidis, Serratia marcescens, and Enterococcus spp. Antimicrob Agents Chemother. 1981; 19:114-6. http://www.ncbi.nlm.nih.gov/pubmed/6787975?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=181367&blobtype=pdf

45. Scribner RK, Wedro BC, Weber AH et al. Activities of eight new β-lactam antibiotics and seven antibiotic combinations against Neisseria meningitidis. Antimicrob Agents Chemother. 1982; 21:678-80. (IDIS 157807)

46. Laferriere C, Marks MI, Welch DF. Effect of inoculum size on Haemophilus influenzae type b susceptibility to new and conventional antibiotics. Antimicrob Agents Chemother. 1983; 24:287-9. http://www.ncbi.nlm.nih.gov/pubmed/6605716?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=185154&blobtype=pdf

47. Preblud SR, Gill CJ, Campos JM. Bactericidal activities of chloramphenicol and eleven other antibiotics against Salmonella spp. Antimicrob Agents Chemother. 1984; 25:327-30. http://www.ncbi.nlm.nih.gov/pubmed/6372681?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=185509&blobtype=pdf

48. Prince AS, Neu HC. Activities of new beta-lactam antibiotics against isolates of Pseudomonas aeruginosa from patients with cystic fibrosis. Antimicrob Agents Chemother. 1981; 20:545-6. http://www.ncbi.nlm.nih.gov/pubmed/6282199?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=181741&blobtype=pdf

49. Lerner SA, Dudek EJ, Boisvert WE et al. Effect of highly potent antipseudomonal β-lactam agents alone and in combination with aminoglycosides against Pseudomonas aeruginosa. Rev Infect Dis. 1984; 6(Suppl 3):S678-88. (IDIS 191958)

50. Corrado ML, Landesman SH, Cherubin CE. Influence of inoculum size on activity of cefoperazone, cefotaxime, moxalactam, piperacillin, and N-formimidoyl thienamycin (MK0787) against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1980; 18:893-6. (IDIS 129185)

51. Michael PR, Alford RH, McGee ZA. Superior activity of N-formimidoyl thienamycin against gentamicin-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1981; 20:702-4. (IDIS 141487)

52. Dibb WL, Kjellevold VA, Digranes A. Pseudomonas aeruginosa and Acinetobacter calcoaceticus: in vitro susceptibility of 150 clinical isolates to five β-lactam antibiotics and tobramycin. Chemotherapy. 1983; 29:332-6. http://www.ncbi.nlm.nih.gov/pubmed/6311491?dopt=AbstractPlus

53. Conrad DA, Scribner RK, Weber AH et al. In vitro activity of BMY-28142 against pediatric pathogens, including isolates from cystic fibrosis sputum. Antimicrob Agents Chemother. 1985; 28:58-63. http://www.ncbi.nlm.nih.gov/pubmed/3929681?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=176310&blobtype=pdf

54. Tausk F, Evans ME, Patterson LS et al. Imipenem-induced resistance to antipseudomonal β-lactams in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1985; 28:41-5. (IDIS 203396)

55. Bustamante CI, Drusano GL, Tatem BA et al. Postantibiotic effect of imipenem on Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1984; 26:678-82. (IDIS 194078)

56. Wu DH, Baltch AL, Smith RP. In vitro comparison of Pseudomonas aeruginosa isolates with various susceptibilities to aminoglycosides and ten β-lactam antibiotics. Antimicrob Agents Chemother. 1984; 25:488-90. http://www.ncbi.nlm.nih.gov/pubmed/6428308?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=185558&blobtype=pdf

57. Zar FA, Kany RJ. In vitro studies of investigational β-lactams as possible therapy for Pseudomonas aeruginosa endocarditis. Antimicrob Agents Chemother. 1985; 27:1-3. http://www.ncbi.nlm.nih.gov/pubmed/3920956?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=176194&blobtype=pdf

58. Bassey CM, Baltch AL, Smith RP et al. Comparative in vitro activities of enoxacin (CI-919, AT-2266) and eleven antipseudomonal agents against aminoglycoside-susceptible and -resistant Pseudomonas aeruginosa strains. Antimicrob Agents Chemother. 1984; 26:417-8. http://www.ncbi.nlm.nih.gov/pubmed/6439116?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=176183&blobtype=pdf

59. McNamara BT, Meyer RD, Pasiecznik KA. In vitro susceptibility of cephalothin-resistant Enterobacteriaceae and Pseudomonas aeruginosa to amikacin and selected new β-lactam agents. Antimicrob Agents Chemother. 1982; 21:753-7. http://www.ncbi.nlm.nih.gov/pubmed/6213196?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=182006&blobtype=pdf

60. Matzkowitz AJ, Baltch AL, Smith RP et al. In vitro comparison of N-formimidoyl thienamycin (MK0787) and azlocillin with three aminoglycosides and ticarcillin against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1982; 21:685-7. (IDIS 157810)

61. Rolfe RD, Finegold SM. Comparative in vitro activity of new beta-lactam antibiotics against anaerobic bacteria. Antimicrob Agents Chemother. 1981; 20:600-9. http://www.ncbi.nlm.nih.gov/pubmed/7325628?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=181759&blobtype=pdf

62. Bansal MB, Chuah SK, Thadepalli H. Susceptibility of intestinal anaerobes to new beta-lactam antibiotics. Chemotherapy. 1984; 30:237-43. http://www.ncbi.nlm.nih.gov/pubmed/6744975?dopt=AbstractPlus

63. Ohm-Smith MJ, Hadley WK, Sweet RL. In vitro activity of new β-lactam antibiotics and other antimicrobial drugs against anaerobic isolates from obstetric and gynecological infections. Antimicrob Agents Chemother. 1982; 22:711-4. http://www.ncbi.nlm.nih.gov/pubmed/7181484?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=183823&blobtype=pdf

64. Kesado T, Watanabe K, Asahi Y et al. Susceptibilities of anaerobic bacteria to N-formimidoyl thienamycin (MK0787) and to other antibiotics. Antimicrob Agents Chemother. 1982; 21:1016-22. http://www.ncbi.nlm.nih.gov/pubmed/6956247?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=182066&blobtype=pdf

65. Martin DA, Sanders CV, Marier RL. N-Formimidoyl thienamycin (MK0787): in vitro activity against anaerobic bacteria. Antimicrob Agents Chemother. 1982; 21:168-9. http://www.ncbi.nlm.nih.gov/pubmed/6952818?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=181847&blobtype=pdf

66. Del Bene VE, Carek PJ, Twitty JA et al. In vitro activity of cefbuperazone compared with that of other new β-lactam agents against anaerobic gram-negative bacilli and contribution of β-lactamase to resistance. Antimicrob Agents Chemother. 1985; 27:817-20. http://www.ncbi.nlm.nih.gov/pubmed/3874597?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=180158&blobtype=pdf

67. Nasu M, Maskell JP, Williams RJ et al. In vitro activity of MK0787 (N-formimidoyl thienamycin) and other beta-lactam compounds against Bacteroides spp. Antimicrob Agents Chemother. 1981; 20:433-6. http://www.ncbi.nlm.nih.gov/pubmed/6282191?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=181720&blobtype=pdf

68. Brown JE, Del Bene VE, Collins CD. In vitro activity of N-formimidoyl thienamycin, moxalactam, and other new beta-lactam agents against Bacteroides fragilis: contribution of beta-lactamase to resistance. Antimicrob Agents Chemother. 1981; 19:248-52. http://www.ncbi.nlm.nih.gov/pubmed/6214986?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=181402&blobtype=pdf

69. Aldridge KE, Sanders CV, Janney A et al. Comparison of the activities of penicillin G and new β-lactam antibiotics against clinical isolates of Bacteroides species. Antimicrob Agents Chemother. 1984; 26:410-3. http://www.ncbi.nlm.nih.gov/pubmed/6334491?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=176181&blobtype=pdf

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