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Unipen

Generic Name: Nafcillin Sodium
Class: Penicillinase-resistant Penicillins
Chemical Name: [2S - (2α,5α,6β)] - 6 - [[(2 - Ethoxy - 1 - naphthalenyl)carbonyl]amino] - 3,3 - dimethyl - 7 - oxo - 4 - thia - 1 - azabicyclo[3.2.0]heptane - 2 - carboxylic acid monosodium salt monohydrate
CAS Number: 7177-50-6

Introduction

Antibacterial; β-lactam antibiotic; penicillinase-resistant penicillin.1 2 4 5 8 47 59 70

Uses for Unipen

Staphylococcal Infections

Treatment of infections caused by, or suspected of being caused by, susceptible penicillinase-producing staphylococci,1 6 10 46 48 59 66 70 71 including respiratory tract, skin and skin structure, bone and joint, and urinary tract infections and meningitis and bacteremia.a A drug of choice for these infections.a

Slideshow: 10 Things to Know About Antibiotic Resistance

Treatment of native valve or prosthetic valve endocarditis caused by susceptible staphylococci.54 69 A drug of choice;54 69 used with or without gentamicin for native valve endocarditis and used in conjunction with rifampin and gentamicin for prosthetic valve endocarditis.54 69

If used empirically, consider whether staphylococci resistant to penicillinase-resistant penicillins (oxacillin-resistant [methicillin-resistant] staphylococci) are prevalent in the hospital or community.a (See Staphylococci Resistant to Penicillinase-resistant Penicillins under Cautions.)

Perioperative Prophylaxis

Has been used for perioperative prophylaxis in patients undergoing neurosurgery or cardiovascular or orthopedic surgery associated with high risk of staphylococcal infections.a Not considered a drug of choice.a

Unipen Dosage and Administration

Administration

Administer by IV injection or infusion or by IM injection.1 63

To reduce risk of thrombophlebitis and other adverse local reactions associated with IV administration (particularly in geriatric patients), administer slowly and take care to avoid extravasation.41 62 63

IV route should be used for relatively short periods of time (e.g., 24–48 hours).1 63

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

IV Injection

Reconstitution and Dilution

Reconstitute vials containing 1 or 2 g of nafcillin by adding 3.4 or 6.8 mL, respectively, of sterile water for injection, bacteriostatic water for injection (with benzyl alcohol or parabens), or 0.9% sodium chloride injection to provide solutions containing 250 mg/mL.1 When dissolved, the appropriate dose of the drug should be further diluted with 15–30 mL of sterile water for injection or sodium chloride injection.1

Rate of Administration

Inject appropriate dose of diluted solution slowly over 5–10 minutes into the tubing of a free-flowing compatible IV solution.1 (See Solution Compatibility under Stability.)

IV Infusion

Reconstitution and Dilution

Reconstitute vials containing 1 or 2 g of nafcillin by adding 3.4 or 6.8 mL, respectively, of sterile water for injection, bacteriostatic water for injection (with benzyl alcohol or parabens), or 0.9% sodium chloride injection to provide solutions containing 250 mg/mL.1 When dissolved, further dilute with a compatible IV solution (see Solution Compatibility under Stability) according to the manufacturer’s directions.1

Alternatively, ADD-Vantage vials containing 1 or 2 may be reconstituted according to the manufacturer’s directions.

Reconstitute 10-g pharmacy bulk package with 93 mL of sterile water for injection or 0.9% sodium chloride injection to provide a solution containing 100 mg/mL.1 Pharmacy bulk packages of the drug are not intended for direct IV infusion; prior to administration, doses of the drug from the reconstituted pharmacy bulk package must be further diluted in a compatible IV infusion solution (see Solution Compatibility under Stability).

Thaw the commercially available injection (frozen) at room temperature or in a refrigerator; do not force thaw by immersion in a water bath or by exposure to microwave radiation.63 A precipitate may have formed in the frozen injection, but should dissolve with little or no agitation after reaching room temperature.63 Discard thawed injection if an insoluble precipitate is present or if container seals or outlet ports are not intact.63 Additives should not be introduced into the injection.63 The injections should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete.63

Rate of Administration

For intermittent IV infusion, infuse over a period of at least 30–60 minutes.63

IM Administration

Inject IM deeply into a large muscle (e.g., gluteus maximus),1 avoiding sciatic nerve injury.59

Reconstitution

For IM injection, reconstitute vial containing 1 or 2 g of nafcillin by adding 3.4 or 6.8 mL, respectively, of sterile water for injection, bacteriostatic water for injection (with benzyl alcohol or parabens), or 0.9% sodium chloride injection to provide solutions containing 250 mg/mL.1

Dosage

Available as nafcillin sodium; dosage expressed in terms of nafcillin.1 63

Duration of treatment depends on type and severity of infection and should be determined by clinical and bacteriologic response of the patient.46 49 59 71 In severe staphylococcal infections, duration usually is ≥2 weeks;59 more prolonged therapy is necessary for treatment of osteomyelitis, endocarditis, or other metastatic infections.46 52 53 55 56 59 71

Pediatric Patients

Staphylococcal Infections
General Dosage in Neonates
IV

Neonates <1 week of age: AAP and others recommend 25 mg/kg every 12 hours for those weighing ≤2 kg and 25 mg/kg every 8 hours for those weighing >2 kg.67 72 The higher dosages are recommended for meningitis.67

Neonates 1–4 weeks of age: AAP and others recommend 25 mg/kg every 12 hours for those weighing <1.2 kg; 25 mg/kg every 8 hours for those weighing 1.2–2 kg; and 25–35 mg/kg every 6 hours for those weighing >2 kg.67 72 The higher dosages are recommended for meningitis.67

IM

10 mg/kg twice daily recommended by manufacturer.1

Neonates <1 week of age: AAP and others recommend 25 mg/kg every 12 hours for those weighing ≤2 kg and 25 mg/kg every 8 hours for those weighing >2 kg.67 72 The higher dosages are recommended for meningitis.67

Neonates 1–4 weeks of age: AAP and others recommend 25 mg/kg every 12 hours for those weighing <1.2 kg; 25 mg/kg every 8 hours for those weighing 1.2 to 2 kg; and 25–35 mg/kg every 6 hours for those weighing >2 kg.67 72 The higher dosages are recommended for meningitis.67

General Dosage in Infants and Children
IV

Children weighing ≥40 kg: manufacturer recommends 500 mg every 4 hours for mild to moderate infections and 1 g every 4 hours for severe infections.1

Children ≥1 month of age: AAP recommends 50–100 mg/kg daily in 4 divided doses for mild to moderate infections or 100–150 mg/kg daily in 4 divided doses for severe infections.67

IM

Children weighing <40 kg: manufacturer recommends 25 mg/kg twice daily.1

Children weighing ≥40 kg: manufacturer recommends 500 mg every 4–6 hours for mild to moderate infections and 1 g every 4 hours for severe infections.1

Children ≥1 month of age: AAP recommends 50–100 mg/kg daily in 4 divided doses for mild to moderate infections or 100–150 mg/kg daily in 4 divided doses for severe infections.67

Staphylococcal Native Valve Endocarditis
IV

AHA recommends 200 mg/kg daily given in divided doses every 4–6 hours for 6 weeks (maximum 12 g daily).69

In addition, during the first 3–5 days of nafcillin therapy, IM or IV gentamicin (3 mg/kg daily given in divided doses every 8 hours; dosage adjusted to achieve peak serum gentamicin concentrations approximately 3 mcg/mL and trough concentrations <1 mcg/mL) may be given concomitantly if the causative organism is susceptible to the drug.69

Staphylococcal Prosthetic Valve Endocarditis
IV

AHA recommends 200 mg/kg daily given in divided doses every 4–6 hours for 6 weeks or longer (maximum 12 g daily).

Used in conjunction with oral rifampin (20 mg/kg daily given in divided doses every 8 hours for 6 weeks or longer) and IM or IV gentamicin (3 mg/kg daily given in divided doses every 8 hours during the first 2 weeks of nafcillin therapy; dosage adjusted to achieve peak serum gentamicin concentrations approximately 3 mcg/mL and trough concentrations <1 mcg/mL).69

Adults

Staphylococcal Infections
General Adult Dosage
IV

500 mg every 4 hours; severe infections may require 1 g every 4 hours.1

IM

500 mg every 4–6 hours; severe infections may require 1 g every 4 hours.1

Acute or Chronic Staphylococcal Osteomyelitis
IV

1–2 g every 4 hours.44 50 51 52 54

When used for treatment of acute or chronic osteomyelitis caused by susceptible penicillinase-producing staphylococci, parenteral therapy usually given for 3–8 weeks;44 50 51 52 53 54 56 58 71 follow-up with an oral penicillinase-resistant penicillin generally is recommended for treatment of chronic osteomyelitis.47 53 55 71

Staphylococcal Native Valve Endocarditis
IV

AHA recommends 2 g every 4 hours for 4–6 weeks.54

Although benefits of concomitant aminoglycosides have not been clearly established, AHA states that IM or IV gentamicin (1 mg/kg every 8 hours) may be given concomitantly during the first 3–5 days of nafcillin therapy.54

Staphylococcal Prosthetic Valve Endocarditis
IV

AHA recommends 2 g every 4 hours for ≥6 weeks in conjunction with oral rifampin (300 mg every 8 hours for 6 weeks or longer) and IM or IV gentamicin (1 mg/kg every 8 hours during the first 2 weeks of nafcillin therapy).54 (See Staphylococci Resistant to Penicillinase-resistant Penicillins under Cautions.)

Staphylococcal Infections Related to Intravascular Catheters
IV

2 g every 4 hours.74

Special Populations

Hepatic Impairment

Dosage adjustments not required unless renal function also impaired.18 27 33 57 60 63 70

Renal Impairment

Modification of dosage generally is unnecessary in patients with renal impairment alone; modification of dosage may be necessary in those with both severe renal impairment and hepatic impairment.18 27 33 57 60 63 70

Cautions for Unipen

Contraindications

  • Hypersensitivity to any penicillin.1 59

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, reported with penicillins.1 Anaphylaxis occurs most frequently with parenteral penicillins but has occurred with oral penicillins.1

Prior to initiation of therapy, make careful inquiry regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other drugs.1 Partial cross-allergenicity occurs among penicillins and other β-lactam antibiotics including cephalosporins and cephamycins.1 34 35 43 45

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

General Precautions

Superinfection/Clostridium difficile-associated Colitis

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

Treatment with anti-infectives may permit overgrowth of clostridia.a Consider Clostridium difficile-associated diarrhea and colitis (antibiotic-associated pseudomembranous colitis) if diarrhea develops and manage accordingly.a

Some mild cases of C. difficile-associated diarrhea and colitis may respond to discontinuance alone.a 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.a

Laboratory Monitoring

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

Perform urinalysis and determine Scr and BUN concentrations prior to and periodically during therapy.1

To monitor for hepatotoxicity, determine AST and ALT concentrations prior to and periodically during therapy.1

Because adverse hematologic effects have occurred with penicillinase-resistant penicillins, total and differential WBC counts should be performed prior to and 1–3 times weekly during therapy.1 a

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of nafcillin and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.1 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.1

Staphylococci Resistant to Penicillinase-resistant Penicillins

Consider that staphylococci resistant to penicillinase-resistant penicillins (referred to as oxacillin-resistant [methicillin-resistant] staphylococci) are being reported with increasing frequency.a

If nafcillin used empirically for treatment of any infection suspected of being caused by susceptible staphylococci, the drug should be discontinued and appropriate anti-infective therapy substituted if the infection is found to be caused by any organism other than penicillinase-producing staphylococci susceptible to penicillinase-resistant penicillins.1 If staphylococci resistant to penicillinase-resistant penicillins (oxacillin-resistant [methicillin-resistant] staphylococci) are prevalent in the hospital or community, empiric therapy of suspected staphylococcal infections should include another appropriate anti-infective (e.g., vancomycin).a

In treatment of endocarditis, consider that coagulase-negative staphylococci causing prosthetic valve endocarditis usually are resistant to penicillinase-resistant penicillins (especially when endocarditis develops within 1 year after surgery).54 Therefore, coagulase-negative staphylococci involved in prosthetic valve endocarditis should be assumed to be resistant to penicillinase-resistant penicillins unless results of in vitro testing indicate that the isolates are susceptible to the drugs.54

Specific Populations

Pregnancy

Category B.1

Lactation

Penicillins are distributed into milk.1 19 20 59 70 Use with caution.1 59

Pediatric Use

Elimination of penicillins is delayed in neonates because of immature mechanisms for renal excretion; abnormally high serum concentrations may occur in this age group.58 63

If used in neonates, monitor closely for clinical and laboratory evidence of toxic or adverse effects.1 59 Determine serum nafcillin concentrations frequently and make appropriate reductions in dosage and frequency of administration when indicated.1 59

Nafcillin solutions that have been reconstituted with bacteriostatic water for injection containing benzyl alcohol should not be used in neonates.c d Although a causal relationship has not been established, injections preserved with benzyl alcohol have been associated with toxicity in neonates.c d

Common Adverse Effects

Hypersensitivity reactions; local reactions (phlebitis, thrombophlebitis); renal, hepatic, or nervous system effects with high dosage.1 a

Interactions for Unipen

Specific Drugs

Drug

Interaction

Comments

Aminoglycosides

In vitro evidence of synergistic antibacterial activity against penicillinase-producing and nonpenicillinase-producing S. aureusa

Anticoagulants, oral (warfarin)

Possible decreased hypothrombinemic effect63 a

Monitor PT and adjust anticoagulant dosage if indicated63 a

Cyclosporine

Possible decreased cyclosporine concentrations63

Monitor cyclosporine concentrations63

Probenecid

Decreased renal tubular secretion of penicillinase-resistant penicillins and increased and prolonged plasma concentrationsa

May be used to therapeutic advantage

Rifampin

In vitro evidence of indifference or synergism against S. aureus with low penicillinase-resistant penicillin concentrations and antagonism with high concentrationsa

Possible delay or prevention of emergence of rifampin-resistant S. aureusa

May be used to therapeutic advantage

Tetracyclines

Possible antagonism1 a

Concomitant use not recommended1 a

Unipen Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following IM injection; peak serum concentrations attained within 30–60 minutes.1

Distribution

Extent

Distributed into synovial,10 pleural,10 pericardial,10 and ascitic fluids.10 Also distributed into liver,30 bone,30 and bile.13 18 30 70

Only low concentrations attained in CSF; concentrations in CNS generally are higher when meninges are inflamed.10 13 21 23 28 42 70

Crosses the placenta.10 31 70 Like other penicillins, probably is distributed into milk.59

Plasma Protein Binding

70–90%.3 4 13 15 16

Elimination

Metabolism

Approximately 60% of a dose metabolized in the liver to inactive metabolites.10 27

Elimination Route

Eliminated mainly via bile; undergoes enterohepatic circulation.26 Only small amounts eliminated in urine.10 13 26 27 33

About 27–31% of an IM or IV dose is eliminated in urine as unchanged drug and active metabolites within 12 hours.12 33 70

Half-life

Adults with normal renal and hepatic function: 0.5–1.5 hours.13 17 33

Children 1 month to 14 years of age: 0.75–1.9 hours.23 25

Neonates: 2.2–5.5 hours in those ≤3 weeks of age and 1.2–2.3 hours in those 4–9 weeks of age.24

Special Populations

Serum concentrations may be higher and half-life slightly prolonged in patients with impaired renal function.10 26 33 Serum half-life is 1.2–1.9 hours in patients with Clcr 3–59 mL/minute per 1.73 m210 13 22 26 33 and 1.8–2.8 hours in those with Clcr <3 mL/minute per 1.73 m2.33

Stability

Storage

Parenteral

Powder for Injection

Solutions containing 250 mg/mL prepared using sterile water for injection, bacteriostatic water for injection, or 0.9% sodium chloride injection are stable for 3 days at room temperature, 7 days when refrigerated, or 90 days when frozen.1 Solutions containing 10–200 mg/mL are stable for 24 hours at room temperature, 7 days when refrigerated, or 90 days when frozen.1

Injection (Frozen)

-20° C or lower.63 Thawed solutions of the commercial frozen injection stable for 72 hours at room temperature (25°C) or 21 days at 5°C.65

Do not refreeze after thawing.63

Compatibility

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

Parenteral

Solution CompatibilityHID

Compatible

Alcohol 5% in dextrose 5%

Dextran 40 10% in dextrose 5%

Dextrose 5% in Ringer’s injection

Dextrose 5% in half-strength Ringer’s injection, lactated

Dextrose 5% in Ringer’s injection, lactated

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

Dextrose 5 or 10% in water

Dextrose 10% in sodium chloride 0.9%

Ionosol T with dextrose 5%

Normosol M of R in dextrose 5% in water

Normosol M, 900 cal

Normosol R

Normosol R, pH 7.4

Polysal M in dextrose 5% in water

Ringer’s injection

Ringer’s injection, lactated

Sodium chloride 0.9%

Sodium lactate (1/6) M

Drug Compatibility
Admixture CompatibilityHID

Compatible

Chloramphenicol sodium succinate

Chlorothiazide sodium

Dexamethasone sodium phosphate

Diphenhydramine HCl

Ephedrine sulfate

Heparin sodium

Hydroxyzine HCl

Lidocaine HCl

Potassium chloride

Prochlorperazine edisylate

Sodium bicarbonate

Sodium lactate

Incompatible

Ascorbic acid injection

Aztreonam

Bleomycin sulfate

Cytarabine

Gentamicin sulfate

Hydrocortisone sodium succinate

Methylprednisolone sodium succinate

Variable

Aminophylline

Verapamil HCl

Vitamin B complex with C

Y-Site CompatibilityHID

Compatible

Acyclovir sodium

Atropine sulfate

Cyclophosphamide

Diazepam

Enalaprilat

Esmolol HCl

Famotidine

Fentanyl citrate

Fluconazole

Foscarnet sodium

Heparin sodium

Hydromorphone HCl

Magnesium sulfate

Morphine sulfate

Nicardipine HCl

Perphenazine

Propofol

Theophylline

Zidovudine

Incompatible

Droperidol

Labetalol HCl

Midazolam HCl

Nalbuphine HCl

Pentazocine lactate

Verapamil HCl

Variable

Diltiazem HCl

Meperidine HCl

Vancomycin HCl

Actions

  • Based on spectrum of activity, classified as a penicillinase-resistant penicillin.4 5 8 59 70

  • Usually bactericidal.1

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

  • Spectrum of activity includes many gram-positive aerobic cocci , some gram-positive bacilli, and a few gram-negative aerobic cocci; generally inactive against gram-negative bacilli and anaerobic bacteria.a Inactive against mycobacteria, Mycoplasma, Rickettsia, fungi, and viruses.a

  • Gram-positive aerobes: active in vitro against penicillinase-producing and nonpenicillinase-producing Staphylococcus aureus and S. epidermidis, S. pyogenes (group A β-hemolytic streptococci), S. agalactiae (group B streptococci), groups C and G streptococci, S. pneumoniae, and some viridans streptococci.a Enterococci (including E. faecalis) usually resistant.a

  • Like other penicillinase-resistant penicillins, nafcillin is resistant to inactivation by most staphylococcal penicillinases and is active against many penicillinase-producing strains of S. aureus and S. epidermidis resistant to natural penicillins, aminopenicillins, and extended-spectrum penicillins.8 10 59 70

  • Staphylococci resistant to penicillinase-resistant penicillins (referred to as oxacillin-resistant [methicillin-resistant] staphylococci) are being reported with increasing frequency.a Complete cross-resistance occurs among the penicillinase-resistant penicillins (dicloxacillin, nafcillin, oxacillin).a

Advice to Patients

  • Importance of discontinuing nafcillin and notifying clinician if evidence of hypersensitivity occurs.1

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

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

  • Importance of informing patients 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.

Nafcillin Sodium in Dextrose

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection

1 g (of nafcillin)

Nafcillin Sodium for Injection

Sandoz

2 g (of nafcillin)

Nafcillin Sodium for Injection

Sandoz

10 g (of nafcillin) pharmacy bulk package

Nafcillin Sodium for Injection

Sandoz

For injection, for IV infusion

1 g (of nafcillin)

Nafcillin Sodium for Injection ADD-Vantage

Sandoz

2 g (of nafcillin)

Nafcillin Sodium for Injection ADD-Vantage

Sandoz

Injection (frozen), for IV infusion

20 mg (of nafcillin) per mL (1 g) in 3.6% Dextrose

Nafcillin Sodium in Iso-osmotic Dextrose Injection Galaxy

Baxter

20 mg (of nafcillin) per mL (2 g) in 3.6% Dextrose

Nafcillin Sodium in Iso-osmotic Dextrose Injection Galaxy

Baxter

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

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3. Neu HC. Penicillins: microbiology, pharmacology, and clinical use. In: Kagan BM, ed. Antimicrobial therapy. 3rd ed. Philadelphia: WB Saunders Company; 1980:20-34.

4. Rolinson GN, Sutherland R. Semisynthetic penicillins. Adv Pharmacol Chemother. 1973; 11:152-220.

5. Marcy SM, Klein JO. The isoxazolyl penicillins: oxacillin, cloxacillin, and dicloxacillin. Med Clin North Am. 1970; 52:1127-43.

6. Barza M. Antimicrobial spectrum, pharmacology and therapeutic use of antibiotics. Part 2: penicillins. Am J Hosp Pharm. 1977; 34:57-67. [PubMed 318800]

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8. Selwyn S. The mechanisms and range of activity of penicillins and cephalosporins. In: Selwyn S, ed. The beta-lactam antibiotics: penicillins and cephalosporins in perspective. London: Hodder and Stoughton; 1980:56-90.

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31. O’Connor WJ, Warren GH, Edrada LS et al. Serum concentrations of sodium nafcillin in infants during the perinatal period. Antimicrob Agents Chemother. 1965:220-2.

32. Grossman M, Ticknor W. Serum levels of ampicillin, cephalothin, cloxacillin, and nafcillin in the newborn infant. Antimicrob Agents Chemother. 1965:214-9.

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36. Couchonnal GJ, Hinthorn DR, Hodges GR et al. Nafcillin-associated granulocytopenia. South Med J. 1978; 71:1356-8. [IDIS 105439] [PubMed 715483]

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41. Tilden SJ, Craft JC, Cano R et al. Cutaneous necrosis associated with intravenous nafcillin therapy. Am J Dis Child. 1980; 134:1046-8. [IDIS 127887] [PubMed 7435462]

42. Richards ML, Prince RA, Kenaley KA et al. Antimicrobial penetration into cerebrospinal fluid. Drug Intell Clin Pharm. 1981; 15:341-68. [IDIS 130577] [PubMed 7023900]

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