Antistaphylococcal Penicillins

Symposium on Antimicrobial Therapy

Antistaphylococcal Penicillins Hamld C. Neu, M.D.*

The first antistaphylococcal pcnicillin was penicillin G, but by the mid 1950's more than 50 per cent of hospital isolates of Staphylococcus aureus were resistant to penicillin G, and the tetracyclines, chloramphenicol, and erythromycin had failed in the therapy of serious staphylococcal infections. The scientists at Beecham Laboratories at the end of the 1950's were able to isolate the 6-aminopenicillanie acid nucleus' and produced shortly the first semisynthetic penicillin, methicillin, which was penicillinase resistant. Subsequently a number of other semisynthetic penicillins have been produced. These include the isoxazolyl penicillins-oxacillin, cloxacillin, dicloxacillin, and flucloxacillin-and three other agents, nafcillin, diphenicillin, and quinacillin, of which only nafcillin is used. Mechanisms of Action and Resistance. All penicillins interfere with cell wall biosynthesis. The antistaphylococcal penicillins bind to specific proteins, transpeptidases, which complete the linkage of the amino acids connecting parallel chains of polysaccharides which make up the cell wall:" Failure to complete the cell wall results in total cell lysis due to the increased osomotic pressure with the grampositive bacteria. The antistaphylococcal penicillins resist hydrolysis by the exocellular l3-lactamase which is produced by S. aureus and S. epidermidis." Some S. aureus and S. epidermidis, however, are resistant to methicillin and to the rest of this class of compounds. The mechanism of resistance appears not to be that of l3-lactamase, but rather appears to be due to failure to bind to penicillin-binding proteins. Fortunately this form of resistance, methicillin-resistant S. aureus, is uncommon-lO per cent of bacteria nationwide. In contrast, it is much more common in S. epidermidis and may reach 50 per cent of isolates in some institutions. Another mechanism of relative resistance is that described by Sabath and colleagues. 4o The mechanism of this socalled tolerance is unknown. It has been postulated to be due to the lack of certain hydrolytic enzymes which act stimulated by the cleavage products as a result of the penicillins. 47 The precise frequency of tolerance is unclear since estimates range from 10 to 60 per cent of S. aureus isolates. The resistance of gram-negative species such as Neisseria, the Enterobacteriaceae, and Pseudomonas is due primarily to failure of the agents to pass through the outer wall of these species. The bulky side-chains of the agents which on the one hand stabilize the molecules against hydrolysis by l3-lactamases hut on the other hand prevent movement through porin protein channels to receptor penicillin-bind*Professor of Medicine and Pharmacology, Columbia University College of Physicians and Surgeons, New York, New York

Medical Clinics of North America-Vo!. 66, No. 1, January 19H2

51

52 ing proteins. Furthermore, the affinity of these agents f(Jr penicillin-hinding proteins is relatively low. In some of the gram-negative species, plasmid-mediated j3-lactamases, Oxa-l, Oxa-2, Oxa-3, do hydrolyze the cornpounds.:\1) These enzymes are of importance primarily because the antistaphylococcal j3-lactamases act as effective inhibitors of a number of the chromosomally mediated and some plasmid-mediated j3-lactamases. Clinical use of this j3-lactamase inhihitory action has been thwarted by their poor entry properties, and the use of these agents as j3-lactamase inhibitors has worked only in treatment of selected urinary tract infections caused by P. aeruginosa. Development of other semisynthetic agents and lIew j3-lactamase inhibitors such as clavulanic acid and penicillanic acid suifc)lle has relegated these j3-lactamase inhibitory properties to that of interest only. In Vitro Activity. There are differences in the in vitro activity of these agents against S. aureus and against other bacteria as is illustrated in Table 1. Penicillin G is given as a referenee compoulld to provide comparison. Methicillin is less active on a fLg/ml basis against staphylococci than are the other agents. The minimal inhibitory concentrations (MICs) of all the compounds are quite similar if the in vitro studies are performed in the presence of normal human serum; that is, there is no increase in the methicillin MIC, whereas that of dicloxacillin for example will inerease ten-fc)ld. 4.11.1H 20.2:l.:lf! The agents also inhibit Streptococcus pyogenes, hut at much higher concentrations than penicillin G does. The samc is less true h)r S. pneumoniae. But nafCillin has a mean MIC of 0.06 fLg/ml fc)l' S. pneumoniae .20 The mean MICs of the compounds against N. gonorrhoeae are 3 fLg/ml, and against H. injluenzae, 50 fLg/ml. Owing to the high protein binding of the agents (see helow) , the levels of free drug are inadequate to inhibit these organisms. None of these agents truly inhihits the true enterococci, S. faeclllis or S. faecium. However, it is interesting to note that the MIC of nafcillin for enterococci is

Table 1.

Comparative in Vitro Stud!1 of Antistaphylococcal Penicillins* Minimal Inhibitory Concentrations (fLglml)

S. aureus, penicillinasenegative S, aurcus penicillinast'positive S. pyogcncs S, viridalls S. faecalis S. pneumolliae

N. gonorrhoeae, penicillinasenegative N, meningitidis H. influcnzae, penicillinase-

negative

PENI-

METHI-

CILUl\ (;

Cl LLI \I

OXACILUI\:

CLOXA-

DILLOX.'\.-

FLlICI.OXA-

CILU:'\I

CILLI\I

CILUI\:

N;\F(;IIJ.JN

0.2

1.0

0.4

0.2

0.1

0.2

0.1

>100

2.0

0.'1

0 ..0

0.1

0.4

0.2

0.0,0 0.1 3 O.S 0.4

0.2 0.8 >100

0.1 0.4 >2,5 0.2 H

0.1

0.1

0.1

>25 0.2 8

>2,5

>25 0.2 H

0.1 0.8

0.1 1

1 25

H 50

8 50

0.4 4

1.(;

16

0.2 H

H

50

16

H SO

H

0.1 4

4 50

ANTI STAPHYLOCOCCAL PENI<:ILLlNS

53

less than 10 f.Lglml, and thus on occasion nafCillin would inhibit organisms in urine or blood when given at high doses intravenously. 10 Activity of the agents against the Enterobacteriaceae and nonfermenting organisms is inadequate, MICs being greater than 100 f.Lg/ml. Anaerobic coccal and bacillary gram-positive species, peptococci, peptostreptococci, and Clostridia arc inhibited. Bacteroides fragilis are resistant, as are other gram-negative anaerobic species. Synergy with Other Antimicrobial Agents. The antistaphylococcal penicillins have been shown to act synergistically with aminoglycosides against S. aureus .10.22.21 ..01 Synergy has been noted for reduction in hoth the minimal inhibitory ,md bactericidallevcls and in terms of a more rapid killing rate. Synergy of nafCillin and gentamicin or tobramycin against some enterococci has hecn demonstrated in vitro but no clinical examples are known. Rifampin has also been shown to act synergistically with oxacillin and nafcillin, hoth in vitro and in animal models of infection. 4R Pharmacology. There are marked differences in the oral absorption, serum levels after parenteral administration and excretion of these drugs which have similar in vitro activity (Tahle 2).2" Methicillin is not acid stable, and thus is ineffective hy the oral route. The oral absorption of oxacillin is less than that of the other isoxazyl penicillins and the oral absorption of nafcillin is erratic whether taken with or without food. Each agent will be considered individually, hut Tahle 2 provides comparative data. Absorption. Methicillin, after an intramuscular dose of 1 gm, will produce mean peak hlood levels of 16 f.Lglml at 30 minutes with levcls of 1 to 1.5 f.Lg/ml at 4 hours and none detectable at 8 hours. With a 2 gm dose, peak levels of 25 f.Lg/ml are present at V2 and 1 hour after injcction, with levels of 3 to 7 f.Lg/ml at 4 hours and 1 f.Lg/ml at 8 hours. Administration of probenecid increases the serum values primarily at later time periods so that a level of 4 f.Lg/ml would be present 6 hours after a 2 gm 1Nl dose, compared to a level of 1.5 f.Lg/ml without probcnecid. Peak serum levels after holus (5 minute) injection of 1 gm are 60 f.Lg/ml. Infusion of 1 gm over 15 minutes will produce a serum level of 32 f.Lg/ml, and infusion of 2 gm, a levcl of 80 f.Lg/ml. At 2 hours the serum levcls are only 2 f.Lglml for the 1 gm dose and 5 f.Lg/ml for the 2 gm dose. The serum levels of the isoxazolyl penicillins after oral administration are markedly differene2.16.17.ls.32.3h.12.H (Table 2). For example, the mean 1 hour blood level after 500 mg of oxacillin is 4 f.Lglml, 6 f.Lg/ml for cloxacillin and 11 f.Lg/ml for dicloxacillin. At 2 hours scrum levels are 1 f.Lg for oxacillin, 5 f.Lg for dox
54

c.

HAHOLD

Table 2.

NEll

Pharmacologic Properties of Anti-staphylococcal Penicillins METIlI-

PR(H'ERTY

C1LIJl\"

Oral absorption, per cent

()XACILLI:,\

Cl,OXA-

DlCLOX ..\.-

FLUCLOXA-

CILLI~

CILLI:"I

CILLIl'\

I\'AFCiLLlN

++

++

50

50-70

10-20, erratic

45

20

10

10

60

4"

6u

12"

12'

11"

80

30

50

65

50

30

0.5

0.5

0.5

0.6

0.7

0

1-2

1-2

1-2

+

++

None

Effect of food Protein binding, per cent

30

50

++++

++

++++

35 91 93 97 93 87 Metabolized, per cent Peak serum level, fLwml 500 mg 1000 mg 2000 mg Excretion, per cent

Serum TV" hr Normal C,., >90ml Renal failure C" <10 ml Liver impairment Effect hemodialysis Dose renal failure C" 20-50 ml C" <10 ml

10

60" 80'

4

++

+

+

1.5

Nil

Nil

Nil

Nil

Nil

Nil

None

None None

None None

None None

None None

None None

ZW8h

'Oral; "IV bolus; 'IV infilsion

dicloxacillin and flucloxacillin are prolonged so that drug is still present in the serum 6 hours after injection. 37.44 Nafcillin produces lower serum levels after intramuscular injection than do the other agents, 1.3 After 500 mg the level is 6.5 fLglml and at 6 hours 1 fLglml. Following intravenous infusion of the isoxazolyl penicillins serum levels at the end of 15 minutes are 70 to 100 fLglml with levels of 25 fLglml at one hour and levels less than 1 fLglml at 6 hours. Serum levels after intravenous administration of cloxacillin and dicloxacillin are greater. These agents are not available for intravenous use in the United States. Nafcillin given intravenously produces levels of 11 fLg/ml at the end of infusion and levels of 0.5 fLg/ml at 6 hours after a dose of 500 mg. Serum levels of oxacillin, cloxacillin, dicloxacillin, and nafcillin are higher in patients with renal failure, not only due to decreased excretion, but because thcre is appreciably more free drug present because of hypo album inemi a and the presence of substances which decrease the binding of these agents to serum proteins. 27,

ANTISTAPHYLOCOC(:AI. PENICII.LIKS

55

Metabolism and Excretion. !vlethicillin, oxacillin, cloxacillin, dicloxacillin, and flucloxacillin are excreted primarily in the urine in the active, unchanged form. 12. lfi. 17,12,:)". '2,1' They are excreted hy both glomerular filtration and tubular secretion. In the case of isoxazolyl drugs some biologically active metabolites are formed. Under normal conditions this is less than 10 per cent of the drug, but rises in the patients with markedly depressed renal function. Larger amounts of cloxacillin, dicloxacillin, and flucloxacilIin are excreted after oral administration than is oxacillin bccause of better absorption. Urine levels after parenteral administration of the drugs are similar. Urinary concentrations after doses of 1 gm exceed 1000 f.LgI ml for several hours. Oxacillin is metabolized to a greater extent than are the other isoxazolyl agents with flucloxacillin, the least metabolized of the group. 6 In contrast to the other agents of this class, nafcilIin is excreted to a lesser degree in the urine with only 30 per cent recovered after an intravenous or intramuscular dose. ,oD,'>:) The majority of the drug is inacti~ated in the liver with perhaps 10 per cent excreted in the bile. The biliary excretion of methicillin and the isoxazolyl penicillins is low. Distribution. All of the agents are widely distributed in various body fluids. 28 ,43,46..>2 Antibacterial levels in pleural, pericardial, ascitic, and joint fluids reach a level equivalent to the serum levels 2 hours after injection. Levels in bone are adequate to eradicate staphyloeocci. tU6 The drugs are excrcted in breast milk and cross the placenta. The drugs do not achieve levels in normal ecrebrospinal fluid. In the presence of inflammation, cerebrospinal fluid levels are extremely variable. Levels in brain pus also have been variable. Levels of nafciIlin in cerebrospinal fluid have been reported to be higher than those achieved with the other antistaphylococcal penicillins. 'I,," Levels of 8 to 88 f.Lg/ml have been reported. All of these drugs' are bound to serum proteins, The range of reported values of serum protein binding are enormous due to differences in techniques utilized to determine protein binding. :)",14 Clearly methicillin is the least protein bound (17 to 43 per cent); whereas, oxacillin is 90 to 93 per cent bound, cloxacillin and flucloxacillin 94 per cent and dicloxacillin the greatest bound at 97 to 98 per cent. NafCiIlin is 87 per cent protein bound. The amount of binding is least when the serum levels are high and greatest at low concentrations. This binding could mean that a serum level of 20 f.Lg/ml for dicloxaeillin could represent 0.6 f.Lg/ml of free drug compared to a total serum level of cloxacillin of 10 f.Lg/ml also yielding 0.6 f.Lg/ml ofiree drug. The precise meaning of protein binding of drug is unclear. Only free drug is able to inhibit bacteria.,),,3,' The protein-bound drug may actually be a reservoir that releases more drug as the drug is excreted or metabolized beeause the binding of the drug to protein is rapidly reversible. Highly protein-bound drugs do not difiilse well into fibrin clots or into skin blisters. In contrast to the problem entering clots,:) the high binding of the drugs to proteins may provide tissue reservoirs when they are administered perioperativeiy since the seromas formed at surgery will contain drug which gradually comes free. This is demonstrated by their much greater half~ life in clots. Pharmacology in Special Situations. In the newborn the peak serum levels of these drugs are lower on a mg per kg basis than in children owing to the larger extracellular spaee in the newborn and premature infant. 26 Serum half-lives in the newborn are longer than those in children or adults, requiring administration of the agents at greater intervals to avoid accumulation. By 2 weeks of life, the serum half-

56

HAHOLD C. NEt!

life of these agents approaches that of oldcr children providcd the inhmt is not of extremely small size, <2000 gm at birth. In contrast to the neonate, the child with cystic fibrosis clears thcse drugs more rapidly than do normals. 2(; ..33 The serum levels are lower for all of the drugs. For example, cystic fibrosis patients eliminatc dicloxacillin 3 times faster than normal subjects. 13 Thus these patients necd to rcceive larger doses than do other patients to achieve comparablc serum and tissue levels. These drugs accumulate in the presence of renal failure to a lesser degree than do some of the other agents. I • 3. 2'.27 :v1ethicillin does not tend to accumulate until renal clearance is below 10 to 15 mllmin since it is metabolized and excreted via the biliary system. Of the isoxazolyl penicillins, accumulation of oxacillin is least since it is the most metabolized. Nafeillin does not accumulate even in anuria, and the half-life is identical in normals and anuric patients so dosage is identical in both groups. Hemodialysis does not appreciably alter the elimination rate of the isoxazolyl penicillins.2.3.27 ..19 There also is minimal removal of the drugs by peritoneal dialysis (Table 2). Untoward Reactions. Untoward reactions to this group of drugs is relatively infrequent (Table 3). All of these drugs can produce hypersensitivity reactions which can be either of the immediate or delayed types ..36 Anaphylaxis is much less common than with penicillin G. Skin rashes are less frequent with these agents than they are with ampicillin. Fever has been reported to follow the use of these drugs. It is most frequent with methicillin.

Table 3.

Adverse Reactions to AntistaphyZococcaZ Penicillins ACENT \IOST FREQCEKCY

FREQUEYfLY REP()In'ED

Rare 2-3%

2-3%

Any Methicillin None \1ethicillin

Gastrointcstinal Diarrhea Enterocolitis

<5% Rare

Cloxacillin Any

Hcmatologic Neutropenia

1-3%

Oxacillin Nafcillin

Hepatic abnormalities Elevated transaminases

<.5%

Oxacillin Nafcillin Oxacillin

Rare

Oxacillin \1ethicillin

REACTION

Allergic Anaphylaxis Skin rash Serum sickness Fever

Nont'

Cholestatic hepatitis Neurologic Seizures

Rcnal Interstitial nephritis

\1cthieillin

ANTISTAPHYLOCOCCAL PENICILLII\S

57

Gastrointestinal side-effects of the use of the drugs have occurrcd most oftcn with oral preparations but arc infrequcnt. Antibiotic associated pseudomembranous cnterocolitis has occurred. Hematologic complications of the use of these drugs have been primarily lcukopenia. 2 l.41,56 It has been noted with all of the agents. There have been absolute neutropenia and dcereases in total white cell count. The phenomenon seems in part to be dose related. Agranulocytosis has been reported, but in most instances the white cell count returns to normal with cessation of therapy. Substitution of onc drug for another, for example, oxacillin for methicillin, has resulted in return of neutropenia. Platelet dysfunction is rare, Eosinophilia has followed the use of all of the drugs. Abnormality of hepatic enzymes has followed use of all of the drugs, but seems to have been reported most often for oxacillin.; Elevation aspartic transaminases occurs and most individuals are not icteric. Reversible cholestatic hepatitis has been reported. Liver function test abnormalities rapidly return to normal whcn drug is stopped. Electrolyte disturbance is infrequent since doses rarely exceed 12 gm per day in adults and the drugs contain only 1.7 to 1,8 mEq of sodium per gram, They also do not usually cause hypokalemia. Neutrotoxicity can occur with these agents, albeit less frequently than with penicillin G, If very large doscs arc given to patients who are in complete renal failure, convulsions may ensue. It has not been reported for nafcillin, Nephrotoxicity is the most frequent toxicity seen with these drugs and it has most often followed use of methicillin. UJ The reaction clinically is characterized by fever, rash, eosinophilia, hematuria, proteinuria, eosinophiluria, and ultimately renal insufficiency, Pathologically the process is that of interstitial nephritis with normal glomerular structure. Although the condition has occurred with use of all of the penicillins, it is clear that the cases of methicillin predominate. The precise mechanism of the injury is unknown and attempts by our group to develop a satisfactory animal model have to date proved unsuccessful. In the majority of cases, renal function returns to normal when the drug is discontinued, Substitution of another penicillin to complete therapy has resulted in return of damage, Methicillin also can produce a hemorrhagic cystitis. The etiology of this reaction of the bladder is unknown, Clinical Use. All of these drugs are indicated only for the treatment of proven or suspected staphylococcal infections due to J3-lactamase-producing isolates. 51 Since fully 90 per cent of hospital-acquired staphylococci and more than 70 per cent of community-acquired staphylococci arc J3-laetamase-positive, these agents should be started in preference to penicillin. H The types of infections treated have been pneumonitis, sepsis, endocarditis, meningitis, brain abscess, osteomyelitis, septic arthritis, and soft tissue infections and renal abscesses. Methicillin was the agent primarily used parenterally in the 1960's, but in recent years it has been replaced in the United States by nafcillin or oxacillin and in Europe by cloxacillin. Oral use has been with cloxacillin or dic!oxacillin in the United States and with flucloxacillin or cloxacillin in Europe. Whether comhination therapy of these antistaphylococcal penicillins with aminoglycosides such as gentamicin will result in greater or more rapid curcs has not been established. Similarly, use of agents such as nafcillin or oxacillin with rifampin to treat the tolerant staphylococci has not been clinically established evcn though

58

I1.\I\()LD

C.

NEll

there is data from in vitro studies amI animal expcriments whieh would support this type of program. Dosage. Mcthicillin is available as a sodium salt in 1, 4, and 6 gm vials which can be diluted witb sodium chloride or dextrose in water. When dilntcd buffered solutions are stable at room temperature felf S hours. It is preferable in view of its short half-life to administer the drug every 4 to 6 hours. Doses are 100 mglkglday and 100 to 300 mglkg/day. Doses to infants less than one week are 100 mg/kg/day given as doses 12 hours apart. Natdllin is available as 1, 2 and 4 gm vials as a sodium salt that is stable in most solutions for 4 hours at room temperature. Dosage to adults are 100 mg/kglday IM and 100 to 300 mg/kg/day IV. Dosage to infants under one week of age is 100 mgl kg/day given as two doses 12 hours apart. Oxacillin is available in the same size vials and should be given in a similar way. Cloxacillin and dicioxacillin are available as capsules and as oral suspension. Doses of cloxacillin are 25 to 100 mglkg/day in f(lllr doses and 12 to 25 mg/kg/day in four doses. Doses as large as 6 gm per day can be given to adults to treat osteomyelitis and endoearditis in patients in whom there is no venous aecess.

REFERENCES 1. Appel, G. B.. and Nell. H. C.: The nephrotoxicity of antilllicrobial agents. N. Engl. J. ',.led .. 296:fifi3. 1977. 2. Bachelor. F. R.. Doyle. F. P .. Naylor. J. 11. C .. et al.: Synthesis of penicillin: (i.alllinopellicillanic acid in penicillin fennentations. Nature, 183:2,57. 1959. 3. Barza, M., Samuelsoll, T., and \Vcinsteill, L.: Penetration of alltibiotics into fibrill loci in vitro. ]1. Comparison of nine antibiotics: Effect of dose and cl<-'grec of protein hindillg. J. Inkct. Dis, 12,9:66, 1974. 4. Bergeron. M. G .. Brush. J. L.. Barza. M .. et al.: Bactericidal activitv and pharlllacology of flucloxacilliu. Am. J. Med. Sci .. 271:13. ]97(i. 5. Bulgcr. H. J.. Lindholm, D. D .. ~Inrrav, J. S .. et al.: Efkct ofllrcnlia on methicillin awl oxacillin blood levels. JA tvI.A .• 187:319. UJ(i4. 6. Colc, ~'1., Kening, M. D., and Ht'\vitt, V. A.: ~Ietabolism of penicilHns to penicilloic acid and 6amiIlopcnidllanic acid in mm) and its signincanc(' ill asscssillg penicillin ahsorpti(m. Antimicrol). Agents Chemother.. 3:403. 1973. 7. Dismukes. w. E.: Oxacillin·indueed hepatic dysillllctiotl. J.A.M.A .. 226:861.197:3. 8. Finland. M.: Emcrgence of antibiotic resistance in hospitals. J!J:3.5-1975. Hev. Inke!. Dis .. 1 :4-21. 1979. 9. Galpin. J. E .. Shina),erger, J. H .. Stanky. T. M .. et al.: Acute interstitial nephritis dill' to methicillin. Am. J. Med., 65(,5):756. 197K. 10. Clew, H. H., :\1oeUerillg, R. C., Jr., and \VcllnersteIl, C.: COlllparative studies of acth'ity of nafdlliIl, oxadlllin and methicillin in comhinatioll with gentalllicin against enterococel. Antilllicrob. Agents Chl'lIIother.. 7:828, 1975. 11. Gravenkcnper, C. F., Benndt, .I. V., Brodie, J. L., et a!.: Dit"loxacillin-in vitro aIld phannacologic comparisons with oxacillin and cloxacillin. Arch. Intern. ~lcd., 116:340. 1965. 12. Hammerstrom, C. F., Cox, F., McHcnry, M. C., et al.: (;Iinical, lal)()ratory allt! phannacological studi<'s of dicloxaeillin. Antimicroh. Agents Chelllother .. 19G(i, p. 67, 19(i7. 13. Jllsko, \V. L., \losovich, L. L., Cerbracht, L. ~1., et a1.: EnhalH_'{·d renal t'XcITtion of dicloxacillill ill paticllts with cystic fibrosis. Pcdiatrics, 56: 1038, 1!17,S. 14. Kane, J. G., Parkcr, H. H., Jordon, G. \V., et al.: Naft·illin COIH.'cntrations in cerebrospinal ({uid during treatmcnt of staphylococcal illfections. Allll. Interll. ~'1l'd., 67::30!1, 1977. 15. Kind, A. C., Tupasi. T. E.. Standiford. H. C" et al.: MechaJlisms responsible f(JI' plasma levels of nafcillin lower than those of oxacillin. Arch. Intern. ',.I('d., 12.5:6/),5, 1970. 16. Kirby. W. M. M., Hosenfeld. L. S .. and Brodi,'. ./.: Oxacillin. Laboratory and c1iJlical ('\·aluatioJl. ].A.M.A .. 181:739, ]962. 17. Kisla, J. \\T., Eickhoff: T. C., aJld Finland, :\'1.: Cloxacillin, activity in vitro and absorption and urinary excretion ill normal young 1fH'11. Am. J. :\'led. Sci., 249:6:36, 1965.

AKTISTAPIlYLO( :OCCAL PEK I( :11.LlKS

J.

0., Finland, :\-1., and \Vilcox, C.: Nafcillin. Antihacterial actioll ill vitro and absorptioIl and J. \tied. Sci., 240':10, 1963. Knox. It. l\laclearen. D. 'vI.. Smith, }. T., et aL BilL lfi21, a comparison with other isoxazolyl penicillins. Brit. Med. }., 2:R31, 1962. Lane, W. H.: Nakillin, a comparative in vitro trial. 'vied. }. Aust., 246:11. 1964. Leventhal, J. 'vI., and Silken, A. B.: Oxacillin-induced neutropenia in childreu. J. Pediat., 89:769, 1976. Lincoln, L. J., \Veinstcin, A. J., Gallagher, M., et a1.: Penicillinase rcsisbmt penicillins pIllS gentamicin in expcrillll'lItalentcrococcal elldoc:trditis. Antimicrob. Agents Chelnothcr., 12:4H4, 1977. Marcy, S. M .. aud Kkin, }. 0.: The isoxazolyl penicillin: Oxacillin, e10xacillin and dicloxacillin. Med. Clin. N. Am., 54:1127, 1970. Marier, H. L., Joyce, N., and Andriole, V. T.: Synergism of oxacillin and gCIltamiLin against enterococci. Anlimicroh. Agents Clwlllother., 8:571, 1975. McCloskey, H. V., and Hayes, C. P .. }r.: Plasma levels of dicloxacillin in olignrie patients and effect on hemodialysis. Antimicroh. Agents Chelllothcr., 1966, p. 770. 1967. !\'icCrackcIl, G. H., Jr.: Pharmacological hasis for antimicrohial therapy illlH'whorn inbnts. AIIl. J. Dis. Child .. 128:407, 1974. Nauta, E. H., 'vlattie, H.: Pharmacokinetics of fiuc\oxacillill and cloxacillin in lwalthv snbjeds and patients 011 chronic intermittent hemndialysis. Brit. J. Clill. Pharm., 2:111, 197,5. Nelson,}. D.: Antibiotic concentrations in septic joint eflilsions. N. Engl. }. Med., 284::349, 1971. Ncn, 11. c.: Th" pellieillins. N.Y. State J. ~Ied., 77:7IiH, 1977. Neu, H. C.: Antibiotic inactivating enzymes aud bacterial resistance. In Loriall, V., ed.: Antihiotics in Laboratory Medicine. Baltimore, Williams & Wilkins, WHO, p. 43:3. Neu, H. (;.: Mechanisms oflJadcrial resistance to antimicrobial agents. Hev. IJlft.~ct. Dis. (ill press). 0(', P. L., Silllollian, S., and Verhoef, J.: Pharmacokinetks of the lI('W pCllicillil1S. CheJllotherapy, 1.9:279, 1973. Richmond, M. H.: Purification and properties of the t'xopcnicillinase from Staplqllococcus aureus. Bioc\l<'JJl . .I .. 88:452, 196:3. Rolinson, G. N.: The significancc of protein hinding of antibiotics in vitro and in vivo. In \Vaterson, A. P., (cd.): Hccent Advances in '\Iedical 'vlicrobiology. J. & A. Churchill Ltd., 1967, p. 254. Rolinsoll, G. N., and Slltherland, R.: The binding ofantil)i()tics to serUl1l proteins. Brit. J. Pharmacol., 2S:b3H, 196.5. Holinson, It N .. and Sntherland, R: SPlllisynthetic penicillins. Adv. Pharm. CIH'JJlotlwr., 11:1152, 1973. Rosenhlatt, }. H.. Kind, A. C, Brodie. J. L., et a1.: Mechanisms responsihle f,)r thc blood level differences ofisoxazolyl pcnicillins. Arch. Intern. Med., 121:345. 1%8. Ruiz, D. E., and \Varncr, D. F.: Nafdllill treatment of Staphylococcus (lurells meningitis. Antimicrob. Agents Chclllother., 9:554. 1976. Sabath, L. D., Carncr, C., \Vileox, C., et al.: Effect of inocululll ;;md of hda-ladalll
lH. Klein,

excretioll in normal young men. Am.

19. 20. 21. 22. 23. 24.

25. 26.

27. 2H. 29. 30. 31. 32. 33. 34.

3,1). 36. 37. 38. 39. 40. 41.

42. 43. 44.

45. 46. 47. 48.

49. 50. 51.

52.

60

HAHOLJ) C. NE\,

53. Whitehollse, A. C., Morgan, .I. D., Schumacher, .I., et a!.: Hlood levels and antistaphylococcal titers produced in human subjects by a rWlli('illillase~rcsistallt penicillin, nafi::illill, ('olllpared with similar penieillins. Antimieroh. Agcnts Chclllother., 1962, p. :384, 1963. 54. \Vise, H. L.: Modern management of severe staphylococcal disease, Medicine, 52:295, HJ73. 55. Yalre, S . .I., Gcrllraeht, L. 1\1., ~1osovich, L. L., et a!.: Pharmacokinetics of methicillin paticllts with cystic fibrosis . .I. Infect. Dis., 135:828, 1977. 56. Yow, M. D., Taber, L. H., Harr"tt F. F., d a!.: A ten-year assessment of IIlcthieillin-associated side effects. Pediatrics, 58:329, 1976. Department of Medicine College of Physicians and Surgeons Columbia University New York, New york 10032