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Penicillin therapy
PENICILLIN THERAPY * WALTER S. PRIEST, M.D. CHICAGO,
ILLINOIS
T
HE discovery of penicilhn is usuaIIy described as accidenta1. But this is not entireIy true. For fifty years prior to Dr. AIexander FIeming’s recognition of the possibIe significance of the Iytic effect of a contaminant mold on an agar cuIture of staphyIococci, many bacterioIogists had observed this phenomenon. In rgoo, Emmerichl isoIated an antibacteria substance from BaciIIus pyocyaneus which was later found to check the growth of diphtheria baciIIi in vitro and to exert a favorabIe action on the clinica disease, However, the true importance of this phenomenon of antibiosis was overIooked for the time being. In September, 1928, while examining some agar pIates of staphIycoccus, Dr. FIeming, (a bacterioIogist at Oxford University) noted complete inhibition of growth in the neighborhood of a contaminant moId which he identified as PeniciIIium of the Notatum group.’ Had it not been for Dr. FIeming’s many years of interest and research in antibacteria agents, it is possibIe that the significance of this observation wouId have been overIooked. FoIIowing it up he found that the mold, grown on the surface of nutrient broth, produced in the broth a powerfu1 antibacteria substance. By rg32,3 he had demonstrated its action in vitro against Streptococci, Staphyand Corynebacterium diphtheriae and had Iocci, Pneumococci shown it to be non-toxic for animaIs and non-irritating to the human conjuctiva. He caIIed the substance PeniciIIin and suggested its use IocaIIy in cIinica1 infections caused by the above organisms. Strangely enough these suggestions were not foIIowed up until after Dubos in rg3g4 pubIished his observations on the antibacteria effect against Gram-positive cocci of an extract of a soi baciIIus. This work Ied to the deveIopment of tyrothricin and gramicidin and stimuIated Dr. H. W. FIorey, also of Oxford, to re-investigate peniciIIin and work out methods for its production and purification * From the Department of Medicine, Wesley MemoriaI Hospital and Northwestern University, Medical School, Chicago. Part of the PeniciIIin used on patients discussed in this paper was furnished by the Committee on Chemotherapeutics and Other Agents of the NationaI Research Council and part by the PeniciIIin Research Committee of Northwestern University Medical SchooI.
PRIEST-PENICILLIN
281
in order to make further clinica application possible. By 1941, he had accummated enough data on its potential chnical usefuhress to enabIe him, during a visit to the United States, to interest the NationaI Research Council and the Department of AgricuIture to undertake the studies of the moId’s growth characteristics and possibilities for Iarge scale propagation. To Dr. CoghiII and Dr. Mayer of the Northern RegionaI Research Laboratory at Peoria beIong much of the credit for this work. To the pharmaceutical houses, and manufacturers of bioIogicaIs and chemicaIs beIong the credit for the actua1 attempts at mass production. At first it was believed that the moId could be satisfactorily grown onIy in smaI1 amounts of nutrient media. This resulted in the type of production in which the moId is grown in individual flasks containing not more than two Iiters of media each. Recovery of 3,000 to IO,OOO units per flask was considered a good yield. ObviousIy it was physicaIIy impossibIe to produce enough by this method to suppIy both miIitary and civilian requirements. Intensive efforts on the part of mycoIogists, chemists and engineers connected with fermentation and commercia1 chemica1 industries resulted in the perfection of methods of growing the moId in submerged cuItures in huge tanks of broth or on bran. The increased production made possibIe by such methods is responsibIe for the civiIian avaiIabiIity of peniciIIin today. From 1941 to May 1st of this year cIinica1 and Iaboratory research on peniciIIin was under the direction of the committee on Drugs and Therapeutics of the NationaI Research Council. As indications of specific clinica usefuIness developed the miIitary forces requisitioned al1 but a very smaI1 amount of the tota production. That which was Ieft was aIIocated to seIected investigators throughout the country and from their studies have come our present knowledge of dosage, methods of administration, rate of absorption and excretion and cIinica1 appIications of the drug. As experience expands this knowIedge wiIl be extended and our present concepts may be modified. However, enough definite information is at hand to remind us that it is not a cure-a11 and the present tendency on the part of some cIinicians to use it in the treatment of everything just because it is now avaiIabIe is unworthy of men of science. Penicillin itself is an acid which reacts chemicaIIy to form saIts and esters. The sodium saIt is the one at present avaiIabIe, although UI37ll
282
PRIEST-PENICILLIN
caIcium barium and ammonium saIts have been used. The peniciIIin unit is an arbitrary measure based on a pIate assay method deveIoped by Dr. FIorey, and is referred to as the FIorey or Oxford unit. The pure saIt is coIorIess but to obtain it in this form is at present impractical and apparentIy unnecessary. The yeIIowish coIor of the commercia1 product is due to harmIess impurities and varies to some extent. This need cause no concern since freedom from toxicity and pyrogens, and a potency within 25 per cent of the stated IeveI is guaranteed by rigid requirements of the FederaI Drug Commission. Most products wiI1 actuaIIy assay higher than the potency indicated on the IabeI. Assays in our own Iaboratory of the product of severa manufacturers revealed onIy one instance of the converse of this. The sodium saIt is highIy soIubIe and markedIy hygroscopic, hence must be kept from contact with moisture unti1 ready for use and at a temperature around 5’~. Under these conditions potency is not affected for at Ieast three months. For so potent a therapeutic agent toxicity for man is practicaIIy ni1. We have given 500,000 units in IOO cc. of saIine intravenousIy in Iess than thirty minutes without significant reaction. Such dosage is stiI1 far beIow the toxic IeveI for animaIs in addition to being unnecessary for the treatment of any condition so far known to be amenabIe to peniciIIin. Rarely urticaria may deveIop during the administration of therapeutic amounts. If this occurs, treatment shouId be discontinued since an occasiona case of exfoIiative dermatitis has been observed. Rapid absorption and excretion is characteristic of the drug. Since it is destroyed by acid and organisms of the coIon group it cannot be given by mouth or rectum. Within five minutes or Iess after intravenous administration it appears in the urine and after a short Iag the rate of excretion paraIIeIs that of administration. ApproximateIy 60 per cent of the amount administered, whether a singIe ‘dose, muItipIe doses or continuous injection, is excreted by the kidneys. The fate of the remainder is not yet entireIy known. It has. been found in high concentrations in biIe thus suggesting its use in certain biIiary tract infections. It aIso appears in saIiva but not in tears or pancreatic juice. 5 Serum Ievels rise rapidIy after intravenous injection, somewhat more sIowIy after intramuscuIar and much sIower after subcutaneous injection. For a given singIe dose serum concentration is higher after intravenous injection
PRIEST-PENICILLIN
283
than by any other method. On the other hand, while serum concentration does not reach the same height after intramuscuIar injection the IeveI is maintained Ionger (thirty to forty-five minutes) and decreases more graduaIIy. FolIowing subcutaneous administration no peniciIIin appears in the bIood for an hour and a half to two hours and the maximum concentration is much the Iowest but, such as it is, remains the Iongest since excretion in the urine is proIonged. Since onIy traces are found in serum two and a haIf to three hours after a singIe intravenous or intramuscuIar injection, the method and frequency of administration become important in pIanning therapy. From the serum IeveI standpoint, continuous intravenous therapy is most desirabIe, and for severe infections, graveIy septic patients and in treating infections with organisms of Iow peniciIIin sensitivity this is the method of choice in our opinion. It has the obvious disadvantage of requiring fairIy close supervision by an inteIligent nurse and the prompt avaiIabiIity of resident physicians skiIIed in intravenous therapy. During the past year we have had considerable experience with this method and have found that, properIy anchored in a smaIl vein of the hand, forearm, foot or ankle, using a No. 2 I gauge needIe, I 14 inches Iong, the patient experiences Iittle inconvenience, is abIe to move about, feed himseIf and even get out of bed. Most of our patients Iearned to reguIate the rate of ffow themselves and only one had specia1 nurses. This coincides with the experience of Dr. W. E. HerreII of the Mayo CIinic. We have been abIe to maintain continuous flow at IO to 12 drops a minute for fifteen days without removing the needIe. By this means IOO,OOO to 400,000 units or more may be administered in a Iiter of soIution per twentyfour hours thus avoiding excessive fluid intake if necessary. No decrease in potency of the soIution was observed at the end of twenty-four hours. Pyrogen reactions have been encountered possibIy due to continued use of the same tubing. No harm has resuIted from these if the tubing is promptIy changed, which can be done without removing the needIe from the vein. Meticulous preparation of the intravenous set in accordance with the technic approved for bIood banks wouId possibIy eIiminate these reactions. Within the past few weeks we have not had pyrogen reactions aIthough using the same brands of peniciIIin, which tends to confirm the suspicion that there might have been an error in the technic of washing the rubber tubing. Venous irritation does occur frequentIy (II3911
284
PRIEST-PENICILLIN
but in our experience this subsides and the veins return to normaI function in most instances. ActuaI thrombosis has been rare. In summary it may be said that the administration of penicilhn is, at present, a hospital procedure and that the continuous intravenous drip method is preferabIe whenever feasibIe since a more nearIy constant serum IeveI can be maintained. However, actua1 clinica resuIts, notabIy in the treatment of gonorrhea, indicate that for many infections, Auctuations in the serum peniciIIin IeveI are unimportant in obtaining a favorabIe resuIt. Hence, the most generaIIy practica1 and effective method of administration wiI1 probably be by intramuscuIar injection at three-hour intervaIs around the cIock, started off by an intravenous injection of a dose two to three times that of the subsequent intramuscuIar dose. It is vitaIIy important that the three-hour scheduIe be adhered to. Some good resuIts have foIIowed administration every four hours, but this shouId not be depended on in critica cases. We beIieve that repeated intravenous injections have manifest disadvantages and no advantage compared with the two methods outlined above. The most frequently used concentration for singIe intravenous or intramuscuIar injections is 5,000 units per cc. of diIuent which may be norma sahne, 5 per cent gIucose in saIine, or distiIIed water. Recently, however, we have had patients compIain of a burning sensation at the site of intramuscuIar injections when such concentration was used. This was not experienced when a concentration of 16,000 units per cc. was used. We have had one occasion to give penicihin by continuous hypodermocIysis over a period of severa days in concentrations of 200 units per cc. No discomfort other than that accompanying simiIar administration of norma saIine was observed. However, in our opinion, this method shouId not be used except in the rare instance in which the patient “ has no veins” and objects to repeated intramuscular injections. In norma individuaIs penicihin does not pass into the subanachnoid space from the bIood stream.‘j Therefore, to be effective in meningitis it must be given intrathecahy as we11 as intramuscuIarIy or intravenousIy. The usua1 intrathecal dose is 10,000 to 20,000 units. However, we have given 50,000 intrathecaIIy without unfavorabIe reaction. There is no point in using penicillin routinely in meningococcic meningitis except in suIfonamide resistant cases. However, it is the drug of choice when a streptococcus or staphylococcus is the offending organism.
PRIEST-PENICILLIN AI1 hospitaIs
at
copies of dosage tions
tabIes
designated
in accordance
referred
peniciIIin
compiIed
for detaiIed
discussion.
and since the currently mately
avaiIabIe
equa1 doses every
response
is favorabIe,
ture is norma
ampouIes
three
reduced
for the next five to seven days.
in which Iist as our
IOO,OOO
units,
a
units in eight approxi-
around
the cIock.
may be continued
to so,ooo
you
in a given case
contain
IOO,OOO
hours
this dosage
then
diseases to this
to use peniciIIin
is to administer
Research
so far. To these
be added
experience broadens. Assuming that you have decided
have
and contraindica-
Additiona
wiI1 no doubt
depots
by the NationaI
with cIinica1 experience
is effective
good ruIe of thumb
as peniciIIin
as we11 as the indications
for the use of peniciIIin
Council are
present
285
If clinical
until tempera-
units per twenty-four
If the response
hours
is not favorabIe,
the
twenty-four hour dose shouId be increased to 200,000 or even 400,ooo units and continuous intravenous drip empIoyed if possibIe. Failure to get a prompt favorabIe response to these doses indicates that either the causative organism is not peniciIIin sensitive or some IocaIized abscess has not been drained, or the disease is due to mixed infection, or is bacteria1 endocarditis. CriticaI cIinica1 judgment must then dictate
what course to pursue.
immediateIy
result
fonamide
favorabIe resistant
very meager
and onIy 40,000
hours but this was sufficient ture from
patient
was admitted
after
abortion.
Large
condition
was
temperature twenty-four
be cited
that
clinica
the apparent
a week of chiIIs and fever IOO,OOO
were
dropped
first
case
Our
suppIy
to cause an immediate
doses of sulfonamide
drip
of an of sulwas
units were given the first twenty-four
iIIustrating
critica1;
the
we treated.
103’~. to normaI with associated
more recent
intravenous
may
pneumonia
As an example
given
to norma
but
hours were up, so 200,000 hours. The temperature
following
of peniciIIin
first
by
twenty-four
started
A
need of Iarger dosage attempted
had been ineffective
units the
faI1 in temperaimprovement.
up again
and her
continuous hours. before
The the
units were given the second dropped to norma and re-
twenty-four mained so and she was discharged on the seventh day. Uterine cuIture showed hemoIytic streptococci. StiII another problem is iIIustrated
by a chiId who deveIoped signs of peritonitis foIIowing operation for a ruptured appendix. She was aImost moribund when peniciIIin was started. SIow improvement resuIted, the temperature became norma and it Iooked as if she was out of troubIe, but the temperature again became septic in character. PeniciIIin was again given, the Ir4rB
286
PRIEST-PENICILLIN
temperature came down but the p&e and genera1 condition remained unfavorabIe. Signs of abscess deveIoped and drainage wiI1 have to be done before recovery can be expected. We have observed this tendency for the temperature to become norma under peniciIIin therapy even though other cIinica1 signs are not equaIIy favorabIe, and it demands a carefu1 search for abscess formation or some other condition, such as thrombophIebitis or an associated organism not affected by peniciIIin. The IocaI use of peniciIIin has particuIar appIication in the surgery of trauma. Experience here is not so definite as in systemic infections. Some observers report favorabIe reports; others do not. ApparentIy the most favorabIe resuIts have been obtained in acute situations, notabIy in empyema, suppurating joints, Sinus tracts, OsteomyeIitis and infected wounds, in which the infecting organism is known to be sensitive. In treating empyema, joints or abscess cavities, aspiration or drainage must first be done, then the cavity partially fiIIed with peniciIIin soIution in a concentration of 250 to 500 units per cc. Repeated fiIIings daiIy, twice daiIy, or in rare instances oftener are necessary. Therapy shouId be controIIed by daily bacteriologica smears. RecentIy we administered peniciIIin intramuscuIarIy in doses of 25,000 to 15,000 units every three hours to a patient who had muItipIe boiIs, one of which had been incised and drained just before injections were started. The abscess became sterile within twenty-four hours without IocaI application of peniciIlin or other antibacteria agents. BoiIs in process of formation did not suppurate. The conjunctive wiI1 toIerate soIutions of 250 to 500 units per cc. In very earIy acute OsteomyeIitis, before sequestrum formation, apparent cures without surgery have foIIowed parentera or a draining administration of peniciIIin. But once sequestrum sinus has formed, it is futiIe to use peniciIIin unIess proper surgery is performed. The resuhing wound offers a chance to use the drug incorporated in a paste made of Ianette wax and vaseIine.7 In any gutter type of wound this has been found an effective means of application. Other conditions of particuIar interest to surgeons of trauma in which peniciIIin has been used with good or favorabIe resuIts are: Sterihzation of peniciIIin sensitive Surface Wounds and Burns. gram-positive organisms has been obtained by dusting with I per cent peniciIIin in suIfaniIamide powder. If signs of sepsis deveIop, parentera administration shouId be combined.
PRIEST-PENICILLIN
287
experience in battIe areasi Deep Wounds. FairIy extensive indicates that severa weeks’ hospitaIization may be saved and generaIIy better end resuIts obtained by closing such wounds immediateIy without extensive debridment. One or more rubber tubes are inserted directIy into the wound or through stab incisions and aIIowed to project beyond the dressings. Tight suturing in layers is to be avoided and the sutures should not be pIaced too near the skin edges. Through the tubing 3 to IO cc. of penicillin soIution containing 250 units per cc. are injected twice daiIy for four days. Injection of too much soIution is to be avoided. Sutures shouId not be removed too soon. Cellulitis. Some of the earIy dramatic resuIts were obtained in treating ceIIuIitis with or without bacteremia since the common organisms are streptococci and staphyIococci. Definite coIIections of pus should be evacuated. We have not personaIIy observed cases of Ludwig’s angina treated with peniciIIin but it wouId seem to be worth using in this infection. Infections of the Hand and Palmar and Tendon Sheaths. Local instiIIation of soIutions by means of tubes pIus parentera administration has given encouraging resuIts. Cavernous Sinus Thrombosis and Infected Thrombopblebitis. Since the common infective organism in cavernous sinus thrombosis is staphylococcus, parentera peniciIIin therapy is indicated. The same appIies to infected thrombophIebitis ar)ywhere if there is reason to believe the offending organism is peniciIIin sensitive. In both conditions we wouId empIoy heparin in sufficient dosage (about 150 mg. per day) to maintain a clotting time of forty-five to sixty minutes, or dicoumarin to maintain a prothrombin time about 250 per cent of normal. CoaguIation time determination must be done twice daiIy and prothrombin time determinations once daiIy if either of these agents is used. Gas Gangrene. WhiIe the organisms responsibIe for gas gangrene are peniciIIin sensitive, disappointing resuIts have foIIowed the use of peniciIIin alone. Large doses (up to 400,000 units per twentyfour hours) combined with anti-serum have given favorabIe results. from the battIe areas has Compound Fractures. Experience emphasized the importance of early cIosure of the wound and IocaI treatment aIong the Iines laid down under “deep wounds.” In addition parentera administration of IOO,OOOunits daiIy shouId he instituted promptly. What can happen when these principIes ur43Il
PRIEST-PENICILLIN
are not carried out as we11as other points in peniciIIin therapy may be Slustrated by the detaiIed consideration of a patient whose chart is shown (Fig. I): WWnv.R% - I-k++ c =
A
FIG. I. Continuous, daily graph of patient with compound fracture referred to in text. A, solid line, daily temperature range; broken line, daily pulse range; diagonal hatchinterrupted ing, sulfathiazole in Grams; w.I., wound irrigation with sulfathiazole; vertical lines, wound irrigation with penicillin; solid black squares, penicillin by continuous intravenous drip; s, incision and drainage; c, chill; T, blood transfusion. B, horizontal hatching in penicillin graph represents the only intramuscularad ministration. Diagonal hatching, intramuscular heparin in milligrams per twenty-four hours added to penicillin solution; horizontal hatching, dicumerol (lower graph) in milligrams per twenty-four hours; solid line with dots, coagulation time in minutes (Lee-White method); solid line with cross, prothrombin time in per cent of normal; A, amputation; P, pleurisy (possible pulmonary embolism); Ph, evidence of thrombophlebitis. C, pulmonary embolism (E); drainage of abscess of left thigh (s); other symbols same as in B. CASE
REPORT
The patient, a man of fifty-two, suffered a compound fracture of the left leg. When he entered the hospital on Dr. A. R. Metz’ service about two weeks later IocaI infection was already present. Evidence of systemic infection soon deveIoped and an attempt to secure drainage was made. CuItures of the wound showed staphylococci. Blood cultures were sterile. Sulfathiazole was without effect. Again IocaI incision for stiI1 better drainage did not improve the situation. Thrombophlebitis of the deep veins of III441
2%
PRIEST-PENICILLIN
FIG. I. For descriptive legend see opposte
page.
PRIEST-PENICILLIN
290
the thigh extending apparentIy to the Iower iIiac branches deveIoped. Local peniciIIin therapy, first by instiIIation of crude filtrate, then by continuous drip of soIution of the sodium saIt into the drainage tubes was tried without apparent effect. PeniciIIin, by continuous intravenous drip in doses of IOO,OOO to 200,000 units per day, pIus heparin, was then instituted. A favorabIe temperature response raised the hope that the situation was under contro1. This was of short duration, however, and the patient grew steadiIy worse even whiIe peniciIIin was being administered. His aversion to Iosing his Ieg delayed amputation unti1 his circuIation began to show signs of faiIure and his condition was desperate. At this point a rapid guiIIotine operation was performed by Dr. Metz. Examination of the Ieg revealed one reason for faiIure of previous IocaI and systemic treatment, nameIy, an abscess aIong and under the Achilles tendon not touched by previous drainage and impossibIe to Iocate unIess the leg had been systematicaIIy ribboned. Improvement was immediate and dramatic. The tremendousIy swoIIen thigh and flank receded at the rate of haIf inch a day. Then the improvement stopped and signs of fresh sepsis developed, accompanied by tenderness in the thigh and swelling. Further thrombophIebitis was diagnosed and heparin* and dicoumarin” administered, foIIowed shortIy by peniciIIin by continuous intravenous drip. No improvement resuIted and signs of IocaIized abscess in the thigh deveIoped. Incision carried down to the IeveI of the deep saphenous vein evacuated about 1,300 cc. of pus. Improvement was again sudden and dramatic and this time apparentIy permanent as he has had a norma temperature for three weeks, is gaining weight rapidIy and has the appearance of a we11 man. This
experience
emphasizes
the
folIowing
points:
(I) The
neces-
earIy IocaI and systemic peniciIIin therapy in compound fractures. We realized Iater that we depended too much on IocaI drainage and suIfonamides in the earIy weeks after admission. (2) The ineffectiveness of systemic peniciIIin in the presence of undrained abscesses. (3) The poor resuIts from IocaI penicilIin therapy of muItiIocuIar infections. (4) The faIse favorabIe temperature response to peniciIIin when a11 other signs remain unfavorabie. (5) The vaIue sity
for
of peniciIIin in promoting a dramaticaIIy course in a desperately iI patient when
favorabIe indicated
postoperative surgery is per-
formed. (6) The fact that peniciIIin cannot repIace indicated surgery. (7) The value of anticoaguIants in the therapy of thrombophIebitis.
* Most of the beparin and all of the dicoumarin (dicumerol) used in treating this patient was supptied through the courtesy of Abbott Laboratories. The intramuscuIar heparin used was obtained from Dr. Leo Loewe, BrookIyn, N. Y. and represents a special formuIa prepared for him by Hoffmann-LaRoche, Inc. U146Jl
PRIEST-PENICILLIN
29’
We be&eve that more extensive spread and emboIism have occurred without the use of these agents.
wouId likely
REFERENCES I.
2.
3. 4. 5.
R. Ueber die morphoIogischen Veranderunger der MiIzbrandbaciIIen bei ihrer Auffosung durch Pyocyanase, Zentralbl. f. Bakt., 27: 776, 1900. FLEMING, A. The antibacteria action of cultures of a penicillium with specia1 reference to their use in the isoIation of B. inhuenzae. Brit. J. Exper. Patb., IO: 226, 1929. FLEMING, A. The specific antibacteria properties of penicihin and potassium teIIurite. J. Patb. +3+Bact., 35: 831, 1932. DUBOS, R. J. BactericidaI effect of extract of soi bacillus on gram-positive cocci. Proc. Sot. Exper. Biol. @ Med., 40: 3 I I, 1939. RAMMELKAMP, C. H. and KEEFER, C. S. The absorption, excretion and distribution of penicillin. J. Chin. ~?West., 22: 4.25, 1943. ABRAHAM, E. P., CHAIN, E., FLETCHER, C. M., GARDNER, A. D., HEATLEY, N. G., JENNINGS, M. A. and FLOREY, H. W. Further observations on peniciIlin. Lancet, EMMERICH,
2: 177, 1941. RAMMELKAMP,
C. H. and HELM, J. D., JR. Excretion
of penicillin in bile. Proc. Sot.
Exper. Biol. @ Med., 54: 31, 1943. 6. RAMMELKAMP,C. H. and KEEFER, C. S. The absorption, excretion, and toxicity of peniciIIin administered by intratheca1 injection, Am. J. Med. SC., 205: 342, 1943. 7. FLOREY, H. W. and CAIRNS, H. Report: A preliminary report to the War OIIice and the MedicaI Research CounciI on Investigations concerning the Use of peniciltin in war wounds. Reported by Garrod, L. P. Brit. M. J., 2: 755, 1943.
DISCUSSION COL. ROBERT H. KENNEDY (Medical Corps) : The ideas here expressed are the persona1 opinions of the discusser and it is to be considered that they represent in no way the opinions of other Army surgeons or the Medical Corps of the Army in general. PenicilIin treatment was commenced at the Percy Jones Genera1 Hospital in JuIy, 1943. Up to the present time it has been used in over one hundred patients. We have found it apparentIy of great vaIue in the smaI1 number of acute cases in which we have used it. NaturaIIy, in a genera1 hospital there are not many acute conditions in which it is to be advised, since these patients are more Iikely to appear in station hospitals. However, we have had occasion to treat one patient with erysipeIas, one with acute sin’usitis, one with acute mastoiditis, as we11 as severa early wound infections. In a11 of these, in which a susceptibIe bacterium was found, it has seemed to us that exceIIent results were obtained. We have had no occasion to use it in acute blood stream infections. For some time in our early experience it was used chiefly in the treatment of chronic osteomyelitis foIlowing gunshot wounds. Its use was continued for as long as seven and one-half weeks. None of us as particuIarIy impressed with its value. It was possible to cIear up streptococcus and staphyIococcus in these wounds, but quite promptly proteus, coliform and
292
PRIEST-PENICILLIN
BaciIlus pyocyaneus wouId appear. On stopping the drug, the streptococcus and staphyIococcus were quite IikeIy to re-appear. In these cases of chronic osteomyelitis, adequate compIete surgery plays the most important r61e and peniciIlin can be considered onIy an adjuvant in the presence of foreign bodies or dead bone. We are unabIe even to state that in this condition penicillin is any more desirabIe than many other drugs that have been used in osteomyelitis. It has been tried in severa cases of empyema following gunshot wounds in which there were large cavities remaining, either with or without bronchia fistuIas, both by IocaI instiIIation and hypodermic administration and we have not been particuIarIy impressed with its value. In the past two months we have started using peniciIIin pre- and postoperativeIy in sequestrectomies and pIastic revision of amputation stumps. PreviousIy we had been using the sulfonamides for this purpose. There were reactions to the suIfonamides in a good many instances, which we beIieved to be due IargeIy to the fact that most of these patients had had suIfonamides for one or more periods during their treatment previousIy. A poor appetite was frequent whiIe suIfonamide was being administered, nausea fairIy common and vomiting not rare. It is also too common to find red bIood ceIIs or gross bIood in the urine. There were numerous instances in which the temperature rise was more than to be expected and in which it feI1 to norma when the sulfonamides were discontinued. For these reasons we changed to peniciIIin, with which in our entire experience there has been but IittIe reaction. This consists almost entirely of an occasiona case of urticaria and rareIy a few red bIood ceIIs in the urine without symptoms. Nausea and vomiting have not occurred with peniciIIin in our experience. While using the sulfonamides it was rare to note any flare-up of ceIIuIitis or other infection after sequestrectomy or revision of a stump. So far it has been just as rare to have this reaction folIowing these operations with penicillin. Therefore, it is impossibIe to say that peniciIIin is any more effective for pre- and postoperative use in previously infected patients, but in our experience thus far, it has been at least as effective and without untoward symptoms. We usuaIIy give the drug for forty-eight to seventy-two hours preoperativeIy and continue postoperativeIy for five to seven days, discontinuing it then if genera1 and IocaI conditions do not seem to require its further use. It has been used pre- and postoperativeIy in two cases of Iobectomy for bronchiectasis with rather marked infection. Each of these Iobectomies heaIed well, but so have a11 the other Iobectomies. As time has gone on our dosage has in genera1 become smaIIer. WhiIe we formerIy used as much as 2q0,000 units a day, we now use in streptococcic cases 80,000 a day and in staphyIococcic cases 120,000 to 160,000 a day. For intramuscuIar and intravenous use we make up the drug in I 0,000 I[148Il
PRIEST-PENICILLIN
293
units per cc., and for Iocal use in 230 to IOOOunits per cc., usually 250. We have found that in an Army hospital intramuscular use is most satisfactory for continued administration, aIthough in an acute case it is given both intramuscuIarIy and intravenousIy for the first twenty-four to forty-eight hours in order to get in a Iarge dose. There is no use in its administration unless it is to be given at Ieast every three hours, day and night. Thi.s, of course, makes it administration difficult in anything but hospital practice. A few patients compIain of burning sensation foIIowing intramuscuIar injection. Quite recently we have had two patients whose clinical course suggested earIy gas baciIIus infection. It is fair to state that gas bacilli were not proved in either case, aIthough in one instance there were two considerabIe areas of necrotic muscIe found on opening up the street wound which had there was prompt been primariIy sutured eIsewhere. In each instance thorough surgery accompanied by IocaI and genera1 use of penicillin and both cases responded promptly. We believe that we can express no opinion about the value of peniciIIin in gas infection. It is unfortunate that the public has been brought to beIieve that this is such a miracle drug. It is our beIief that it is a most vaIued addition to our armamentarium, but that proper compIete surgery is more important than any drug. WALLACE E. HERRELL (Rochester, Minn.): PeniciIIin therapy, I believe, may be recorded as one of the great advances in medicine, and for that reason the enthusiasm with which it has been received is unparaIIeIed. This enthusiasm must, of course, in time be tempered as more and more is Iearned about the uses as we11 as the Iimitations of peniciIIin. As I Iooked at the bottIes which Dr. Priest showed a few moments ago in which penicillin was grown, I couId not heIp but think of the transition which has occurred since Professor FIorey visited at the Mayo CIinic in 1941, at which time we had these Aat bottIes a11 over the laboratory. As you may recaI1, it required IOO Iiters of the brew at that time to obtain enough peniciIIin to treat one patient for one day. What has happened since then is, of course, a great accompIishment and a great tribute to the scientific and industria1 organizations of this country. With regard to the IocaI use of peniciIIin, I might remind you that the broth fiItrate containing peniciIIin has proved satisfactory particuIarIy when one does not have avaiIabIe the more purified peniciIIin. The broth fiItrate is an entireIy safe agent and can be obtained by simpIy fltering off the moId from the broth in which it is grown. This broth as we11 as the sodium or the caIcium salt has been used with good resuIts in the Iocal treatment of bacteria1 infections. The sodium saIt in the buIk is somewhat irritating. On the other hand, the caIcium saIt has not proved to be irrita-
294
PRIEST-PENICILLIN
tive. The calcium salt is aIso more stabIe as evidenced by the fact that my colIeagues and I have kept caIcium saIt in the dry state for as Iong as six months at room temperature without finding any Ioss of potency. This, we beIieve, is of tremendous value particuIarIy in connection with its use in theaters of war where refrigeration is not aIways avaiIabIe. I was much interested and gratified to Iearn that Dr. Priest and his associates have found the continuous intravenous drip method of administering peniciIIin satisfactory. We have aIways believed that it was a satisfactory method if one is equipped to handle it. This much is certain, it is the onIy safe way by which a constant lever of peniciIIin can be maintained in the bIood. The burning sensation and IocaI irritation associated with repeated intramuscuIar injections at times are somewhat troubIesome. It has been apparent recentIy, however, that the degree of pigmentation of peniciIIin itself may affect this reaction somewhat. WhiIe the IocaI or systemic reactions vary with different batches of peniciIIin, there is some evidence that the more deepIy pigmented the peniciIIin is, as a ruIe, the more IikeIy one is to encounter these side effects. A word about the use of peniciIIin in the treatment of suppurative diseases of the joints and OsteomyeIitis which are, of course, of primary interest to this group. I concur compIeteIy in the opinion that peniciIIin is effective in the treatment of acute osteomyelitis. I might remind you, however, that the so-caIIed masking effect which has been noted in the past in connection with sulfonamide therapy may occur with peniciIIin therapy in the treatment of acute hematogenous osteomyelitis. In one or two patients who were under treatment with peniciIIin for acute osteomyeIitis, we have been badIy fooled concerning the success of the treatment by the deveIopment of some quiet Iesion which could be identified onIy by roentgenoIogic examination. In the treatment of chronic OsteomyeIitis peniciIIin aIone is not the answer. UnIess one is prepared to eradicate the focus and then combine peniciIIin therapy with other accepted forms of treatment, the resuIts are not going to be satisfactory, at Ieast this has been our experience at the clinic. I also might mention that the resuIts in the treatment of OsteomyeIitis of the Aat bones are in genera1 better than the resuIts obtained in the treatment of osteomyelitis of the Iong bones. We aIso have obtained satisfactory results in the treatment of subacute or spreading OsteomyeIitis of the fIat bone owing to anaerobic and partiaIIy anaerobic streptococci. I beIieve one of the discussants has already deaIt with the question of phIebitis which occasionaIIy may occur folIowing the intravenous administration of peniciIIin and also the question of pyrogenic reactions. However, these pyrogenic reactions are not troubIesome at present since practicaIIy a11 the peniciIIin avaiIabIe is pyrogen free. The onIy other toxic reaction of any significance which deserves mention at present is the urticaria and U15o11
PRIEST-PENICILLIN
295
dermatitis which may be encountered in no more than 2 or 3 per cent of patients. This skin reaction is bound to occur in certain individuaIs who are sensitive to molds and to moId products. If a severe dermatitis occurs during the course of penicillin therapy, one caution shouId be exercised: if one continues to force peniciIIin in the face of such a lesion, the possibiIity that a more extensive and probabIy exfoliative dermatitis may develop must be kept in mind. WALTER S. PRIEST (cIosing): I was hoping CoIoneI Kennedy wouId mention the primary closure of wounds which has been done at some of the battle fronts. Having had no persona1 experience, I feIt inadequate to discuss it. Reports have indicated good results. Extensive dkbridement is not done. Wounds are mereIy cIeaned, dusted with peniciIIin and sutured. Sometimes a smaI1 stab wound is made and a rubber tube drain inserted through which peniciIIin is subsequently instiIIed. It might be a point worth investigating by those of you who see wounds of this type. I am giad both CoIoneI Kennedy and Dr. HerreII depIored the tendency at present for peniciIIin to be used for anything and everything. We are seeing it used that way around the hospita1, and it should not be done. I observed one case of spreading osteomyehtis of the jaw, in which peniciIIin was ineffective, but I think in genera1 the experience would coincide with that of Dr. HerreII.
ILLINOIS
T
HE discovery of penicilhn is usuaIIy described as accidenta1. But this is not entireIy true. For fifty years prior to Dr. AIexander FIeming’s recognition of the possibIe significance of the Iytic effect of a contaminant mold on an agar cuIture of staphyIococci, many bacterioIogists had observed this phenomenon. In rgoo, Emmerichl isoIated an antibacteria substance from BaciIIus pyocyaneus which was later found to check the growth of diphtheria baciIIi in vitro and to exert a favorabIe action on the clinica disease, However, the true importance of this phenomenon of antibiosis was overIooked for the time being. In September, 1928, while examining some agar pIates of staphIycoccus, Dr. FIeming, (a bacterioIogist at Oxford University) noted complete inhibition of growth in the neighborhood of a contaminant moId which he identified as PeniciIIium of the Notatum group.’ Had it not been for Dr. FIeming’s many years of interest and research in antibacteria agents, it is possibIe that the significance of this observation wouId have been overIooked. FoIIowing it up he found that the mold, grown on the surface of nutrient broth, produced in the broth a powerfu1 antibacteria substance. By rg32,3 he had demonstrated its action in vitro against Streptococci, Staphyand Corynebacterium diphtheriae and had Iocci, Pneumococci shown it to be non-toxic for animaIs and non-irritating to the human conjuctiva. He caIIed the substance PeniciIIin and suggested its use IocaIIy in cIinica1 infections caused by the above organisms. Strangely enough these suggestions were not foIIowed up until after Dubos in rg3g4 pubIished his observations on the antibacteria effect against Gram-positive cocci of an extract of a soi baciIIus. This work Ied to the deveIopment of tyrothricin and gramicidin and stimuIated Dr. H. W. FIorey, also of Oxford, to re-investigate peniciIIin and work out methods for its production and purification * From the Department of Medicine, Wesley MemoriaI Hospital and Northwestern University, Medical School, Chicago. Part of the PeniciIIin used on patients discussed in this paper was furnished by the Committee on Chemotherapeutics and Other Agents of the NationaI Research Council and part by the PeniciIIin Research Committee of Northwestern University Medical SchooI.
PRIEST-PENICILLIN
281
in order to make further clinica application possible. By 1941, he had accummated enough data on its potential chnical usefuhress to enabIe him, during a visit to the United States, to interest the NationaI Research Council and the Department of AgricuIture to undertake the studies of the moId’s growth characteristics and possibilities for Iarge scale propagation. To Dr. CoghiII and Dr. Mayer of the Northern RegionaI Research Laboratory at Peoria beIong much of the credit for this work. To the pharmaceutical houses, and manufacturers of bioIogicaIs and chemicaIs beIong the credit for the actua1 attempts at mass production. At first it was believed that the moId could be satisfactorily grown onIy in smaI1 amounts of nutrient media. This resulted in the type of production in which the moId is grown in individual flasks containing not more than two Iiters of media each. Recovery of 3,000 to IO,OOO units per flask was considered a good yield. ObviousIy it was physicaIIy impossibIe to produce enough by this method to suppIy both miIitary and civilian requirements. Intensive efforts on the part of mycoIogists, chemists and engineers connected with fermentation and commercia1 chemica1 industries resulted in the perfection of methods of growing the moId in submerged cuItures in huge tanks of broth or on bran. The increased production made possibIe by such methods is responsibIe for the civiIian avaiIabiIity of peniciIIin today. From 1941 to May 1st of this year cIinica1 and Iaboratory research on peniciIIin was under the direction of the committee on Drugs and Therapeutics of the NationaI Research Council. As indications of specific clinica usefuIness developed the miIitary forces requisitioned al1 but a very smaI1 amount of the tota production. That which was Ieft was aIIocated to seIected investigators throughout the country and from their studies have come our present knowledge of dosage, methods of administration, rate of absorption and excretion and cIinica1 appIications of the drug. As experience expands this knowIedge wiIl be extended and our present concepts may be modified. However, enough definite information is at hand to remind us that it is not a cure-a11 and the present tendency on the part of some cIinicians to use it in the treatment of everything just because it is now avaiIabIe is unworthy of men of science. Penicillin itself is an acid which reacts chemicaIIy to form saIts and esters. The sodium saIt is the one at present avaiIabIe, although UI37ll
282
PRIEST-PENICILLIN
caIcium barium and ammonium saIts have been used. The peniciIIin unit is an arbitrary measure based on a pIate assay method deveIoped by Dr. FIorey, and is referred to as the FIorey or Oxford unit. The pure saIt is coIorIess but to obtain it in this form is at present impractical and apparentIy unnecessary. The yeIIowish coIor of the commercia1 product is due to harmIess impurities and varies to some extent. This need cause no concern since freedom from toxicity and pyrogens, and a potency within 25 per cent of the stated IeveI is guaranteed by rigid requirements of the FederaI Drug Commission. Most products wiI1 actuaIIy assay higher than the potency indicated on the IabeI. Assays in our own Iaboratory of the product of severa manufacturers revealed onIy one instance of the converse of this. The sodium saIt is highIy soIubIe and markedIy hygroscopic, hence must be kept from contact with moisture unti1 ready for use and at a temperature around 5’~. Under these conditions potency is not affected for at Ieast three months. For so potent a therapeutic agent toxicity for man is practicaIIy ni1. We have given 500,000 units in IOO cc. of saIine intravenousIy in Iess than thirty minutes without significant reaction. Such dosage is stiI1 far beIow the toxic IeveI for animaIs in addition to being unnecessary for the treatment of any condition so far known to be amenabIe to peniciIIin. Rarely urticaria may deveIop during the administration of therapeutic amounts. If this occurs, treatment shouId be discontinued since an occasiona case of exfoIiative dermatitis has been observed. Rapid absorption and excretion is characteristic of the drug. Since it is destroyed by acid and organisms of the coIon group it cannot be given by mouth or rectum. Within five minutes or Iess after intravenous administration it appears in the urine and after a short Iag the rate of excretion paraIIeIs that of administration. ApproximateIy 60 per cent of the amount administered, whether a singIe ‘dose, muItipIe doses or continuous injection, is excreted by the kidneys. The fate of the remainder is not yet entireIy known. It has. been found in high concentrations in biIe thus suggesting its use in certain biIiary tract infections. It aIso appears in saIiva but not in tears or pancreatic juice. 5 Serum Ievels rise rapidIy after intravenous injection, somewhat more sIowIy after intramuscuIar and much sIower after subcutaneous injection. For a given singIe dose serum concentration is higher after intravenous injection
PRIEST-PENICILLIN
283
than by any other method. On the other hand, while serum concentration does not reach the same height after intramuscuIar injection the IeveI is maintained Ionger (thirty to forty-five minutes) and decreases more graduaIIy. FolIowing subcutaneous administration no peniciIIin appears in the bIood for an hour and a half to two hours and the maximum concentration is much the Iowest but, such as it is, remains the Iongest since excretion in the urine is proIonged. Since onIy traces are found in serum two and a haIf to three hours after a singIe intravenous or intramuscuIar injection, the method and frequency of administration become important in pIanning therapy. From the serum IeveI standpoint, continuous intravenous therapy is most desirabIe, and for severe infections, graveIy septic patients and in treating infections with organisms of Iow peniciIIin sensitivity this is the method of choice in our opinion. It has the obvious disadvantage of requiring fairIy close supervision by an inteIligent nurse and the prompt avaiIabiIity of resident physicians skiIIed in intravenous therapy. During the past year we have had considerable experience with this method and have found that, properIy anchored in a smaIl vein of the hand, forearm, foot or ankle, using a No. 2 I gauge needIe, I 14 inches Iong, the patient experiences Iittle inconvenience, is abIe to move about, feed himseIf and even get out of bed. Most of our patients Iearned to reguIate the rate of ffow themselves and only one had specia1 nurses. This coincides with the experience of Dr. W. E. HerreII of the Mayo CIinic. We have been abIe to maintain continuous flow at IO to 12 drops a minute for fifteen days without removing the needIe. By this means IOO,OOO to 400,000 units or more may be administered in a Iiter of soIution per twentyfour hours thus avoiding excessive fluid intake if necessary. No decrease in potency of the soIution was observed at the end of twenty-four hours. Pyrogen reactions have been encountered possibIy due to continued use of the same tubing. No harm has resuIted from these if the tubing is promptIy changed, which can be done without removing the needIe from the vein. Meticulous preparation of the intravenous set in accordance with the technic approved for bIood banks wouId possibIy eIiminate these reactions. Within the past few weeks we have not had pyrogen reactions aIthough using the same brands of peniciIIin, which tends to confirm the suspicion that there might have been an error in the technic of washing the rubber tubing. Venous irritation does occur frequentIy (II3911
284
PRIEST-PENICILLIN
but in our experience this subsides and the veins return to normaI function in most instances. ActuaI thrombosis has been rare. In summary it may be said that the administration of penicilhn is, at present, a hospital procedure and that the continuous intravenous drip method is preferabIe whenever feasibIe since a more nearIy constant serum IeveI can be maintained. However, actua1 clinica resuIts, notabIy in the treatment of gonorrhea, indicate that for many infections, Auctuations in the serum peniciIIin IeveI are unimportant in obtaining a favorabIe resuIt. Hence, the most generaIIy practica1 and effective method of administration wiI1 probably be by intramuscuIar injection at three-hour intervaIs around the cIock, started off by an intravenous injection of a dose two to three times that of the subsequent intramuscuIar dose. It is vitaIIy important that the three-hour scheduIe be adhered to. Some good resuIts have foIIowed administration every four hours, but this shouId not be depended on in critica cases. We beIieve that repeated intravenous injections have manifest disadvantages and no advantage compared with the two methods outlined above. The most frequently used concentration for singIe intravenous or intramuscuIar injections is 5,000 units per cc. of diIuent which may be norma sahne, 5 per cent gIucose in saIine, or distiIIed water. Recently, however, we have had patients compIain of a burning sensation at the site of intramuscuIar injections when such concentration was used. This was not experienced when a concentration of 16,000 units per cc. was used. We have had one occasion to give penicihin by continuous hypodermocIysis over a period of severa days in concentrations of 200 units per cc. No discomfort other than that accompanying simiIar administration of norma saIine was observed. However, in our opinion, this method shouId not be used except in the rare instance in which the patient “ has no veins” and objects to repeated intramuscular injections. In norma individuaIs penicihin does not pass into the subanachnoid space from the bIood stream.‘j Therefore, to be effective in meningitis it must be given intrathecahy as we11 as intramuscuIarIy or intravenousIy. The usua1 intrathecal dose is 10,000 to 20,000 units. However, we have given 50,000 intrathecaIIy without unfavorabIe reaction. There is no point in using penicillin routinely in meningococcic meningitis except in suIfonamide resistant cases. However, it is the drug of choice when a streptococcus or staphylococcus is the offending organism.
PRIEST-PENICILLIN AI1 hospitaIs
at
copies of dosage tions
tabIes
designated
in accordance
referred
peniciIIin
compiIed
for detaiIed
discussion.
and since the currently mately
avaiIabIe
equa1 doses every
response
is favorabIe,
ture is norma
ampouIes
three
reduced
for the next five to seven days.
in which Iist as our
IOO,OOO
units,
a
units in eight approxi-
around
the cIock.
may be continued
to so,ooo
you
in a given case
contain
IOO,OOO
hours
this dosage
then
diseases to this
to use peniciIIin
is to administer
Research
so far. To these
be added
experience broadens. Assuming that you have decided
have
and contraindica-
Additiona
wiI1 no doubt
depots
by the NationaI
with cIinica1 experience
is effective
good ruIe of thumb
as peniciIIin
as we11 as the indications
for the use of peniciIIin
Council are
present
285
If clinical
until tempera-
units per twenty-four
If the response
hours
is not favorabIe,
the
twenty-four hour dose shouId be increased to 200,000 or even 400,ooo units and continuous intravenous drip empIoyed if possibIe. Failure to get a prompt favorabIe response to these doses indicates that either the causative organism is not peniciIIin sensitive or some IocaIized abscess has not been drained, or the disease is due to mixed infection, or is bacteria1 endocarditis. CriticaI cIinica1 judgment must then dictate
what course to pursue.
immediateIy
result
fonamide
favorabIe resistant
very meager
and onIy 40,000
hours but this was sufficient ture from
patient
was admitted
after
abortion.
Large
condition
was
temperature twenty-four
be cited
that
clinica
the apparent
a week of chiIIs and fever IOO,OOO
were
dropped
first
case
Our
suppIy
to cause an immediate
doses of sulfonamide
drip
of an of sulwas
units were given the first twenty-four
iIIustrating
critica1;
the
we treated.
103’~. to normaI with associated
more recent
intravenous
may
pneumonia
As an example
given
to norma
but
hours were up, so 200,000 hours. The temperature
following
of peniciIIin
first
by
twenty-four
started
A
need of Iarger dosage attempted
had been ineffective
units the
faI1 in temperaimprovement.
up again
and her
continuous hours. before
The the
units were given the second dropped to norma and re-
twenty-four mained so and she was discharged on the seventh day. Uterine cuIture showed hemoIytic streptococci. StiII another problem is iIIustrated
by a chiId who deveIoped signs of peritonitis foIIowing operation for a ruptured appendix. She was aImost moribund when peniciIIin was started. SIow improvement resuIted, the temperature became norma and it Iooked as if she was out of troubIe, but the temperature again became septic in character. PeniciIIin was again given, the Ir4rB
286
PRIEST-PENICILLIN
temperature came down but the p&e and genera1 condition remained unfavorabIe. Signs of abscess deveIoped and drainage wiI1 have to be done before recovery can be expected. We have observed this tendency for the temperature to become norma under peniciIIin therapy even though other cIinica1 signs are not equaIIy favorabIe, and it demands a carefu1 search for abscess formation or some other condition, such as thrombophIebitis or an associated organism not affected by peniciIIin. The IocaI use of peniciIIin has particuIar appIication in the surgery of trauma. Experience here is not so definite as in systemic infections. Some observers report favorabIe reports; others do not. ApparentIy the most favorabIe resuIts have been obtained in acute situations, notabIy in empyema, suppurating joints, Sinus tracts, OsteomyeIitis and infected wounds, in which the infecting organism is known to be sensitive. In treating empyema, joints or abscess cavities, aspiration or drainage must first be done, then the cavity partially fiIIed with peniciIIin soIution in a concentration of 250 to 500 units per cc. Repeated fiIIings daiIy, twice daiIy, or in rare instances oftener are necessary. Therapy shouId be controIIed by daily bacteriologica smears. RecentIy we administered peniciIIin intramuscuIarIy in doses of 25,000 to 15,000 units every three hours to a patient who had muItipIe boiIs, one of which had been incised and drained just before injections were started. The abscess became sterile within twenty-four hours without IocaI application of peniciIlin or other antibacteria agents. BoiIs in process of formation did not suppurate. The conjunctive wiI1 toIerate soIutions of 250 to 500 units per cc. In very earIy acute OsteomyeIitis, before sequestrum formation, apparent cures without surgery have foIIowed parentera or a draining administration of peniciIIin. But once sequestrum sinus has formed, it is futiIe to use peniciIIin unIess proper surgery is performed. The resuhing wound offers a chance to use the drug incorporated in a paste made of Ianette wax and vaseIine.7 In any gutter type of wound this has been found an effective means of application. Other conditions of particuIar interest to surgeons of trauma in which peniciIIin has been used with good or favorabIe resuIts are: Sterihzation of peniciIIin sensitive Surface Wounds and Burns. gram-positive organisms has been obtained by dusting with I per cent peniciIIin in suIfaniIamide powder. If signs of sepsis deveIop, parentera administration shouId be combined.
PRIEST-PENICILLIN
287
experience in battIe areasi Deep Wounds. FairIy extensive indicates that severa weeks’ hospitaIization may be saved and generaIIy better end resuIts obtained by closing such wounds immediateIy without extensive debridment. One or more rubber tubes are inserted directIy into the wound or through stab incisions and aIIowed to project beyond the dressings. Tight suturing in layers is to be avoided and the sutures should not be pIaced too near the skin edges. Through the tubing 3 to IO cc. of penicillin soIution containing 250 units per cc. are injected twice daiIy for four days. Injection of too much soIution is to be avoided. Sutures shouId not be removed too soon. Cellulitis. Some of the earIy dramatic resuIts were obtained in treating ceIIuIitis with or without bacteremia since the common organisms are streptococci and staphyIococci. Definite coIIections of pus should be evacuated. We have not personaIIy observed cases of Ludwig’s angina treated with peniciIIin but it wouId seem to be worth using in this infection. Infections of the Hand and Palmar and Tendon Sheaths. Local instiIIation of soIutions by means of tubes pIus parentera administration has given encouraging resuIts. Cavernous Sinus Thrombosis and Infected Thrombopblebitis. Since the common infective organism in cavernous sinus thrombosis is staphylococcus, parentera peniciIIin therapy is indicated. The same appIies to infected thrombophIebitis ar)ywhere if there is reason to believe the offending organism is peniciIIin sensitive. In both conditions we wouId empIoy heparin in sufficient dosage (about 150 mg. per day) to maintain a clotting time of forty-five to sixty minutes, or dicoumarin to maintain a prothrombin time about 250 per cent of normal. CoaguIation time determination must be done twice daiIy and prothrombin time determinations once daiIy if either of these agents is used. Gas Gangrene. WhiIe the organisms responsibIe for gas gangrene are peniciIIin sensitive, disappointing resuIts have foIIowed the use of peniciIIin alone. Large doses (up to 400,000 units per twentyfour hours) combined with anti-serum have given favorabIe results. from the battIe areas has Compound Fractures. Experience emphasized the importance of early cIosure of the wound and IocaI treatment aIong the Iines laid down under “deep wounds.” In addition parentera administration of IOO,OOOunits daiIy shouId he instituted promptly. What can happen when these principIes ur43Il
PRIEST-PENICILLIN
are not carried out as we11as other points in peniciIIin therapy may be Slustrated by the detaiIed consideration of a patient whose chart is shown (Fig. I): WWnv.R% - I-k++ c =
A
FIG. I. Continuous, daily graph of patient with compound fracture referred to in text. A, solid line, daily temperature range; broken line, daily pulse range; diagonal hatchinterrupted ing, sulfathiazole in Grams; w.I., wound irrigation with sulfathiazole; vertical lines, wound irrigation with penicillin; solid black squares, penicillin by continuous intravenous drip; s, incision and drainage; c, chill; T, blood transfusion. B, horizontal hatching in penicillin graph represents the only intramuscularad ministration. Diagonal hatching, intramuscular heparin in milligrams per twenty-four hours added to penicillin solution; horizontal hatching, dicumerol (lower graph) in milligrams per twenty-four hours; solid line with dots, coagulation time in minutes (Lee-White method); solid line with cross, prothrombin time in per cent of normal; A, amputation; P, pleurisy (possible pulmonary embolism); Ph, evidence of thrombophlebitis. C, pulmonary embolism (E); drainage of abscess of left thigh (s); other symbols same as in B. CASE
REPORT
The patient, a man of fifty-two, suffered a compound fracture of the left leg. When he entered the hospital on Dr. A. R. Metz’ service about two weeks later IocaI infection was already present. Evidence of systemic infection soon deveIoped and an attempt to secure drainage was made. CuItures of the wound showed staphylococci. Blood cultures were sterile. Sulfathiazole was without effect. Again IocaI incision for stiI1 better drainage did not improve the situation. Thrombophlebitis of the deep veins of III441
2%
PRIEST-PENICILLIN
FIG. I. For descriptive legend see opposte
page.
PRIEST-PENICILLIN
290
the thigh extending apparentIy to the Iower iIiac branches deveIoped. Local peniciIIin therapy, first by instiIIation of crude filtrate, then by continuous drip of soIution of the sodium saIt into the drainage tubes was tried without apparent effect. PeniciIIin, by continuous intravenous drip in doses of IOO,OOO to 200,000 units per day, pIus heparin, was then instituted. A favorabIe temperature response raised the hope that the situation was under contro1. This was of short duration, however, and the patient grew steadiIy worse even whiIe peniciIIin was being administered. His aversion to Iosing his Ieg delayed amputation unti1 his circuIation began to show signs of faiIure and his condition was desperate. At this point a rapid guiIIotine operation was performed by Dr. Metz. Examination of the Ieg revealed one reason for faiIure of previous IocaI and systemic treatment, nameIy, an abscess aIong and under the Achilles tendon not touched by previous drainage and impossibIe to Iocate unIess the leg had been systematicaIIy ribboned. Improvement was immediate and dramatic. The tremendousIy swoIIen thigh and flank receded at the rate of haIf inch a day. Then the improvement stopped and signs of fresh sepsis developed, accompanied by tenderness in the thigh and swelling. Further thrombophIebitis was diagnosed and heparin* and dicoumarin” administered, foIIowed shortIy by peniciIIin by continuous intravenous drip. No improvement resuIted and signs of IocaIized abscess in the thigh deveIoped. Incision carried down to the IeveI of the deep saphenous vein evacuated about 1,300 cc. of pus. Improvement was again sudden and dramatic and this time apparentIy permanent as he has had a norma temperature for three weeks, is gaining weight rapidIy and has the appearance of a we11 man. This
experience
emphasizes
the
folIowing
points:
(I) The
neces-
earIy IocaI and systemic peniciIIin therapy in compound fractures. We realized Iater that we depended too much on IocaI drainage and suIfonamides in the earIy weeks after admission. (2) The ineffectiveness of systemic peniciIIin in the presence of undrained abscesses. (3) The poor resuIts from IocaI penicilIin therapy of muItiIocuIar infections. (4) The faIse favorabIe temperature response to peniciIIin when a11 other signs remain unfavorabie. (5) The vaIue sity
for
of peniciIIin in promoting a dramaticaIIy course in a desperately iI patient when
favorabIe indicated
postoperative surgery is per-
formed. (6) The fact that peniciIIin cannot repIace indicated surgery. (7) The value of anticoaguIants in the therapy of thrombophIebitis.
* Most of the beparin and all of the dicoumarin (dicumerol) used in treating this patient was supptied through the courtesy of Abbott Laboratories. The intramuscuIar heparin used was obtained from Dr. Leo Loewe, BrookIyn, N. Y. and represents a special formuIa prepared for him by Hoffmann-LaRoche, Inc. U146Jl
PRIEST-PENICILLIN
29’
We be&eve that more extensive spread and emboIism have occurred without the use of these agents.
wouId likely
REFERENCES I.
2.
3. 4. 5.
R. Ueber die morphoIogischen Veranderunger der MiIzbrandbaciIIen bei ihrer Auffosung durch Pyocyanase, Zentralbl. f. Bakt., 27: 776, 1900. FLEMING, A. The antibacteria action of cultures of a penicillium with specia1 reference to their use in the isoIation of B. inhuenzae. Brit. J. Exper. Patb., IO: 226, 1929. FLEMING, A. The specific antibacteria properties of penicihin and potassium teIIurite. J. Patb. +3+Bact., 35: 831, 1932. DUBOS, R. J. BactericidaI effect of extract of soi bacillus on gram-positive cocci. Proc. Sot. Exper. Biol. @ Med., 40: 3 I I, 1939. RAMMELKAMP, C. H. and KEEFER, C. S. The absorption, excretion and distribution of penicillin. J. Chin. ~?West., 22: 4.25, 1943. ABRAHAM, E. P., CHAIN, E., FLETCHER, C. M., GARDNER, A. D., HEATLEY, N. G., JENNINGS, M. A. and FLOREY, H. W. Further observations on peniciIlin. Lancet, EMMERICH,
2: 177, 1941. RAMMELKAMP,
C. H. and HELM, J. D., JR. Excretion
of penicillin in bile. Proc. Sot.
Exper. Biol. @ Med., 54: 31, 1943. 6. RAMMELKAMP,C. H. and KEEFER, C. S. The absorption, excretion, and toxicity of peniciIIin administered by intratheca1 injection, Am. J. Med. SC., 205: 342, 1943. 7. FLOREY, H. W. and CAIRNS, H. Report: A preliminary report to the War OIIice and the MedicaI Research CounciI on Investigations concerning the Use of peniciltin in war wounds. Reported by Garrod, L. P. Brit. M. J., 2: 755, 1943.
DISCUSSION COL. ROBERT H. KENNEDY (Medical Corps) : The ideas here expressed are the persona1 opinions of the discusser and it is to be considered that they represent in no way the opinions of other Army surgeons or the Medical Corps of the Army in general. PenicilIin treatment was commenced at the Percy Jones Genera1 Hospital in JuIy, 1943. Up to the present time it has been used in over one hundred patients. We have found it apparentIy of great vaIue in the smaI1 number of acute cases in which we have used it. NaturaIIy, in a genera1 hospital there are not many acute conditions in which it is to be advised, since these patients are more Iikely to appear in station hospitals. However, we have had occasion to treat one patient with erysipeIas, one with acute sin’usitis, one with acute mastoiditis, as we11 as severa early wound infections. In a11 of these, in which a susceptibIe bacterium was found, it has seemed to us that exceIIent results were obtained. We have had no occasion to use it in acute blood stream infections. For some time in our early experience it was used chiefly in the treatment of chronic osteomyelitis foIlowing gunshot wounds. Its use was continued for as long as seven and one-half weeks. None of us as particuIarIy impressed with its value. It was possible to cIear up streptococcus and staphyIococcus in these wounds, but quite promptly proteus, coliform and
292
PRIEST-PENICILLIN
BaciIlus pyocyaneus wouId appear. On stopping the drug, the streptococcus and staphyIococcus were quite IikeIy to re-appear. In these cases of chronic osteomyelitis, adequate compIete surgery plays the most important r61e and peniciIlin can be considered onIy an adjuvant in the presence of foreign bodies or dead bone. We are unabIe even to state that in this condition penicillin is any more desirabIe than many other drugs that have been used in osteomyelitis. It has been tried in severa cases of empyema following gunshot wounds in which there were large cavities remaining, either with or without bronchia fistuIas, both by IocaI instiIIation and hypodermic administration and we have not been particuIarIy impressed with its value. In the past two months we have started using peniciIIin pre- and postoperativeIy in sequestrectomies and pIastic revision of amputation stumps. PreviousIy we had been using the sulfonamides for this purpose. There were reactions to the suIfonamides in a good many instances, which we beIieved to be due IargeIy to the fact that most of these patients had had suIfonamides for one or more periods during their treatment previousIy. A poor appetite was frequent whiIe suIfonamide was being administered, nausea fairIy common and vomiting not rare. It is also too common to find red bIood ceIIs or gross bIood in the urine. There were numerous instances in which the temperature rise was more than to be expected and in which it feI1 to norma when the sulfonamides were discontinued. For these reasons we changed to peniciIIin, with which in our entire experience there has been but IittIe reaction. This consists almost entirely of an occasiona case of urticaria and rareIy a few red bIood ceIIs in the urine without symptoms. Nausea and vomiting have not occurred with peniciIIin in our experience. While using the sulfonamides it was rare to note any flare-up of ceIIuIitis or other infection after sequestrectomy or revision of a stump. So far it has been just as rare to have this reaction folIowing these operations with penicillin. Therefore, it is impossibIe to say that peniciIIin is any more effective for pre- and postoperative use in previously infected patients, but in our experience thus far, it has been at least as effective and without untoward symptoms. We usuaIIy give the drug for forty-eight to seventy-two hours preoperativeIy and continue postoperativeIy for five to seven days, discontinuing it then if genera1 and IocaI conditions do not seem to require its further use. It has been used pre- and postoperativeIy in two cases of Iobectomy for bronchiectasis with rather marked infection. Each of these Iobectomies heaIed well, but so have a11 the other Iobectomies. As time has gone on our dosage has in genera1 become smaIIer. WhiIe we formerIy used as much as 2q0,000 units a day, we now use in streptococcic cases 80,000 a day and in staphyIococcic cases 120,000 to 160,000 a day. For intramuscuIar and intravenous use we make up the drug in I 0,000 I[148Il
PRIEST-PENICILLIN
293
units per cc., and for Iocal use in 230 to IOOOunits per cc., usually 250. We have found that in an Army hospital intramuscular use is most satisfactory for continued administration, aIthough in an acute case it is given both intramuscuIarIy and intravenousIy for the first twenty-four to forty-eight hours in order to get in a Iarge dose. There is no use in its administration unless it is to be given at Ieast every three hours, day and night. Thi.s, of course, makes it administration difficult in anything but hospital practice. A few patients compIain of burning sensation foIIowing intramuscuIar injection. Quite recently we have had two patients whose clinical course suggested earIy gas baciIIus infection. It is fair to state that gas bacilli were not proved in either case, aIthough in one instance there were two considerabIe areas of necrotic muscIe found on opening up the street wound which had there was prompt been primariIy sutured eIsewhere. In each instance thorough surgery accompanied by IocaI and genera1 use of penicillin and both cases responded promptly. We believe that we can express no opinion about the value of peniciIIin in gas infection. It is unfortunate that the public has been brought to beIieve that this is such a miracle drug. It is our beIief that it is a most vaIued addition to our armamentarium, but that proper compIete surgery is more important than any drug. WALLACE E. HERRELL (Rochester, Minn.): PeniciIIin therapy, I believe, may be recorded as one of the great advances in medicine, and for that reason the enthusiasm with which it has been received is unparaIIeIed. This enthusiasm must, of course, in time be tempered as more and more is Iearned about the uses as we11 as the Iimitations of peniciIIin. As I Iooked at the bottIes which Dr. Priest showed a few moments ago in which penicillin was grown, I couId not heIp but think of the transition which has occurred since Professor FIorey visited at the Mayo CIinic in 1941, at which time we had these Aat bottIes a11 over the laboratory. As you may recaI1, it required IOO Iiters of the brew at that time to obtain enough peniciIIin to treat one patient for one day. What has happened since then is, of course, a great accompIishment and a great tribute to the scientific and industria1 organizations of this country. With regard to the IocaI use of peniciIIin, I might remind you that the broth fiItrate containing peniciIIin has proved satisfactory particuIarIy when one does not have avaiIabIe the more purified peniciIIin. The broth fiItrate is an entireIy safe agent and can be obtained by simpIy fltering off the moId from the broth in which it is grown. This broth as we11 as the sodium or the caIcium salt has been used with good resuIts in the Iocal treatment of bacteria1 infections. The sodium saIt in the buIk is somewhat irritating. On the other hand, the caIcium saIt has not proved to be irrita-
294
PRIEST-PENICILLIN
tive. The calcium salt is aIso more stabIe as evidenced by the fact that my colIeagues and I have kept caIcium saIt in the dry state for as Iong as six months at room temperature without finding any Ioss of potency. This, we beIieve, is of tremendous value particuIarIy in connection with its use in theaters of war where refrigeration is not aIways avaiIabIe. I was much interested and gratified to Iearn that Dr. Priest and his associates have found the continuous intravenous drip method of administering peniciIIin satisfactory. We have aIways believed that it was a satisfactory method if one is equipped to handle it. This much is certain, it is the onIy safe way by which a constant lever of peniciIIin can be maintained in the bIood. The burning sensation and IocaI irritation associated with repeated intramuscuIar injections at times are somewhat troubIesome. It has been apparent recentIy, however, that the degree of pigmentation of peniciIIin itself may affect this reaction somewhat. WhiIe the IocaI or systemic reactions vary with different batches of peniciIIin, there is some evidence that the more deepIy pigmented the peniciIIin is, as a ruIe, the more IikeIy one is to encounter these side effects. A word about the use of peniciIIin in the treatment of suppurative diseases of the joints and OsteomyeIitis which are, of course, of primary interest to this group. I concur compIeteIy in the opinion that peniciIIin is effective in the treatment of acute osteomyelitis. I might remind you, however, that the so-caIIed masking effect which has been noted in the past in connection with sulfonamide therapy may occur with peniciIIin therapy in the treatment of acute hematogenous osteomyelitis. In one or two patients who were under treatment with peniciIIin for acute osteomyeIitis, we have been badIy fooled concerning the success of the treatment by the deveIopment of some quiet Iesion which could be identified onIy by roentgenoIogic examination. In the treatment of chronic OsteomyeIitis peniciIIin aIone is not the answer. UnIess one is prepared to eradicate the focus and then combine peniciIIin therapy with other accepted forms of treatment, the resuIts are not going to be satisfactory, at Ieast this has been our experience at the clinic. I also might mention that the resuIts in the treatment of OsteomyeIitis of the Aat bones are in genera1 better than the resuIts obtained in the treatment of osteomyelitis of the Iong bones. We aIso have obtained satisfactory results in the treatment of subacute or spreading OsteomyeIitis of the fIat bone owing to anaerobic and partiaIIy anaerobic streptococci. I beIieve one of the discussants has already deaIt with the question of phIebitis which occasionaIIy may occur folIowing the intravenous administration of peniciIIin and also the question of pyrogenic reactions. However, these pyrogenic reactions are not troubIesome at present since practicaIIy a11 the peniciIIin avaiIabIe is pyrogen free. The onIy other toxic reaction of any significance which deserves mention at present is the urticaria and U15o11
PRIEST-PENICILLIN
295
dermatitis which may be encountered in no more than 2 or 3 per cent of patients. This skin reaction is bound to occur in certain individuaIs who are sensitive to molds and to moId products. If a severe dermatitis occurs during the course of penicillin therapy, one caution shouId be exercised: if one continues to force peniciIIin in the face of such a lesion, the possibiIity that a more extensive and probabIy exfoliative dermatitis may develop must be kept in mind. WALTER S. PRIEST (cIosing): I was hoping CoIoneI Kennedy wouId mention the primary closure of wounds which has been done at some of the battle fronts. Having had no persona1 experience, I feIt inadequate to discuss it. Reports have indicated good results. Extensive dkbridement is not done. Wounds are mereIy cIeaned, dusted with peniciIIin and sutured. Sometimes a smaI1 stab wound is made and a rubber tube drain inserted through which peniciIIin is subsequently instiIIed. It might be a point worth investigating by those of you who see wounds of this type. I am giad both CoIoneI Kennedy and Dr. HerreII depIored the tendency at present for peniciIIin to be used for anything and everything. We are seeing it used that way around the hospita1, and it should not be done. I observed one case of spreading osteomyehtis of the jaw, in which peniciIIin was ineffective, but I think in genera1 the experience would coincide with that of Dr. HerreII.