PENICILLIN-MEDICINE FROM MOLDBy BANNS WIl~TZ

Duriny the 1~8t Jew lIlQlltM. 1Jorio"4 aen.ratiunal report have appeared illthe prea8 about a lIelt' df'''(1 called penicilli" u·h·ich i8 81.ppoaed tu P086C88 ",imet/lolU'lualilly prupcrties. ··Time... in 1:t" iaBUtI oj -'1.larch 15. 1941, 11'1:"t 80 Jur (JR to RUY:

"I'en,cilh" w,illIlUI.·c more lit.'cl< than war cal. 8pend," atld cven Clmrchillllwntionedthe 'lew drn(J in one oj Ilia speechu.

We hove jUlie rueiv(U! detailed moterial 0" pwicillin Jrom E;urope. (md Dr.llUfI7l1i Wirtz oJ. 'hmlgllUi. who obta,;ned his degree ;n plwrmace'l/.;clJ at the Unit· rllityoj liO'lll, Genna"y. telllJ our readers about the nalur and significance oj elle '/IC.,O

medicament in tlw jollowi'l(J areicle.-K.M.

RED BLOOD FROM GREEN LEAVES 205

or ftl1lgi, he laid the foundation for effectivecoulltermCll.'lures. Once an enemy is rec­ognized, it is possible to Jay bare his w('akpoints and to construct the necc8sary defen­sive weapons. The same applies to theinfectious diseases. Starting Ollt from Koch's

applied to the deep wound by means of atube. In other cases a compress withchlorophyll or an ointment containing chlo­rophyll was applied. Serious bone diseases,inflammation of the brain, and many oasesof mouth infections, angina vincenti, andpyorrhEa alt'Wlam have been cured.

For quite a number of years, chlorophyllpreparations for injection have been markctedby reputable firms for the treatment oftuberculosis and arteriosclerosis. The Ameri­can specialists Robert Ridpaths and T.Carroll Davis have had excellent results inthe treatment of 1,000 cases of infections ofthe respiratory organs. They reported thatthey had not seen a single case treak>d withchlorophyll where the patient had not beeneither oompletely cured or at least shownconsiderable improvement. Chlorophylltampons inserted in the nose during coldshave been outstandingly succossful in givinginstant relief. Patients with a cold in thehead or the nose were greatly relieved withintwenty-four hours.

How does chlorophyll destroy bacteria orhamper their growth? Beyond the fact.sthat it strengthens the cell walls, hampersthe growth of the bacteria, and gives thcbody a chance to mobilize its own defenses.doctors know very little. Perhaps there issomething in the theory that the effectproduced by chlorophyll is produced by itshampering influence on the vitamin metabo­lism of the bacteria, which latter are-likehumans and animals--dependent on thepresenco of cert.ain substances or a vitamincharacter.

__ to employ chlorophyll to fight bacteria!.. the best antiseptics usually have oneiildvUltage in that, if they are strongIDOOgh to kiU the cau8CS of the disease, theyGften disturb the function of the surround·.. tissue at the same time. Might chloro­.yU enable the body to fight the invadingl.Cteria and yet spare the tissue?

Laboratory experiments have shown that,it itself, chlorophyll does not have thepower to kill off bacteria. But when it is inllODtact with live tissue it seems to strength.eo the ceLIs' power of resistance and tohamper the growth of bacteria. Its specifioIbility of breaking down carbon dioxide andreleasing the oxygen spells doom for theblcteria, which can only live in suppuratingJJOunds beyond the rcach of air. Even inaenerous doses chlorophyll has shown noirritating effect. The department for ex·perimental pathology at Templo is nowpreparing various ointments containingohlorophyll for all kinds of infeotions and isexperimenting with them. Incidentally,aintments containing chlorophyll, usually in~dition to sulfonamides, have already beenmarketed in China.

Last year, a dozen well-known doctorspublished their experiences with chlorophyllin the American Journal of Surgery. All inall, some 1,200 cases, from deep-seatedinfections to superficial skin injuries, hadbeen treated by these men, and in case aftercue the report ended: case cured. Patientsarrived with a ruptured appendix and in·cipient peritonitis; after the necessary opera­tion, a chlorophyll solution was successfully

WHEN Robert Koch proved morethun sixty years ago that a certaingroup of diseases, now known under

the collective name of ··infectious diseases,"bas its cause in the activity of numerous kindsof tiny parasites such as~bacteria, protozoa,

206 THE XXtb CENTURY

discovery, several methods for their preven­tion or cure were developed. At first thegreatest success was achieved by the injec­tion of the blood serum from animals thathave been inoculated with the respectivebacteria or their toxins. Such serums, whenintroduced into the human body, provide itwith the necessary power to resist andcombat an infection by virtue of the anti·bodies it contains. In addition to thisserum therapy, chemotherapy was evolved,i.e., the treatment of the disease by chemicalreagents that have a toxic effect upon themicroorganism causing the disease, withoutlleriously harming the patient.

The success of this latter method, thewide employment of which began withGermany's Gerhard Domagk's publicationon his experiments with sulfa drugs in 1935,WIlS llO overwhelming that it appeared atfirst as if this was the only promising methodof combating such infectious diseases aspneumonia, typhoid, angina, scarlet fever,or gonorrhea. Hence the experts of thewhole world turned their attention to testingand impro"ing the sulfa drugs, with theresult that another promising discovery inthis field lay fallow for many years.

In 1928 Dr. Alexander Fleming, Professorof Bacteriology at St. Mary's HospitalMedical School, University of London, wasstudying the growth and propert.ies of staphy.lococci, a genus of cocci bacteria most com­monly found in boils, abscesses, carbunclesand similar suppurative processes. One dayhe observed that part of the medium inwhich he was culturing these staphylococcihad been invaded by mold. A few dayslater, Dr. Fleming noticed that the moldhad cleared a wide, bacteriafree area betweenitself and the staphylococci-perhaps hadkilled them. Realizing the importance ofthis phenomenon, he began to devote bisattention to it. :First he identified thatpart,icular mold as PeniciUium notatum, aclose relative to the ordinary mold, Penicil·lium glaucum, that annoys us by its appear­ance on stale bread, shoes, imperfectlysealed preserves, etc. Dr. Fleming thenb'Tew the mold on a liquid medium in glasscontainers. The mold lIecreted a substanceinto t,he medium which was capable ofpreventing the growth of disease-producingmicroorganisms. Dr. Fleming named thisby-product penicillin.

Although several similar antibiotics-i.e.,antibodies produced by bacteria to stemthe growth of their rivals-were known,

none had 80 far been employed su<:ee88fullyin medicine. The reasons for this were theircomparative toxicity and the difficulty ofproducing them.

Fleming therefore examined his penicillinespecially for its toxic effect on the animalorganism and found that the medium con.taining penicillin was no more poisonous toanimals than the pure medium. Above &11,penicillin did not harm the white bloodcorpuscles, the human organism's chief troopeof defense against harmful germs.

After the therapeutic effect of penicillinhad been proved by excellent results in thetreatment of infected wounds with a liquidcontaining penicillin, the question of pro·ducing it was studied. Although it bec&m8possible in 1932 to raise the mold in asynthetic medium, the penicillin itself couldnot be extracted in a concentrated, stableform without losing its effectiveness. Nu.merous attempts to overcome this difficultywere unsuccessful. And when in 1935 thesulfa drugs, which c:>mbine normal condi.tions of manufacture with their great effec·tiveness and comparatively low toxicity,commenced their triumphal march againstthe infectious diseases, Dr. }~leming andother researchers on penicillin believed thatthe latter would hardly attain any practicalsignificance as an antiseptic beside thesulfonamides.

With the increasing employment of thesulfonamides, however, it became apparentthat, beside the various bacteria they succeedin laying low, there are some germs whichare insufficiently or not at all affected. Italso turned out that the therapeutic resultdepends to a large extent on whether thedrug can reach the focus of infection in aneffective concentration. In cases where theinfection has advanced to a stage at whichnecrosis, phlegmon, or thrombosis has set in,the chances of a cure have proved to belimited.

Hence medical science began to seek formeans of closing these gaps. According tothe Shanghai TimeJJ Week of August 9, 1944,Japanese research workers have been ex­perimenting with penicillin for ten years.In England Dr. H. W. Florey and Dr. E. B.Chain of Oxford's Sir William Dunn School ofPathology resumed the interrupted work withpenicillin. With the aid of a large researchteam, they succeeded in developing a methodby which penicillin could be extracted fromthe culture medium and rid-at least partial.

PENICILLIN-MEDICINE FROM MOLD 207

the sensitiveness of this organic substancewhich, in contraBt to the sulfa drugs, placedgreat obstacles in the way of large-scalemanufacture. It took months of work onthe part of Dr. Florey's entire team to pro­duce enough penicillin to treat one or twopatients. Moreover, the first man treatedshowed violent by-effects in the form of fitsof shivering and rising temperature, whichwere, however, traced to impurities whichit was later possible to remove. Researcherssuccessfully went to work to discover tech­nical methods of production with a sufficientyield, so that today it has become possibleto provide pure, concentrated penicillinpreparations on a comparatively large andincreasing scale. But it is doubtful whetherit will ever be possible to cover all require­ments by the culture method, aa it is verydifficult to protect the mold from bacteriain the air whose enzymes tend to destroy it.This problem will hence only be fully solvedby the chemical synthesis of penicillin which,although probably possible, has so far notyet been effected. Before penicillin can besynthesized, its exact chemical compositionmust be known. However, the difficultiesinvolved in obtaining the absolutely puresecretion of Penicalium 1wtatum (there a.re atleast 100,000 molds and fungi, and there arealways spores of some of these molds in theair) have resulted in several formulas forthe chemical composition of penicillin havingbeen advanced so far. Some scientistsregard it as a peptide of the formula~4H32N2012; others claim it to be a hydro­aromatic compound C2,HStOlO..~2 or C14H I9OaN or C2tHS6011N; and finally there i:; onegroup of scientists who maintain that penicil­lin is a nitrogenfree compound.

Nor is it possible to determine the weightof the penicillin contained in a given solutionwithout an exact knowledge of the chemicalcomposition,although the exactdeterminat ionof the penicillin content of such a solutionis essential to its therapeutical application.Hence the biological test method has beenresorted to. That quantity of penicillin wasdetermined which, dissolved in 50 cc of meatextract., was just able completely to arrestthe growth of a specific culture of Staphy­loc()ccu8 aureus. This quantity was namedan Oxford unit, or also a Florey or HeatIeyunit. In view of the rapid secretion ofpenicillin from the body, vast quantities ofthese units are needed. In the case ofpneumococci infections, for inst.ance, theamount of penicillin needed for a cure isaround 100,000 Oxford units, while there

impurities without destroying itsy. Now it became possible to study

_ bacteriological and pharmacological~teristics of penicillin by means of

. ents on animals. The following im­J,8$Dt facts were established :

(I) Absence of any toxic effects on mice.'other animals.

f2) White blood corpuscles and tissuetultures are not harmed by concentrationsIevera1 hundred times greater than arelIeCe88lU'y for preventing the growth ofIlIcteria.

(3) The efficacy is affected neither byblood, pus, nor putrefaction of tissues.

(4) The efficacy is also scarcely affected.y the number of bacteria present.

(5) Penicillin is absorbed when injectediito muscle or blood stream.

(6) Penicillin is useless when given bymouth aB it is destroyed by acid stomachjuices.

(7) Penicillin disappears from the bloodwithin two hours, being largely excreted in~e urine; hence large doses must be givenat short intervals for several days.

. The examination of the efficacy of penicil­lin on the germs of the various infectiousdiseases showed that penicillin, too, is nopanacea against all pathogenic germs. Thefollowing bacteria. proved to be particularlylensitive to the drug: Streptococcus PYOf/enes(suppurating wounds, puerperal fever);Staphylococcu8 aureU8 (diseases of the bone,,carbuncles); Streptococcus pneumQniae (pneu­monia); Corynebacterium dl:phtheriae (diph­theria); Clostridium welchi-i, septicum, oedema­hens (gas gangrene) ; Neisseria gonorrhoeae(gonorrhea); Neisseria meningitidis (meningi­iis, typhus). Less sensitive were, on theother hand, the germs causing typhoid fever.',Wholly resistant were those of plague,oholera, dysentery, and tuberculosis.

Penicillin's effectiveness consists in that itprevents the dividing and multiplying of thebacteria affected by it. The drug is, ineffect, as the technical term has it, a bac­teriostatic, while most antiseptics as, forexample, carbolic acid, kill the bacteriadirectly.

Although the characteristics of penicillinwere now known and the experiments onanimals had pro\ided good results, thedrug was still far from being introducedinto general medical practice. Again it was

have been reports on the curing of serioUIstreptococcus cases which mention the in­jection of 830,000 to 7,900,000 Oxford units.

According to the latest information, thereare seven manufacturers in Great Britainand 21 in America (two Canadian, the restUS) now producing penicillin or soon to bein production. America expecu about 200billion units a month to be produced by theend of the yeM. The American factorieswill have a· top capacity of nine pounds(almOllt i billion units) a day, comparedwith a total production last year of about15 pounds. Prices now vary from US$2.85to $10 for 100,000 uniu (la,gt year's price:$20).

The small quantities produced until re­cently make it obvious that there are notnearly as many reportll available on 8UCCe8ll­ful treatment.s as was the case some tenyears ago when the sulfonamides were intro·duced. Nevcrthele88, there exists alreadyenough material to permit the conclusionthat, in cases where sufficient quantities ofpenicillin are obtainable, the drug canproduce amazing results.

By far the greatest experience has beengained in the treating of war wounds withpenicillin. The bacteriologist Florey andthe surgeon Cairns of Oxford joined theBritish troops in ~.orth Africa and Italy forthree months to make observatious on thespot. After some initial failures. they ob­tained very favorable results. The dangerof infection in the case of war wounds waspractically eliminated. The best resultswere achieved by powdering the woundswith a mixture of penicillin and sulfonamide.

Extremely impre88ivc results were at­tained with penicillin in the treatment ofsulfonamide-resistant cases of gonorrheawhich, with few exceptioll1l, were cured intwo days. Numerous cases of otherwisehopeless staphylococcus infections were alsocured with penicillin, among them osteomy­letitis (inflammation of the bone marrow),infections of the skin- and subcutaneoustissues (furuncles, etc.), and other infectioll1l.

In the case of pnewnococcus and meningo.coccus infections, experience has provedfavorable but not extensive, as here theexcellence of the sulfonamides is undisputed,and there is no rea.son to employ penicillinfor diseases in which simpler methods leadto· the same result. The same applies to alarge number of other infectious diseases,such as arthritis, infections of the urinary

tract, infections of the noee, sinus, and ••uloers, cellulitis, infections of the haudI,burns, etc. Many authors report on es.cellent results with penicillin in the t;reM.ment of these diseases; but at the mOllltlll&these fields of indication are of no practioilsignificance. For almost the entire pl'ellllUproduction goes to the armed forces for thetreatment of &1l kinds of wounds, only a8Dl&1l surplus being released for the treat­ment of civilians. Naturally, this limitedquantity is reserved mainly for such Cuelwhere other drugs have failed.

Whether penicillin will hold its own besidethe proven medicaments used today, orwhether it may even repIaoe these, will onlybecome apparent when the medical worldcan be supplied with unlimited quantities atcompetitive prices, which is not yet thecase. It looks as if penicillin or similarby-producu of other microorganisms, 8uchas pyocyanase, tyrothricin, gramicidin,claviformin, patulin, spinul08in, citrinin,gliotoxin, aspergillin, flavicin, clavacin, andactinomycin, may be able to close the gapeleft by the sulfonamide therapy. Vmoosreportll have already been published accord·ing to which most human and animal patho­genic germs can be arrested in their growthby one or the other antibiotic. This is alaotrue of the particularly insell1litive acid·resisting bacilli. Indeed, even the tuber·culosis bacillus, which is otherwise practicallyimpregnable, has been succe88fully attackedby preventing its growth, not by penioillin,but by actinomycin, an antibiotic a,nalogoulto penicillin but obtained from a differentmold.

It would thus appear as if, wit.h the aidof antibiotic and chemothera.peutic sub­stances, practically all infectious diseaseswill be preventable or curable in future. Itis also entirely within the realm of po88ibility- and this is Florey's opinion too - thatan antibiotic will be obtained one dayfrom one of the countlo88 microorgan­isms which will prove to be tho universalcure for &1l diseases caWled by germs.

Perhaps a step in this direction hasalready been made in Japan, where Pro·fesser Dr. Masahiko Kuroya of the TohokuImperial University and his assistant Dr.Shikaji Kondo recently announced thediscovery of a new type of penicillin witha fungus.growth-prevention power manytimes greater than t,hat of Dr. Fleming'spenicillin.