PENICILLINASE RESISTANT PENICILLINS TREATMENT OF … · staphylococcal disease. Wehave used four of these new penicillins (methicillin, nafcillin, oxacillin and cloxacillin) in the

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although it has the advantage of being givenorally, seems less effective, and ampicillinsimilarly. Comparative statistical evidence ofthe value of the various penicillins and of theantibiotics is not available, and would bedifficult to obtain, but I have no personaldoubt that at present in the acute infectionmethicillin and chloramphenical are the twomost effective drugs.A major anxiety is the development of

bacterial resistance in the child with repeatedor persistent infection. This develops sooneror later in all these children and makes thecontinued prophylactic use of antibioticsunwise.

An antibiotic free from this drawback wouldbe of the greatest value: in about 12 childrenwith cystic fibrosis treated for up to one yearwith daily fucidin I have as yet had no caseof drug resistance. But this may in anycase not develop with any drug given prophyl-lactically for a year or more.For the pseudomonas there appears to be

no 'answer at present, whether the antibioticis given by mouth, injection or by aerosol.

REFERENCES

IACOCCA, V. F., BIBINGA, M. S., and BARBERO, G. J.(1963): Amer. J. Dis. Child., 106, 315.

PENICILLINASE RESISTANT PENICILLINS IN THETREATMENT OF SURGICAL STAPHYLOCOCCAL

INFECTIONSALEXANDER M. RUTENBURG

Beth Israel Hospital, 330 Brookline A venue, Boston 15, Massachusetts

THE development of a unique series of synthe-tic penicillins resistant to hydrolysis by penicil-linase has permitted effective control ofstaphylococcal disease.We have used four of these new penicillins

(methicillin, nafcillin, oxacillin and cloxacillin)in the treatment of about 500 patients withstaphylococcal infections, half of whom hadfailed to respond to therapy with otherantibiotics.

Staphylococci resistant to penicillin G aloneor along with other micro-organisms werecultured prior to new penicillin therapy in allpatients. Patients with well localized areas ofsuppuration without systemic reaction orwithout evidence of spreading infection whocould be expected to respond to incision anddrainage only, were not included. The condi-tions treated can be summarized under thefollowing classifications:

1. Primary soft tissue infections.2. Post-operative wound infections.3. Intra-abdominal sepsis.4. Infections complicaiing peripheral vas-

cular disease.5. Lower respiratory tract infections.6. Enterocolitis.7. Septicemia.

8. Osteomyelitis.9. Miscellaneous infections.Results were evaluated on a clinical and

bacteriological basis. Criteria for a goodresult were: subjective improvement, defer-vescence within 48-72 hours, return of theelevated leukocyte count to normal, steriliza-tion of an infected nidus such as woundexudate, urine, sputum or blood and woundhealing.

If these responses were not elicited theresult was considered poor. Seventy-eight percent of patients with a variety of staphylococcalinfections responded to therapy with the newantistaphylococcal penicillins.For the purpose of this discussion I should

like to deal in greater detail with the use ofthe new penicillins in the treatment ofstaphylococcal enterocolitis, septicemia andcertain types of soft tissue infections.

EnterocolitisThirteen patients with staphylococcal entero-

colitis had received prior broad spectrum anti-biotic therapy either in the form of tetracyclineor neomycin sulfate and phthalylsulfathiazole(Sulfathalidine) for preoperative bowel pre-paration. All were dehydrated and had

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H. R. POST OPERATIVE ENTEROCOLITIS

104

103

LiL 102 /a:H 101-

LU 99-H 98.6-

98

97-

140-130*- , ,, %_% ,%

1 000X

LU 90-Cl)-J 80

,1 70- "6050

Staphcil lin1.5 Gms. qid

Stools 2695 2080 525 265 895

DAYS 2 3 4 5 6 7 8 9FIG. 1.-Postoperative enterocolitis in a 65-year-old woman.

electrolyte imbalance from profuse, watery-diarrhcea. Clinically they were febrile and hadtachycardia, abdominal distension and tender-ness. Two patients were hypotensive. Tenpatients received oxacillin, two methicillin andone cloxacillin. The duration of therapy rangedfrom four to 17 days. All 13 patients showeda good response with subsidence of diarrhoea,clinical improvement, eradication of staphylo-cocci from the stools, and return to normalfecal flora.An illustrative case (Fig. 1) is a 65-year-old woman

with profuse, watery diarrhoea, fever of 1030 F.,tachycardia, leukocytosis and fluid and electrolyteloss three days after an abdominal operation.Staphylococci in pure culture were identified on

stool smear and culture. Tetracycline, which she hadbeen receiving since operation, was discontinued andmethicillin (1.5 g every six hours) administered.Within 48 hours she was afebrile, the diarrhoeasubsided, and staphylococci were eliminated fromthe stool. She received methicillin for eight days andwas discharged well on the 11th postoperative day.Figure 2 shows the result of oxacillin therapy in

a patient who developed staphylococcal enterocolitiswhile receiving neomycin.

Figure 3 shows the postoperative progress of an84-year-old patient who developed staphylococcalenterocolitis after operation and showed a goodresponse to oxacillin.

SepticemiaTwenty-one patients with a clinical diagnosis

of septicemia received oxacillin. The primary



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105102- -

TEMP. ioo -*-..98696

OXACILLIN DAOELY4 I|

STOOL CULTURE + + + + - - -FOR STAPH. AUREUS

NEOMYCIN -';fl

DIARRHEA STOOL

POST. OP. DAYS * 4 5 6 7 8 9 10

FIG. 2.-Staphylococcal enteritis post porta-caval shunt in 53 year old male.

102

TEMP *-ns96

OXACILLIN - lO q L0Q P.o. q6h.STOOL CULTURE + + + O O O °STAPH.AUREUS+ + + 0 0 0 0

DIARRHEASTOOLS I I a * * l 1 0

DAYS 24 25 26 27 28 29 30 31

FIG. 3.-Postoperative staphylo-coccal enteritis in 84 year oldmale.

sites of the infection included the skin, lungs, thewound, an indwelling intravenous polyethylenecatheter, deep soft tissue abscess, the heart(endocarditis), and an aortic prosthesis. Allwere acutely ill with fever, leukocytosis, andother signs of acute systemic infection. Four-teen of the 21 patients had failed to respondto prior antibiotic therapy. In all patientsstaphylococci were isolated from the blood.The critically ill patients received oxacillin ormethicillin intravenously for the first 48 to 96hours. L arger doses of methicillin than oxacil-

lin were required. Subsequently, the drug wasgiven intramuscularly (0.5 to 1.0 g. every 4 to6 hours). Four received oxacillin intramuscu-larly from the beginning of therapy. Durationof therapy ranged from 10 to 20 days in mostinstances.

Fifteen of the 21 patients responded totherapy. The blood was sterilized and therewas no recurrence within a six to ten weekperiod of observation. In one patient theresult was indeterminate because of concurrenttherapy with chloramphenicol. The second



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POSTOP. DAYS 9 10 11 12 13 14 15 16 17 18 19 20 37 38 39 40 41 42

106 LAPAROTOMY BACK PAINLAPAROTOMY102

I0I

TEMP. 100j

99-98.6.

98- DIED

BLOOD) WOUND - E. COLI

CULTURES PERIT. S. AUREUS BLOODP GRAFT-S. AUREUSAORTASTERILE

GRAFTS PERIT.)

P - 50 - mi-i -

PROSTAPHLINAM.I

FIG. 4.-60 year old male with septicemia-infected aortic graft.

patient (Fig. 4) developed intermittent feverand leukocytosis nine days after resection of anaortic aneurysm and dacron graft. He wasexplored because of sudden vascular collapse.At operation he had extensive periaortic andperigraft sepsis with septic intra-aorticthrombosis. Cultures of the peritoneal exudate,aorta, aortic thrombus, and peripheral bloodyielded coagulase-positive penicillin G-resistantStaph. aureus which was sensitive to oxacillin(M.I.C. 0.18 ,ug./ml.). Postoperatively hereceived oxacillin intramuscularly (3 g.) andintraperitoneally (1.5 g.). His recovery wasremarkably prompt and progressive withsterilization of the blood land peritoneal fluid.A wound infection due to Esch. coli was con-trolled with a-amino benzyl penicillin (2 to4 g. daily). He was well until the 37th dayafter the exploratory laparotomy when hedeveloped severe back pain. Explorationrevealed leakage at the aortic suture line witha huge retroperitoneal hematoma. The graftwas replaced with considerable difficulty.Cultures of a segment of the old dacron graftyielded Staph. aureus. This confirmed thefamiliar contention that infections cannot becontrolled nor wounds sterilized in the pre-sence of a foreign body. His subsequent post-operative course was poor. He developed

auricular fibrillation, vascular collapse, anddied 72 hours later, probably because ofmyocardial infarction. At post mortem therewas no evidence of infection, thrombosis, orleakage at the graft site. A third patient failedto respond because of inadequate therapy.Three patients died within one to four daysinitiation of oxacillin therapy.

ilustrative CasesCase 1. A 64-year-old diabetic with glomerulone-

phritis developed a staphylococcal urinary tractinfection after insertion of an indwelling catheter(Fig. 5). He failed to respond to penicillin G,erythromycin, and chloramphenicol given concur-rently. He was critically ill with intermittent feverto 104'F., and coagulase-positive Staph. aureus wascultured from his blood. Methicillin (20 g./day individed doses, was given intravenously fortwo days and intramuscularly (12 g./day individed doses) for seven days. Thereafter, he showedsterilization of the blood and gradual subsidence ofthe signs and symptoms of his infection. Methicillintherapy was continued intramuscularly for 25 addi-tional days with a gradual decrease in the daily dose.He was cured after 34 days of treatment with atotal dose of 274 g.

Case 2. A 34-year-old male with chronic myelo-genous leukemia received corticosteroids, radiationand alkylating agents. He developed extensive soft-tissue infections with multiple furuncles and car-buncles which involved most of his body surfacesand a septicemia due to Staph. aureus resistant topenicillin G, streptomycin, tetracycline and chlor-



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HOSPITAL DAYS 5 10 15 20 25 30 40

104

103-

102-

TEMP. 101-

100,

9998.6

98

20-TOTAL

DAILY 15-

DOSE I0-METHICILLIN

(gns.) 5

FIG. 5.-64 year old male with staphylococcalsepticemia, glomerulonephritis and diabetesmellitus.

HOSPITAL DAYS 20 22 241 26128 30 32 1 34 36 38

103-

102-

TEMP. K00-

99 L98.6

98.

Debrideoments

BLOOD B WOUNDS + +STAPH AUREUS __+ _ -_ -_-

METHICILLIN

PREDNISONE

ALKYLATINGAGENT

FIG. 6.-34 year old male with leukemia,multiple carbuncles and septicemia.

TEMP. 102 X98696-140 -

000PULSE. 20

BLOOD CULTURE+FOR STAPH. AUREUS ++ + + 0 0 0 0

OXACILLIN - .V. I.u 1.oqgCHLOROMYCETIN -

PENICILLIN G , .1DAYS IN HOSP. 5 6 7 8 9 10 11 12 13 14 15 16

FIG. 7.-Septicemia stemming from anindwelling intravenous catheter in 86 yearold female.



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FIG. 8.-61 Staphylococcal septicemia, allergicvasculitis and soft tissue sepsis.

amphenicol. He was in severe pain, febrile andsemicomatose. After 24 hours of intravenous methi-cillin therapy (8 g.) his striking improvement (Fig.6) and control of infection permitted appropriatesurgical excision, drainage and debridement of 62soft-tissue lesions. After six days of therapy, cul-tures of the wounds, peripheral blood and pharynxwere negative for staphylococci. He recovered fromhis infection after three weeks of methicillintherapy.Case 3 shows response to oxacillin of a patient

with staphylococcal septicemia stemming fromindwelling intravenous catheter (Fig. 7).Case 4. A 61-year-old patient with hypertension

and renal failure due to "allergic" vasculitis deve-loped suppurative lesions of the buttock, presacralarea and elbow while receiving corticosteroids.Staphylococci were cultured from his wounds aswell as his blood. After 24 hours of methicillintherapy (Fig. 8) he showed defervescence and strik-ing control of his infection. Adequate drainageof all soft-tissue lesions was established by excisionof suppurative necrotic tissue. Thereafter, hebecame afebrile and wound cultures were negativefor staphylococci. Methicillin was continued for 25days during which secondary closure of the largesoft-tissue defects was carried out successfully.

CommentThese data indicate the efficacy of methicil-

lin and oxacillin in the treatment of staphylo-coccal septicemia. The survival of 15 of 21patients, in many of whom the infection was

compounded by underlying chronic disease, isan eloquent testimony of the efficacy of semi-synthetic penicillins in this disease. It ispossible that the dosage of oxacillin or methi-cillin administered was greater than the mini-mum requirement and equally satisfactorytherapeutic results could have been achievedwith lower dosages. This can be determinedby further clinical experience.

CarbunculosisA third category of staphylococcal infections

treated with methicillin, oxacillin, nafcillin andcloxacillin consists of over 100 patients withfurunculosis and carbunculosis. In many, con-ventional incision and drainage was inadequateand resulted in persistence of local suppura-tion as well as seeding of satellite lesions andmore distant furuncles and carbuncles. A moreadequate removal of all necrotic and suppura-tive tissue accomplished by elliptical excisionalong with methicillin, oxacillin, cloxacillin ornafcillin therapy resulted in prompt control ofthe infection. In several instances subsequentskin grafts or closure of the defect with aZ-plasty or full thickness flap were required.

Another illustrative case is that of a 67-year-old diabetic with a history of chronic recur-rent furunculosis who developed a giantstaphylococcal carbuncle in the left posteriorchest. He had failed to respond to incisionand drainage and therapy with penicillin G,streptomycin, erythromycin, tetracycline andchloramphenicol. After 24 hours of methicillintherapy the suppurative lesion was widelyexcised. Methicillin therapy was continuedand two weeks thereafter closure of the cleanwound was accomplished with the aid of asplit thicklness skin graft. His recovery wasuneventful.

In these patients with recurrent staphylo-coccal infections new penicillin administrationfor 15 to 120 days was required. After initialclearance with the first course of therapy,recurrences were seen in about 10% andthese patients required an additional courseof therapy. Thereafter, these patients andthose who responded to the initial course oftherapy remained free from infection for thesix to 12 months of follow-up observations.

DiscussionFrom the use of these four synthetic penicil-

lins in a large group of patients with varioustypes of staphylococcal infections, the follow-ing impressions have emerged:

I



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(1) All are effective in vitro and in vivoagainst penicillinase producing staphylococciand most other common gram positivebacteria.

(2) Oxacillin appears to be the most effectiveagent for intramuscular or intravenous injec-tion in the treatment of infections due topenicillin G-resistant staphylococci. In vitroand pharmacological data suggest that paren-teral oxacillin is superior to methicillin largelybecause of the lower amounts of the drugrequired.

(3) Cloxacillin is most useful for oral useand yields more regular absorption thianoxacillin and nafcillin and more uniform andhigher serum levels. It appears to be superiorto oxacillin because of better and more uni-form absorption after ingestion, lower degrada-tion by the liver and possibly greater resistanceto penicillinase hydrolysis than other syntheticpenicillins (Bunn and Milicich, 1963; Graven-kemper, Sweedler, Brodie, Sidell and Kirby,1963).Although the new penicillins are also

effective against certain other gram-positivebacteria such as streptococci andpneumococci on a weight basis, they are lessactive against these micro-organisms than ispenicillin G. Staphylococci resistant to peni-cillin G required higher concentrations ofoxacillin, methicillin, cloxacillin or nafcillinfor inhibition than did penicillin G sensitivestaphylococci, pneumococci and certain sensi-tive strains of streptococci. Therefore, the newpenicillins are not the drugs of choice forthe treatment of infections due to gram-positive bacteria other than penicillinase-producing staphylococci. However, dosesrecommended for the control of infectionsdue to the latter micro-organisms are suffi-ciently large to also control infections due topneumococci, penicillin G-sensitive staphylo-cocci and most strains of streptococci. Thenew penicillins are ineffective against gramnegative bacteria and most strains of Strept.fecalis.As with other antibiotics the new penicillins

are effective in the treatment of surgical infec-tions of the soft tissues if coupled with appro-priate surgical management. After removal offoreign bodies, drainage of abscesses, anddebridement of necrotic tissue the recovery ofmany critically ill patients furnished evidenceof the considerable efficacy of the supportivevalue of these drugs. High dosage and pro-longed therapy are sometimes required, par-

ticularly in septicemia, and certain otherrecurrent infections, as furunculosis.The new penicillins demonstrated apparent

efficacy in the treatment of a large series ofpatients with staphylococcal infections.However, the lack of untreated controls or

patients alternately treated with other anti-biotics imposes obvious reservations ondefining the relative value of these agents incomparison to certain other antibiotics in thecontrol of staphylococcal infections. On theother hand, of the wide variety of infectionstreated the satisfactory responses of patientswith enterocolitis and septicemia evince theeffectiveness of new penicillin therapy. Inmany of these patients new penicillin therapywas initiated promptly on the basis of theclinical diagnosis. The infection was also fre-quently presumed to be due to staphylococcion the basis of a smear and a gram stain andsubsequently confirmed by culture. Failure toinstitute prompt therapy can result in thera-peutic failure.Of the patients with severe infections who

did not respond, failure was attributed toinfections due to resistant strains of gram-negative bacteria or Strept. fecalis, death of amoribund patient early in therapy, or thepresence of an indwelling foreign body orundrained sepsis. In a few patients receivingconcurrent therapy with other antibiotics, thegood response could not be attributed solelyto the new penicillin. The prompt response tooxacillin, methicillin or cloxacillin therapy ofall gravely ill patients with staphylococcalenterocolitis was particularly striking.

Superinfections with gram-negative bacteriaduring therapy occurred in patients withwound infections, occlusive peripheral vasculardisease, and infections of the respiratory tract.Repopulation of the wounds or sputum withgram-negative bacteria was not always asso-ciated with symptomatic superinfection, andtreatment with other antibiotics was notrequired in all of these patients.

Evaluation of the proper role of the newpenicillins in the recovery of patients with softtissue infections was more difficult because ofadjuvant measures such as incision and drain-age of localized lesions, debridement, removalof foreign bodies, local heat, etc. However,most of these patients were seriously ill withspreading staphylococcal infections and anti-biotic therapy was required to control theextension of the septic process or metastaticspread.



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Staphylococcal strains resistant to oxacillinor cloxacillin were not encountered. Pastexperience with methicillin, as well as withother antibiotics, has shown that resistantstrains occasionally develop following pro-longed and injudicious use of these agents. Itis possible that the same situ!ation may arisewith oxacillin or cloxacillin, although so farno post-therapy-resistant strains have beenreported. The useful life of these drugs willbe extended by avoidance of routine prophy-lactic use and inadequate dosage forms and byemploying appropriate surgical managementof the infection, including adequate drainage,debridement, removal of foreign bodies, etc.

In a few patients gastrointestinal side effectsensued with the larger doses of oral oxacillinand nafcillin but not as yet with cloxacillin.Characteristic "penicillin" type of rash wasalso observed with all of the new penicillinsand therefore, all new semisynthetic penicillinsshould be administered with care to patientswith a history of allergy to penicillin G. Onthe other hand, of 20 patients previously

sensitive to penicillin G, 16 did not react tooxacillin and four did not react to cloxacillin.However, hypersensitivity to penicillin G issometimes not seen during 'a repeat course,so that the absence of such symptoms, whenoxacillin, given after a previous course ofpenicillin G had produced a hypersensitivityreaction, does not always indicate that thepatient was hypersensitive to penicillin G andnot to oxacillin.Minimal requirements of therapy are early

recognition and bacteriological diagnosis,prompt and adequate antibiotic therapy withan effective agent, and surgical control of theprimary foci of infection by drainage, debride-ment and removal of foreign bodies.

REFERENCESBUNN, P. A., and MILICICH, S. (1963): Antimicrobial

Agents and Chemotherapy, Amer. Soc. Micro-biol., p. 220.

GRAVENKEMPER, C. F., SWEEDLER, D. R., BRODIE,J. L., SIDELL, S., and KiRBY, W. M. M. (1963):Antimicrobial Agents and Chemotherapy, Amer.Soc. Microbiol., p. 231.

DISCUSSIONH. A. VAN GEUNS (The Hague, Holland).

I would like to report some results from twoclinical trials which my colleague Dr. Kerrebijnand I were running at an out-patient clinic forasthmatic children in Queen Juliana's Child-ren's Hospital in the Hague during the 1962/63and 1963/64 winters.Apart from children with simple asthmatic

attacks we see many children with recurrentbronchial infections especially during the wintermonths.

In Holland it is a widely used practice toprotect such children during the winter monthsby continuous administration of sulphonamides.However, we found that about one third of allthe pneumococci isolated from such patientsproved to be resistant to sullphonamides, andthis 'has been confirmed by other Dutch invest-igators.

In our first trial 75 children were studied,their ages ranging from four to twelve years.They had all suffered for at least a year fromrecurrent infections of the lower respiratorytract with an allergic basis. The children con-cerned are all selected cases as we accepted onlythose patients referred from the general out-patient clinic which were judged to be serious

enough to be treated by our special team. Allthe children were first examined by the E.N.T.specialist, and were vaccinated with influenzavirus vaccine.The patients were distributed at random over

three groups of similar age and comparableliving conditions. The prophylactic treatmentwas given each morning before 'breakfast.Group one consisted of 24 children takingpropicillin (125 mgms.), Group two, 26 child-ren taking sulphadimidine (500 mgms.), andGroup three 25 children taking a placebo (onetablet each morning). The experiment wasorganised on a double-blind basis. Every childwas examined at least once a month.The results of the prophylactic treatment

were judged mainly from the number andseverity of the respiratory infections developedby the children. Infection was judged on thebasis of the findings in the sputum, X-rayexamination and 'physical examination. Asecondary criterion was the general impressiongained by the parents of the child's condition inthe period of treatment as compared to thatin the previous year or years.



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PENICILLINASE RESISTANT PENICILLINS TREATMENT OF … · staphylococcal disease. Wehave used four of these new penicillins (methicillin, nafcillin, oxacillin and cloxacillin) in the