POSTGRAD. MED. J. (1964), 40, 590

THE INVESTIGATION OF AN OUTBREAK OFPSEUDOMONAS PYOCYANEA INFECTION

IN A PIEDIATRIC UNITJ. JACOBS, M.D., M.R.C.P., D.C.H.

Visiting Professor of Paediatrics, and Head of Department of Paediatrics, Hadassah University Hospital,University of Jerusalem, Israel.

Consultant Padiatrician, Welsh Regional Hospital Board and United Cardiff Hospitals, Lecturer inPaediatrics, Welsh National School of Medicine.

THE INTRODUCTrION of potent antimicrobialagents has resulted in the lesser frequency ofpotentially fatal infections caused by 8-haemo-lytic streptococci and pneumococci, but thegreater frequency of staphylococcal, fungal andother bacterial infections of the coliform andrelated gram-negative species. Pseudomonaspyocyanea or Ps. aeruginosa owing to its notori-ous resistance to therapy occupies a uniqueposition.

Charrin (1890) first recognised pseudomonasas a pathogen in man and recently manydescriptions of the disease have been given.Curtin (1957), a leader in the Lancet (1961),Rogers (1960), Markley, Audmendi, Charezand Bazan, (1957), Sussman and Stevens (1960),Williams (1960), Lubsen (1961), Curtin, Peters-dros and Sennott (1961), and McCabe and GeeJackson (1962), all warn of the frequencyof the infection in young and debilitatedpatients, in burns, in orthopaedic cases, inurinary problems, in gram negative septicemia,in geriatric patients, in premature infants andthose with congenital abnormalities. Deathswere frequent in most of the series.

Clinical MaterialBetween July, 1960 and March, 1964 some

73 cases of Ps. pyocyanea infection have beenseen in paediatric units in various hospitals inCardiff. The patients could be placed in thefollowing groups:

1. Associated with prematurity-49 patientswith nine deaths including two infants with con-genital abnormality of the urinary tract and onecleft pa'late with other congenital abnormalities,(trisomy 18). These occurred in a prematureunit (A).

2. Associated with congenital abnormalities-16 patients. (a) 12 meningomyeloceles (7 died)in a pxediatric unit (B) (b) one child with cleftlip and palate (trisomy 15-17) (who died laterbut not of the disease) in a paediatric unit (C)(c) one child with hydroureter and hydro-nephrosis (alive) in a paediatric unit (C) (d)two children with abnormal hearts (large

patent ductus; pulmonary atresia) (both died)in a paediatric unit (D) of a chest hospital.

3. Associated with leukwemia- two patients(who died later but not of the disease) in apaediatric unit (C).

4. Associated with chronic disease-twopatients with fibrocystic disease (both diedlater but not of the disease) in a pwediatricunit (C).

5. Chance findings- four patients: - twowith infected urine (in a pxediatric unit), oneneonatal infant with no obvious abnormalitywho survived (in a paediatric unit) and oneneonatal infant with no obvious underlyingabnormality (transferred from a neonatal paedia-tric unit with a chest infection to a chest unit)who died of pyocyaneas infection of lungs.

In these various infants, positive swabs wereobtained from umbilicus (4), urine (29--includ-ing two at post mortem), lung (10-all at postmortem), rectal swabs and stools (51), skin (3),ear (3), eye (3), nose and throat (34), meninges(two-at post mortem) and pericardial fluid(one-at post mortem).

Classical Symptoms and SignsOf the premature infants in group 1, 30 were

admitted from home or from outside maternityunits, whilst 19 were born in the hospitalcontaining the premature unit. The weights laybetween 2 lbs. 4 ozs. (1,023 g.) and 5 lbs. 5 ozs.(2,360 g.). The disease commenced at the age ofone to fifteen days and deaths occurred fromone to twenty-three days after birth. 19 infantshad signs of respiratory distress syndromewithin eight hours of birth and it was difficultto recognise when the respiratory problem hadaltered to one of a generalised infection. Latercases showed a fall in temperature (from95°F to 870°F), a gradual increase in cyanoticattacks and, in some cases a peculiar type ofdiarrhoea with a brownish-black stool, semisolid in character, sometimes with slime orblood. Some infants had an odd membrane onthe mouth, starting with thrush-like whitepatches, but proceeding to small brown

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October, 1964 JACOBS: Investigation of Outbreak of Pseudomonas Pyocyanea Infection 591

lesions with black centres. These lesions spreadto cheek and oropharynx and later to theanus, the rectal margin often being everted.Occasional infants had convulsions (only onebeing associated with meningitis). The infantsregurgitated easily, became anorexic and oftendied after vomiting blood. The abdomenshowed the picture of ileus with distensionand ladder patterning. Oedema was a prominentfeature.

Various skin lesions were seen, a toxicerythema (like erythema multiforme); "ecthymagangrenosum" with a characteristic maculechanging to an indurated area with a blacknecrotic centre; generalised purpura (in oneproceeding to ecchymoses); pustular lesions(being clusters of vesicles growing Ps. pyo-cyanea) and small pink nodules.The blood picture showed little. Anaemia and

leucocytosis were rarely seen, the common find-ing being the presence of toxic granules witha neutrophilic shift to the left. Thrombopeniawas noted in two cases.

Sixteen cases had had previous antibiotictherapy (13 methicillin or cloxacillin and threeampicillin) and of these four died, whereasfive died of the remaining cases not given anti-biotics previously.

In the 16 patients in Group 2, the infectiondeveloped at the operation sites which becamebrown-black and necrotic. Meningitis appearedwith the usual physical signs (pyrexia, neckstiffness, bulging of fontanelle, lethargy, vomit-ing, cyanotic attacks and convulsions.Occasionally patients seemed to ,live in symbio-sis with the organism. Death was from septic-aemia and meningitis. Antibiotics had beenpreviously used. The patients in the chest unitwere considered to be cardiac problems, inone instance with a superadded pulmonaryinfection. Skin lesions developed in one justbefore death, whilst in both the organism wasonly found at death (again antibiotics had beenused).

In groups 3 and 4, infective episodes wereshown to be due to Ps,pyocyanea infection, butthe patients survived. All patients had been onantibiotics, the leukaemia' patients also havinghad steroids and methotrexate.

In group 5 one mature infant died at theage of five weeks in a chest unit after transferfrom a neonatal unit. Multiple antibiotics hadbeen given for a chest infection, but ventilationbecome inadequate even after tracheostomy.Post Mortem FindingsThe characteristic lesion on the tongue

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FIG. 1.-Skin, showing arteritis of vessel in dermis.H& E X 80.

showed an area of muscle necrosis and infiltra-tion. Gram stains showed numerous gramnegative bacilli in the necrotic areas. The lungsshowed intra-alveolar and intra-bronchial poly-morphonuclear exudates and haemorrhage. Inplaces there was necrosis and abscess formationwith gram negative bacilli. The walls of smallblood vessels showed acute inflammatoryarteritis (Fig. 1) the thrombosis secondary tothis leading to arterial occlusion and smallinfarct-like areas (Fraenkel, 1917). The affinityof the organism for the wal,ls of small vesselswas seen in all tissues showing lesions, i.e.,skin, lung, brain and kidney. (Fig. 1).

In the gut necrotic non-exudative lesions wereseen with a yellowish opaque centre and deepred margins.Investigation of Epidemics

In the premature unit involved, cases haveoccurred over a period of more than three-and-a-half years. Conditions in such a unit areconducive to epidemics in that infants arein debilitating situations, often being verysmall, occasionally having congenital abnormal-ities liable to high levels of bilirubin withresultant lethargy and difficulty in feeding,while the unit is liable to sudden increases innumbers in the ward with overcrowdingof nurse/patient ratio. Such patients are proneto respiratory difficulties and tend to be treatedwith an "antibiotic cover" to prevent possibleinfection or deal with apparent infection. Againbeing small and in poor condition they tend tobe nursed in an incubator with a relativelyhigh humidity atmosphere. (Hoffmann &Finberg, 1955). The ambient temperature andhumidity in a premature unit tends to be higherthan average. All these conditions produce asituation in which infections like Monilia

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592 POSTGRADUATE MEDICAL JOURNAL October, 1964

TABLE IMODES OF SPREAD

Dust Previous casesDust 1 Methods of cleaningAirborne Incubators, Air-particles Humidifiers conditioning

Hand driersNose

HandsDressings

Contact Suction tubes, oxygen supply"Sterilising" materials (quarternary com-pounds, etc.).Injections

Procedures Lumbar punctureIntravenous tubes

albicans and Ps. pyocyanea tend to flourish.All the cases concerned in the unit had been

in incubators. Those admitted from other unitscould not have been initially affected in thisway. All methods of spread were considered(Table 1).Swabs were taken (1) from skin, nose and

throat of all personnel (doctors, nurses, tech-nicians, cleaners, mothers), (2) piped oxygensets. (3) Floors, wal,ls, basins and sinks (4)incubators-from the water in the humiditytank as well as walls and floor of the appara-tus. Plates were put out in the unit.

All chemical antiseptic procedures werereviewed-the fluid in the tube holding thermo-meters, for keeping polythene tubes for feeding,for cleaning tubing, for cleaning incubators,etc.Drying procedures, the use of hot air hand

driers, towels, both ordinary and paper, werelooked at as a possible sourse of infection.

Techniques used were found to beinadequate. Quaternary compounds werebeing used in many places (incubator,thermometer tubes, Woolf bottles, for dampingdust and cleaning tubing). Rubber tubingwas left attached to suction apparatus andfound to contain moisture.

No positive swabs were found initially inany part of the unit except in the incubatorswhich had held a case. Later swabs werepositive in various sinks.A general investigation in various wards in

the hospital (including the labour ward), andnearby hospitals, showed that there was nouniform policy in any section with regardto sterilization. For thermometers sterilization(Table 2) involved the use of some six differentmaterials-some of which looked nice but wereof no value from a sterilization point of view.Brushes were cleaned in a variety of substances;rubber tubing was treated with one of sevendifferent media. In general the antiseptic usedrelated to the material which the sister incharge of a ward had been accustomed tousing in her training hospital. With regard tostrength of solution used, it could be takenas a general rule that wherever solutions weremade up on the ward from a stock solutionwhich required diluting, the final solutior wasusually dependent on how the person makingup the solution felt about the colour ratherthan on suggested dilutions needed.

In the chest unit where the two childrenwere infected, about eight adult chest caseswere also infected. Here positive swabs wereobtained from the noses of radiographer, physio-therapist, nurses, orderlies, cleaner, laboratorytechnician and one doctor, as well as in therubber tubing attached to anaesthetic appara-tus, sucker, nozzle, a brush from a cleaningbottle, the outside of a pulmoflater and alsoon plates put in the post-operative ward.Positive swabs were obtained from a sinkand from a wall.

In the unit with the meningomyeloceles, thepositive swabs were obtained from the sinkdisposal unit, but not from the atmosphere orany personnel.

In the units concerned an attempt was firstmade to assess the value of antiseptics incommon use. Dilutions of antiseptic in termsof the active ingredient 'after a 21-minute

TABLE 2THERMOMETERS

Hospital Hospital Hospital Hospital Hospital'A' 'B' 'C' 'D' 'E'

Roccal (5) Glycothymoline (13) Savlon (1) Phenol (1) Glycothymoline (7)Glycothymoline (3) Glycothymoline (7) Glycothymoline (3)Savlon (2) Hibitane (1) Hibitane (5)Bradosol (4)Dettol (1)Hibitane (2)

(The number represent the numbers of wards using material)

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October, 1964 JACOBS: Investigation of Outbreak of Pseudomonas Pyocyanea Infection 593

contact test of antiseptic and bacteria werenoted (Table 3), Table 4 shows the ratiobetween dilution for complete kill andrecommended strength.A change was made in the premature unit

to the use of hibitane, C.T.A.B. and hexa-chlorophene, as well as savlon (a mixture ofchlorhexidine 1.5 per cent. w/v, -and centri-mide 15 per cent). Ps. pyocyanea has beenshown to survive in cetrimide alone('Cetavlon'), (cetyltrimethylammonium cro-mide) (Robinson 1957) especially when barkcorks were used in the bottles. Anderson(1959) grew the organism in the humidifyingwater in an operating theatre ventilation plant.Coliform bacteria have also been found at thesame site, also in incubators and where lumbarpuncture needles have been inadequatelycleansed. McLeod and Mason (1963) haveshown how topical antibiotics ('polybactrin'polymyxin 0.4 per cent., neomycin 1 per centand bacitracin 1 per cent) are superior tochlorhexidine or domiphen as local methodsof killing bacteria.

TreatmentThe tendency of Ps. pyocyanea infections to

occur in damaged ischaemic and fibrotic ordebilitated patients (premature infants, con-genital abnormality, "poor genetic material"-trisomy 15-17, 18 etc.") (Smith 1963) makestherapy difficult. The most important part oftreatment is prevention of the entry of theorganism into the patient, but as the organismis ubiquitous this means keeping a carefulcheck on the conditions of susceptible patientsand their surroundings. (Table 5). Regularsurveys must be taken of personnel, apparatus,procedures and antiseptics in use. Greatthought must be taken before antibiotics areprescribed and their use in prophylaxis aban-doned. "Chemotherapy without bacteriologyis guesswork." Serious considerations shouldbe given to the use of disposable apparatusof all kinds-brushes, tubing, syringes, needlesand so on, so that the need for the use ofantiseptics will diminish.A relief can be obtained by closing down a

particular unit and fumigating with formalde-hyde vapour. In the premature unit involvedthis procedure has had to be repeated for onlytemporary relief has been obtained, and theinfection has continued for almost four years.The sinks have given an intermittentpositive finding of organisms to a degree thatone wondered whether the U-tube part of the

TABLE 32m-MINUTE CONTACT TESTS OF ANTISEPTICS WITHBACTERIA IN WATER, BROTH AND 25% BLOOD BROTH

Ps.pyocyanea25%

Water Broth BloodHibitane (Chlorhexidine) 80,000 20,000 2,000Domiphen bromide ,(Bradosol) 48,000 2,000 400Phenoctide 10,000 400 100p,Chlor-m-xylenol 3,330 312 1044.8 % solutionCetavlon (Cetrimide) 8,000 1,000 400Benzalkonium chloride (Roccal) 32,000 1,500 500Sodium Hypochlorite 10,000 200The figure show the final dilution of antiseptic in

terms of the active ingredient

TABLE 4RATIO BETWEEN DILUTION FOR COMPLETE KILL ANDRECOMMENDED USER STRENGTH-22 MINUTE CONTACT

Recommended Ps.pyocyaneadilution formidwifery 25 %

lotion Broth bloodHibitane 2% 1/40 10 1Domiphen bromide 5% 1/100 1 0.2p-Chlor-m-xylenol 1/25 0.6 0.24.8% solutionCetavlon 1% 1/10 1 0.4Benzalkonium chloride 1/10-1/20 1.5-7.5 0.4-0.21%Sodium hypochlorite 1% 1/20 0.025

TABLE 5PREVENTION

1. Review of all chemical antiseptic procedures2. Review use of antibiotics3. Review water-borne carriage of disease (also air-

borne)4. Bacteriological supervision of staff, patients5. Isolation of cases6. Adequate treatment7. Closure of unit

drainage might represent a constant source ofre-infection. An attempt to sterilize this areaby use of Phenoxetol (phenoxyethanol) instrength above one per cent or WescodyneFluid (Iodine-detergent complex (idophor)from 1/160 (one ounce to a gallon) to 1/20(eight ounces to the gallon)), Dettol and Lysolhave had only a temporary effect on thepositive swabs from the washbasin and sinks.Treatment of the actual disease in a patienthas varied from the use of Phenoxetol one per

cent as a local application to a skin lesion orto a discharging ear, to streptomycin by intra-muscular injections alone (dosage 20-40

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594 POSTGRADUATE MEDICAL JOURNAL October, 1964

mg./kg./day) or with polymyxin B. Colistinhas been used in the majority and thiosporinin about three cases. Of the nine deaths inthe premature group, three were virtually deadbefore treatment was started (as were the twocases in the chest unit), two more were treatedearly in the experience of polymyxin, theremaining four being two with colistin and twowith thiosporin.The experience of finding infants apparently

having respiratory distress with positive swabsfor Ps. pyocyanea is becoming increasinglycommon (personal communications-otherunits). There is now a tendency to treat anyepisode of pyrexia changing to hypothermiaof odd ileus or skin rash or sudden anorexiain the premature babies, by giving one of thepolymyxin series.The polymyxin preparations used have been

polymyxin B. sulphate, sulphomethylpolymyxin(both in dosages of 2,000 units/kg. 4 hourly),colistin sulphate and colistin methanesulphonate(both in dosages of 50-100,000 units/kg. 6-8hourly). It would seem that the first and thirdare virtually the same as the second and fourthpreparations. No evidence of toxicity has beenseen in the dosage used.No more than impressions of the value of

therapy can be given, for the disease doesseem to vary from the patient living in sym-biosis with the organism, to a severe septicae-mia with rapid death. To evaluate any agent,the stage of the disease at which diagnosis ismade and treatment started has to be judged.Using one of the polymyxins, certainly patientswith generalised cedema and cyanotic attackshave been seen to recover.

No toxic reactions to polymyxin B in theform of renal damage (other than that due tothe disease) or fever were seen (the otherdescribed effects of dizziness, ataxia, peri-pheral neuritis, parasthesia, especially itchingand facial flushing, not being recognised). Withcolistin no fever, apparent pain at site ofinjection or nausea was seen, nor leucopenia orazotaemia.The other infants in the series (meningo-

myeloceles), were treated by intramuscular,intravenous and intraventricular colistin andseven died, so that only two with meningitistended to recover from the disease whilst theother three seemed to confine their disease tothe local area with little generalised spread.The leukaemia patients had negative swabs

after the use of colomycin. The children withfibrocystic disease did not get disseminateddisease when given colomycin, although be-coming intermittently positive. The other casesresponded to systemic colomycin; Zynotracinpowder (xanthocillin, zinc bacitracin, hydro-cortisone) was used locally on the umbilicus.An attempt was made to isolate each case

as it developed and "prevention of crossinfection" techniques carried out.SummaryA total of 73 cases of pyocyanea infection

have occurred, in 49 premature infants, 16 withcongenital a'bnormalities, two with leukzemia,two with fibrocystic disease and four otherchildren with infection.The available means of treating the infection

and endeavouring to prevent further cases havebeen described.

RIR?FRFRNCF.ANDERSON, K. (1959): Pseudomonas Pyocyanea disseminated from the Air Cooling Apparatus, Med. J. Aust.,

1, 529.CHARRIN, A. (1890): Maladie Pyoconique chez 1'Homme, C. R. Soc. Biol. (Paris), 9, 496.CURTIN, J. A., PETERSDORF, R. G., and BENNETT, I. L. Jr. (1957): Acquired Arteriovenous Fistula complicated

by Ps. aeruginosa Endarteritis and Endocarditis, Bull. Johns Hopk. Hosp., 101, 140.- (1961): Pseudomonas Bacteremia, Review of 91 Cases, Ann. intern. Med., 54, 1077.

FRAENKEL, E. 1(1917): Weiters Untersuchungen uber die Menschen-pathogenitat des Bacillus Pyocyaneus, Z.Hyg. Infekt. -Kr., 84, 369.

HOFFMAN, M. A., and FINBERG, I. (1955): Pseudomonas Infection in Infants associated with High HumidityEnvironments, Pediatrics, 46, 624.

LUBSEN, N., BUISSEVAIN, W., and FASS, H. (1961): Chlorhexidine as the Probable Cause of an Increase inProteus Rettgeri Infections of the Urinary Tract. Lancet, i, 921.

MCCABE, W. R. and JACKSON, G. G. (1962): Gram-negative Bacteremia, Arch. intern. Med., 110, 847,856.

ROBINSON, G. L. (1957): Pscudomonas Pyocyanea in Cetrimide (correspondence), Brit. med. J., i, 1242.MARKLEY, K., GURMENDI, G., CHAREZ, P. M., and BAZAN, A. (1957): Fatal Pseudomonas Septicaemia in Burned

Patients, Ant;. Surg. 145, 175.LANCET (1960): 'Green for Danger', ii, 352.MCLEOD, J. W., MASON, J. M., and PILLEY, A. (1963): Prophylactic Control of Infection of the Urinary Tract

Consequent on Catheterisation, Lancet, i, 292.ROGERS, K. B. (1960): Pseudomonas Infections in a Children's Hospital, J. Appl. Bact., 23, 3.SMITH, D. W. (1963): The No. 18 Trisomy and D, Trisomy Syndromes, Ped. Clin. N. Amer., 10, 389.SUSSMAN, M., and STEVENS, J. (1960): Pseudomonas Pyocyanea Wound Infection, Lancet, ii, 734.WILLIAMS, R., WILLIAMS, E. D., and ADAMS, D. E. (1960): Cross Infection with Pseudomonas Pyocynanea,

Lancet, i, 376.

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