Journal J014rnai of ofAntimicrobial Antimicrobial Chemotherapy Chemotherapy (1979) (1979) 55 (Suppl. (Suppl. A), A), 13-20 13-20
Infections Infections with with Gram Gram....negath'e negative rods rods
Department Department of ofPaediatrics Paediatricsand andNeo!1atalMedicfne, NeoftatalMedicirte, .lJammersmith .Hammersmith Hospital, Hospital, DuCane W12 DRS, England England DuCane Road, Road, London London WI20HS,
Most Most Gram~negative Gram·negative rods rods have have been been known known to to affect affect the the fetus fetus or or newborn newborn infant infant (see (see Table I), though some of them very rarely compromise the healthy adult host. Table I), though some of them very rarely compromise the healthy adult host. They They may may exert exerttheir their influence influencein in different different ways ways during duringpregnancy pregnancyand andafter afterbirth; birth; and andititseems seems more more relevant to discuss the conditions they induce than each species separately. relevant to discuss the conditions they induce than each species separately.
Pregnancy Pregnancy infectious infections affecting affecting the the fetus fetus In In early earlygestatioll, gestation, aa proportion proportion of ofabortions abortions are are associated associated with with chorioamnionitis, chorjoamnionitis~ and and aa number number of of those those are are very very likely likely due due to to Gram-negative Gram-negative bacilli. bacilli. Later Later in ill pregnancy pregnancy Naeye Naeye and and his his colleagues colleagues (Naeye (Naeye & & Blanc, Blanc, 1970; 1970; 1973; 1973; Naeye, Naeye, Tafari, Tafari, Judge, Judge, Gilmour Gilmour && Marboe, Marboe, 1977) 1977) have have shown shown that that approximately approximately one one third third of ofstillbirths stillbirths and alld early early neonatal neonatal deaths deaths are are associated associated with with an an infected infected intrauterine intrauterine environment environment as as judged judged by by chorio· chorin-amnionitis. proportion rises rises as as socioeconomic socioeconomic status status falls, falls, and and if if there there is is aa family family amniollitis. This This proportion history history of of previously previously unsuccessful unsuccessful pregnancies. pregnancies. Florid Florid maternal maternal infections infections that that cause cause premature premature expUlsion expulsion of ofan an embryo embryo or or fetus fetus are are rare rare now, now, for for bacterial bacterial illness illness is is usually usually recognized recognized promptly promptly and and treated treated with with antimicrobial antimicrobial therapy. therapy. At At the the beginning beginning of of the the century century however however Salmonella Saiinonella typhi typhi was was incriminated incriminated (Hicks (Hicks & & French, French. 1905) 1905) alld and in in certain certain parts parts of ofthe the world world such such as as India India fetal fetal loss loss from from maternal maternal cholera cholera still still contilmes. continues, In In the the latter latter illness illness maternal maternal pyrexia, pyrexia, toxaemia toxaemia and and profound profound acidosis acidosis are are likely likely to to precipitate precipitate miscaniage misc.anlage or or pre~term pre~term labour labour (Hirschhorn, (Hirschhorn, Chowdhury Chowdhury & & Lindenbaum, Lindenbaum, 1969), 1969), rather rather than than the the actual actual transplacental transplacental infection infection which whiCh occurred occurred with with typhoid typhoid fever fever (Hicks (Hicks & & French. French. 1905). 1905). CampyloMeter Campylobacterfetus fetus (Eden, (Eden, 1966) 1966) aud and Brucella Brucella abortus abortus (Poole, (Poole, Whitehouse Whitehouse & & Gilchrist, Gilchrist, 1972) 1972) have have also also been beenincriminated incriminatedin inassociation associationwith withabortion. abortion. A A more more mundane mundane and and often often asymptomatic asymptomatic maternal maternal infection infection which which may may affect affect the the fetus fetus indirectly indirectly isis pregnancy pregnancy bacteriuria. bacteriuria. The The majority majority of ofurinary urinary tract tract infections infections at at any any age ageare afC due dueto to Gram-negative Gram~negative bacilli, bacilli,and and Kass Kass && Zinner Zinner(1973) (1973)have havestated statedthat thatbetween between 33and and 8/~ 8 %of ofpregnant pregnantwomen, women, depending depending on on age, age, parity parity and and socioeconomic socioeconomic status, status~ may may be beinvolved. involved. Controversy Controversyhas hasalways alwayssurrounded surrounded the thequestion questionof ofwhether whetherthere thereisisaa direct direct association association between between such such pregnancy pregnancy bacteriuria bacteriuria and and pre~term pre-term birth, birth, and/or and/or intrauterine intrauterine growth growth retardation, retardation, and andwhether whether effective effective sterilization sterilization of ofthe the urine urine will will reverse reverse this this trend. trend. There ofcourse courseaa known knownassociation associationbetween betweenan anincreased increasedincidence incidenceof ofbacteriuria bacteriuriaand and Thereisisof low low socioeconomic socioeconomic status, status. and and henveen benveen the the latter, latter, low low birth birth weight weight and and intrauterine intrauterine 13 13
0305-7453j79/0AOOl3+08 Q305-1453179fOAOO13 +08$01.00/0 $01.00{0
© © 1979 1979The TheBritish BritishSociety Societyfor for Antimicrobial AntimicrobialChemotherapy Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 1, 2015
Pamela Pamela A. A. Davies Davies
P. P. A. A. Davies Davies
14
Table I. Gram-negative genera which have involved the fetus or newborn Edwardsiella Enterobacter Escherichia Flavobacterium Fusobacterium Haemophilus Klebsiella Moraxella
Pasteurella Proteus Pseudomonas Salmonella Serratia Shigella Vibrio Yersinia
growth retardation. Large numbers are required to discriminate between these variables, and the answers are not yet forthcoming.
Intrapartum infections
The earlier the onset of bacterial sepsis in the infant after birth the greater the certainty that the infection has been maternally derived. Final proof rests on the isolation of the identical organism from the maternal birth canal and from the blood, cerebrospinal fluid (CSF), urine or other infected material of the sick infant. The factors determining intrapartum infection are presumably varied: among them must be bacterial numbers in the birth canal, bacterial virulence, duration of labour, duration of membrane rupture, the need or otherwise for obstetric interference, and gestational age. Lack of specific maternal bactericidal antibody too sounds theoretically important. Such IgG antibody is transferred to the fetus largely in the last trimester of pregnancy, but some authors reporting Haemophilus injluenzae sepsis in newborn infants have been unable to detect the presence of such antibody (Mathies, Hodgman & & Ivler, 1965; Collier, Connor & & Nyhan, 1967). On the other hand, the vast majority of young adults are thought to possess it (Fothergill & & Wright, 1933) and some doubts have been raised about these findings on technical grounds (Mpairwe, 1972). However Feigin & Dodge (1976) have pointed out that possession of such maternal antibody does not necessarily protect against neonatal disease, and evidence for this has been adduced in the experimental animal as well as the human. In a survey of early (~48 h of age) bacteraemia in newborn infants, Jeffery, Mitchison, Wigglesworth & & Davies (1977) found that Gram-negative bacilli were responsible for the condition in 0'4/1000 0·4/1000 births at Hammersmith Hospital between the years 1967 to 1975 inclusive. This incidence compared with that of 0'6/1000 due to Gram-positive organisms. Since the routine for drawing blood culture before starting antimicrobial therapy, or immediately at death may not always have been followed, these figures should be taken as a minimum incidence. The signs of such early infection were the same whether Gram-negative or Gram-positive organisms were involved. Respiratory distress and recurrent apnoea occurred in the majority. The mean age at diagnosis of Gram-negative sepsis however (39 h) was significantly later than that occurring in group-B streptococcal (GBS) bacteraemia (13 h) or in bacteraemia caused by other Gram-positive bacteria (24 h). In the fatal cases, death also occurred later (42 h versus 21 and 33 h respectively). Hyaline membrane formation and/or pneumonia was present in two-thirds of the cases and, as in GBS infection, the hyaline membranes were often infiltrated with masses of
Downloaded from http://jac.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 1, 2015
Acinetobacter Aeromonas Alkaligenes Bacteroides Bordetella Brucella Campylobacter Citrobacter
Infections rods Infections with with Gram-negative Gram-negative rods
15 15
Later neonatal illness Bacterial illness illness which which has has its onset after 48 h of age can still Bacterial still be be maternally maternally derived, derived, but but the environment environment comes comes to to play an increasingly important part the part as as the the infant infant enters enters the the second week of life. second week of life.
Pneumonia Pneumonia Pneumonia isis the the commonest commonest of all neonatal bacterial infections, Pneumonia infections, but but Gram-negative Gram-negative organisms are rarely responsible in the healthy mature infant; the pretorm organisms are rarely responsible infant; the preterm infant infantnursed nursed in neonatal intensive care units however has his upper respiratory tract largely in neonatal intensive respiratory tract largelycolonized colonized byGram-negative Gram-negative organisms organisms (Graham, 1975), and is much by much more more vulnerable. vulnerable.Pseudomonas Pseudomonas aeruginosa is particularly notorious for its ability to flourish in aeruginosa is particularly flourish in the the humidification humidification units units of resuscitation resuscitation aud and suction apparatus, incubators and mechanical of mechanical ventilators ventilators ifif scruscrupulous regular regular cleansing cleansing is is not not carried carried out pulous out (see (see review review by by Davies, Davies, 1971). 1971). Other Otherfreeliving freeliving organisms, all all Gram-negative, Gram-negative, have have also also been been incriminated organisms, incriminated in in what what must must be be considered considered largely hospital-acquired infection (American Journal of Diseases of Chz1dren, 1961; largely hospital-acquired infection (American Journal of Diseases of Children, 1961; Becker, 1962). 1962). Preterm Preterm infants infants with with respiratory Becker, respiratory distress distress syndrome syndrome or or recurrent recurrent apnoea apnoea are those those particularly particularly at at risk. risk. Pneumonia Pneumonia caused are caused by by these these organisms organisms isis often often characcharacof bacteria, necrosis, and a lack of inflammatory terized histologically by large numbers terized histologically by large numbers of bacteria, necrosis, and a lack of inflammatory response, in in contrast contrast to to Gram-positive Gram-positive pulmonary pulmonary infection response, infection (Wigglesworth, (Wigglesworth, J.J. S. S.personal personal communication). Pneumatocele formation, once thought to be characteristic of communication). Pneumatocele formation, once thought to be characteristic ofStaphyloStaphylococcus aureus aureus infection, infection, is is known known to to occur coccus occur with with E. E. coli coli (Levy, (Levy, O'Connor O'Connor && Ingall, Ingall, 1977). 1977). Urinary tract tract infection infection Urinary Escherichia coli coli causes causes over over three-quarters three-quarters of of neonatal neonatal urinary urinary tract tract infections, infections, with with Escherichia Klebsiella and and Proteus Proteus species species involved involved occasionally. Klebsiella occasionally. The The incidence incidence depends depends to to some some extent on on the the gestational gestational age age of of the the populations extent populations examined, examined, but but screening screening surveys surveys of of infants in in maternity maternity units units have have suggested infants suggested one one of of about about l:;'-~ 1 % of of livebirths live births (Lincoln (Lincoln && Winberg, 1964; 1964; Littlewood, Littlewood, Kite Kite & & Kite, Winberg, Kite, 1969). 1969). Craig Craig (1935) (1935) demonstrated demonstrated that that infected infected males outnumbered infected females by 1·9: 1, and several studies since then males outnumbered infected females by 1·9: 1, and several studies since then have havecorrocorroborated this this finding finding (see (see review review by borated by Smallpeice, Smallpeice, 1968). 1968). This This of ofcourse course isis consistent consistentwith withthe the sex incidence of serious neonatal infection in general (Washburu, Medearis & Childs, sex incidence of serious neonatal infection in general (Washburn, Medearis & Childs, 1965), though though quite quite different different from from the 1965), the marked marked female female preponderance preponderance of of urinary urinary tract tract infections at all other ages. This has led to the supposition that where aetiology is coninfections at all other ages. This has led to the supposition that where aetiology is concerned blood stream infections may be more important than ascending jnfections in the cerned blood stream infections may be more important than ascending infections in the first weeks of life.
first weeks of life.
Downloaded from http://jac.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 1, 2015
(Gram-negative) not to say that fulminant Gram-negative Gram-negative infections infections (Gram-negative) organisms. organisms. This This is is not to say that fulminant do injluenzae sepsis sepsis has has been beenseen seen do not not occur occur in in the the first first 12 12 to 24 h of life: rapidly fatal H. influenzae by 1977), and and has has also also been beendescribed describedby by byus uspresenting presenting very very soon after after birth (Jeffery et al., 1977), others very rarely rarely found found in in the the others (Bale (Bale && Watkins, Watkins, 1978). H. H. injluenzae however is only very genital and Bacteroides Bacteroides species speciesare are genital tract tract during during pregnancy; pregnancy; Escherichia coli, Proteus spp., and Stanley, 1975). 1975), the Hurley && Stanley, the Gram-negative Gram-negative bacilli bacilli most commonly present (de Louvois, Hurley and It is perhaps perhaps not not surprising surprising that that and all all have have been been incriminated incriminated in intrapartum infection. It bacterial nearly three three quarters quarters bacterial numbers numbers in in the the blood stream have a bearing on mortality: nearly of than l0000rganisms/ml 1000 organisms/mlwere were ofinfants infants with with E. E. coli coli septicaemia in whom counts of more than found, Presumably those those proven proven cases cases & Schoenknecht, 1974). PresUlnably found, died died (Dietzman, (Dietzman, Fischer & which (Dunham, 1933) 1933) had had low low which recovered recovered in in the preantibiotic and chemotherapy era (Dunham, numbers numbers of of circulating circulating organisms.
16
P. Davies P. A. A. Davies
Meningitis Escherichia coli still appears to be the commonest cause of neonatal meningitis in this country, but a large number of other Gram-negative bacilli, particularly others of the Enterobacteriaceae have also been incriminated over the years. Some of the latter are responsible for a severe vasculitis and extensive cerebral necrosis (Cussen and Ryan, 80% 1967; Shortland-Webb, 1968). About 80 % of the E. coli strains responsible for neonatal meningitis carry the Kl K1 capsular antigen, which is immunochemically similar to the capsular polysaccharide of Neisseria meningitidis (Schiffer et al., 1976). These authors believe that the organism's invasiveness is more likely to be attributable to Kl K1 than to 0a or H antigens. Although infants can present with and die from meningitis in the first of life, a later and often more insidious presentation characterizes many cases, and is 48 h oflife, probably responsible for delayed diagnosis. This in turn may account for the persisting high mortality rates, and the frequency with which survivors may be handicapped. Very occasionally an established hydrocephalus is present before the diagnosis is made (Vogel, Ferguson & & Marcy (1976) in a review of the literature & Gotoff, 1978). Klein & give the three most often recorded presenting signs as a raised temperature (61 % of cases), lethargy (50%) and anorexia or vomiting (49%). Treatment must aim to produce an effective concentration of suitable drug in the CSF. This is less easily achieved in the neonatal period than at other ages because the comparatively high doses of antimicrobial drugs necessary may lead to systemic toxic effects. These occur because there is a relative inefficiency of metabolizing and excretory mechanisms at this period of life. The aminoglycosides, though giving an excellent spectrum for the organisms likely to be involved, do not penetrate CSF well. There is also suggestive evidence that even if given by the lumbar route, the ventricular concentration of the drug may be inadequate, and allow a persisting ventriculitis (Helms, 1977). This complication is frequently found at autopsy, as is some degree of hydrocephalus (Berman & Banker 1966). Thus if the aminoglycosides are to be used, they need to be instilled ventricularly, either by a skilled operator using ventricular puncture, or via a ventriculostomy reservoir (Salmon, 1972). The alternative to this potentially damaging passage of needle or catheter
Downloaded from http://jac.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 1, 2015
The signs of urinary tract infections may be minimal and non-specific or absent though when accompanying blood stream infection or meningitis a much more serious illness occurs, sometimes with unusual jaundice and haemolytic anaemia. Diagnosis rests on the pure growth on culture of 100,000 organisms/ml or more from an uncontaminated urine sample (see review by Davies, 1971 for methods of collection), or on any growth from a suprapubic aspirate. As an emergency bedside measure, the finding of bacteria on microscopy of freshly collected unstained, centrifuged or uncentrifuged urine has been found to correlate well with a significant growth on culture (Robins, White, Rogers & Osman, 1975; Littlewood, Jacobs & Ramsden, 1977). Negative cultures from urine caught in a collecting bag can safely be taken to rule out urinary tract infections at that time, but positive cultures need further corroboration by more meticulous methods of collection, or suprapubic aspiration. Since bacteraemia may be present, the dosage of drugs used for treatment should not be reduced below those normally used for serious neonatal infection, at least initially, even though the majority are excreted entirely by the kidney. Congenital malformations of the urinary tract are not commonly found in neonatal urinary tract infection, but it is now preferred practice to perform radiological investigation in all cases, and to arrange for long term follow-up.
Infections Infections with with Gram-negative Gram-negative rods rods
17 17
through developing brain is the such as as chloramphenicol chloramphenicol or or cothrough developing brain substance substance is the use use of of drugs drugs such cotrimoxazole, both of which penetrate CSF reasonably well. However for some trimoxazole, both of which penetrate CSF reasonably well. However for some of of the the potential Gram-negative potential Gram-negative bacillary bacillary invaders, invaders, such such as as P. P. aeruginosa, aeruginosa, they they would would not not consticonstitute levels in both CSF tute effective effective therapy. therapy. Measurement Measurement of of drug drug levels in both CSF and and blood, blood, whatever whatever the the treatment decided on, is of first importance. treatment decided on, is of first importance. Gastroenteritis Gastroenteritis
Necrotizing Necrotizing enterocolitis enterocolitis
This This illness illness is is characterized characterized clinically clinically by by abdominal abdominal distension distension with with ileus, ileus, bile bile stained stained vomit or gastric aspirate, and the passage of blood per rectum with or without diarrhoea vomit or gastric aspirate, and the passage of blood per rectum with or without diarrhoea (Santulli, radiographically by by signs signs of or more (Santulli, et et at., al., 1975) 1975) and and radiographically of localized localized or more generalized generalized intramural air, with or without perforation and portal vein gas (Berdon, & intramural air, with or without perforation and portal vein gas (Berdon, Grossman Grossman & Baker, 1965). It has occurred frequently in many neonatal intensive care units in recent Baker, 1965). It has occurred frequently in many neonatal intensive care units in recent years. bacilli in in its years. The The role role of of Gram-negative Gram-negative bacilli its development development is is uncertain, uncertain, for for the the condition condition probably has a complex aetiology (Fetterman, 1971). Certain of them, not surprisingly, probably has a complex aetiology (Fetterman, 1971). Certain of them, not surprisingly, have been been cultured from the the blood stream or or peritoneum of established established cases cases (Nelson, (Nelson, have cultured from blood stream peritoneum of 1975), as have Gram-positive organisms, though more rarely. It is probably 1975), as have Gram-positive organisms, though more rarely. It is probably unwise unwise at at present to ascribe ascribe aa primary certain that present to primary role role to to them, them, though though it it seems seems certain that without without colonizacolonization not occur. fact that of the the gut gut the the condition condition would would not occur. The The fact that necrotizing necrotizing enterocolitis enterocolitis tion of occasionally occurs in the presence of established bowel pathogens salmonellae occasionally occurs in the presence of established bowel pathogens such such as as salmonellae (Nelson, 1975), the frequently observed clustering of cases, and the knowledge (Nelson, 1975), the frequently observed clustering of cases, and the knowledge that that strict strict infection control measures may be associated with a reduction in incidence (Book, et al., al., infection control measures may be associated with a reduction in incidence (Book, et 1977), one to to suppose suppose that importance. 1977), lead lead one that an an infective infective element element is is of of prime prime importance. Other Other infections infections
Gram-negative bacilli responsible for number of of other other neonatal Gram-negative bacilli have have been been responsible for aa number neonatal infections. infections. Among 1969), solitary solitary liver Among these these are are cerebral cerebral abscess abscess (Eberhard, (Eberhard, 1969), liver abscess abscess (Kandall, (Kandall, Johnson & Gartner, Gartner, 1974; 1974; Brans, Brans, Ceballos & Cassady, 1974) adrenal adrenal abscess abscess (Favara, (Favara, Johnson & Ceballos & Cassady, 1974) Akers & & Franciosi, Franciosi, 1970), and septic arthritis (Nelms (Nelms et et al., al., 1968; 1968; Berant & Akers 1970), osteomyelitis osteomyelitis and septic arthritis Berant & Kahana, 1969; 1969; Nade, 1977), orchitis & Stewart, 1958) and and otitis Kahana, Nade, 1977), orchitis (McCartney (McCartney & Stewart, 1958) otitis media media (Victorin, 1972). They They have have infected cephalhaematomata (Levy, (Victorin, 1967; 1967; Bland, Bland, 1972). infected cephalhaematomata (Levy, O'Connor O'Connor & Ingall, Ingall, 1967; 1967; Lee Lee & & Berg, Berg, 1971), 1971), scalp scalp abscesses of electrodes electrodes & abscesses secondary secondary to to the the placing placing of (Feder, MacLean MacLean & & Moxon, Moxon, 1976) 1976) and and neonatal neonatal mastitis mastitis (Stetler (Stetler et et al., al., 1970). 1970). Characteristic (Feder, Characteristic skin from indurated indurated erythematous erythematous rashes rashes with with some of the the freeliving freeliving skin lesions lesions have have ranged ranged from some of
Downloaded from http://jac.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 1, 2015
Salmonellae, enteropathogenic E. E. coli coli have have in in the considered to Salmonellae, shigellae shigellae and and enteropathogenic the past past been been considered to be the three Gram-negative Gram-negative organisms organisms responsible responsible for for infective enteritis in the newborn. be the three infective enteritis in the newborn. Recent work, however, by pioneering pioneering veterinary veterinary studies, studies, has Recent work, however, much much of of it it stimulated stimulated by has demonstrated that that certain certain serogroups serogroups of of E. E. coli coli may enterotoxic and demonstrated may be be enterotoxic and cause, cause, as as in in cholera, of fluid fluid into into the the small bowel lumen lumen ;; others others may may be enteroinvasive, cholera, an an outgoing outgoing of small bowel be enteroinvasive, at., 1971). having the ability, ability, like like shigellae, shigellae, to to invade invade the the intestinal mucosa (DuPont (DuPont et having the intestinal mucosa et aI., 1971). The laboratory work needed time consuming The laboratory work needed to to demonstrate demonstrate these these properties properties is is time consuming and and still still essentially It is is also also now now being being realized realized that that enterotoxicity enterotoxicity and and essentially aa research research procedure. procedure. It enteroinvasiveness may be possessed by by other bowel organisms. also enteroinvasiveness may be possessed other bowel organisms. Furthermore Furthermore it it is is also clear that the the older older established established enteropathogenic enteropathogenic serogroups serogroups of of E. E. coli coli (Neter, (Neter, 1959) 1959) clear that may neither enteroinvasive nor enterotoxic, may be be neither enteroinvasive nor enterotoxic, while while some some may may be be either either enteroinvasive enteroinvasive or enterotoxic, both (see (see reviews by Sack, 1975; Marcy, Marcy, 1976). or enterotoxic, and and others others may may be be both reviews by Sack, 1975; 1976).
18
P. A. Davies
Gram-negative rod infections (Foley et al., 1961) to the purplish necrotic lesions of P. aeruginosa. Gram-negative rods may also cause death in infants with inborn errors of metabolism (Levy, et al., 1977) and sepsis due to E. coli may be increased in infants having intramuscular iron (Barry & Reeve, 1977). Prevention
References American Journal of Diseases of Children Water bugs in the bassinet. 101: 273-7 (1961). Bale, J. F. & Watkins, M. Fulminant neonatal Hemophilus in/luenzae pneumonia and sepsis. 233-4 (1978). Journal of Pediatrics 92: 233---4 Barry, D. M. J. & Reeve, A. W. Increased incidence of Gram-negative neonatal sepsis with intramuscular iron administration. Pediatrics 60: 908-12 (1977). Becker, A. H. Infection due to Proteus mirabilis in newborn nursery. American Journal of Diseases of Children 104: 355-9 (1962). Berant, M. & & Kahana, D. Klebsiella osteomyelitis in a newborn. American Journal of Diseases of Children 118: 634-7 (1969). Berdon, W. E., Grossman, H. & Baker, D. H. Necrotizing enterocolitis in the premature infant. Annales de Radiologie 8: 85-9 (1965). Berman, P. H. & Banker, B. Q. Neonatal meningitis: a clinical and pathological study of 29 cases. Pediatrics 38: 6-24 (1966). Bland, R. D. Otitis media in the first six weeks of life: diagnosis, bacteriology and management. Pediatrics 49: 187-97 (1972). Book, L. S., Overall, J. C., Herbst, J. J., Britt, M. R., Epstein, B. & Jung, A. L. Clustering of necrotizing enterocolitis: interruption by infection-control measures. New England Journal of Medicine 297: 984-6 (1977). Brans, Y. W., Ceballos, R. & Cassady, G. Umbilical catheters and hepatic abscesses. Pediatrics 53: 264-6 (1974). Collier, A. M., Connor, J. D. & Nyhan, W. L. Systemic infection with Hemophilus in/luenzae in very young infants. Journal of Pediatrics 70: 539-47 (1967). Craig, W. S. Urinary disorders occurring in the neonatal period. Archives of Disease in Childhood 10: 337-54 (1935). Cussen, L. J. & Ryan, G. B. Hemorrhagic cerebral necrosis in neonatal infants with enterobacterial meningitis. Journal of Pediatrics 71: 771-6 (1967). Davies, P. A. Bacterial infection in the fetus and newborn. Archives of Disease in Childhood 46: 1-27 (1971). de Louvois, J., Hurley, R. & & Stanley, V. C. Microbial flora of the lower genital tract during pregnancy: relationship to morbidity. Journal of Clinical Pathology 28: 731-5 (1975). Dietzman, D. E., Fischer, G. W. & & Schoenknecht, F. D. Neonatal Escherichia coli septicemiabacterial counts in blood. Journal of Pediatrics 85: 128-30 (1974).
Downloaded from http://jac.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 1, 2015
The prevention of neonatal infection is of profound importance, because once established it can be so damaging to rapidly growing organs. As so many of the Gram-negative rods are primary inhabitants of the bowel it follows that faecal-oral transmission has to be prevented whenever possible. This is primarily achieved in neonatal units by conscientious and effective handwashing before and after handling the newborn. Regular disinfection of apparatus and the reduction of organic dirt in such units to an absolute minimum are also essential. Breast feeding is well known to reduce the numbers of E. coli and other Gram-negative organisms in the infant bowel, and there is suggestive evidence that if infants suck liberal amounts in the first week or so of life they may have some protection from infections caused by enteric bacteria (Winberg & Wessner, 1971). E coli strains possessing the Kl K1 antigen are found much less often in faeces of breast fed infants than in those of artiSorensen, 1975). ficially fed infants (0rskov & S0rensen,
Infections with with Gram-negative Gram-negative rods Infections rods
19
Downloaded from http://jac.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 1, 2015
Dunham, E. C. Septicemia in the newborn. American Journal of Diseases of Children 45: 229-53 (1933). DuPont, H. L., Formal, S. B., Hornick, R. B., Snyder, M. J., Libonati, J. P., Sheahan, D. G., La Brec, E. H. & Kalas, J. P. Pathogenesis of Escherichia coli diarrhea. New England Journal of Medicine 285: 1-9 (1971). Eberhard, S. J. Diagnosis of brain abscesses in infants and children. A retrospective study of twenty-six cases. North Carolina Medical Journal 30: 301-13 (1969). Eden, A. N. Perinatal mortality caused by Vibrio fetus. Review and analysis. Journal ofPediatrics 68: 297-304 (1966). Favara, B. E., Akers, D. R. & Franciosi, R. A. Adrenal abscess in a neonate. Journal ofPediatrics 77: 682-5 (1970). Feder, H. M., MacLean, W. C. & Moxon, R. Scalp abscess secondary to fetal scalp electrode. Journal of Pediatrics 89: 808-9 (1976). Feigin, R. D. & Dodge, P. R. Bacterial meningitis: newer concepts of pathophysiology and neurologic sequelae. Pediatric Clinics of North America 23: 541-56 (1976). Fetterman, G. H. Neonatal necrotizing enterocolitis-old pit-faIl pit-falI or new problem? Pediatrics 48: 345-8 (1971). Foley, J. F., GraveIle, & Chin, T. D. Y. Achromobacter septicemiaGravelle, C. R., Englehard, W. E. & fatalities in prematures. I. Clinical and epidemiological study. American Journal of Diseases of Children 101: 279-88 (1961). Fothergill, L. D. & & Wright, J. Influenzal meningitis. The relation of age incidence to the bactericidal power of blood against the causal organism. Journal of Immunology 24: 273-84 (1933). Graham, J. M. An investigation into the aerobic and anaerobic bacterial flora of normal and ill/low birthweight newborn babies. Ph.D. thesis, University of London (1975). Helms, P. J. Relapsing E. coli Kl antigen meningitis in a newborn. Archives of Disease in Childhood 52: 152-4 (1977). Hicks, H. T. & French, H. Typhoid fever and pregnancy, with special reference to foetal infection. Lancet i: 1491-3 (1905). A. & & Lindenbaum, J. Cholera in pregnant women. Hirschhorn, N., Chowdhury, A. K. M. A. Lancet i: 1230-2 (1969). Jeffery, H., Mitchison, R., Wigglesworth, J. S. & Davies, P. A. Early neonatal bacteraemia. Comparison of Group B streptococcal, other Gram-positive and Gram-negative infections. Archives of Disease in Childhood 52: 683-686 (1977). KandaIl, S. R., Johnson, A. B. & Gartner, L. M. Solitary neonatal hepatic abscess. Journal of Kandall, Pediatrics 85: 567-9 (1974). Kass, E. H. and Zinner, S. H. Bacteriuria and pyelonephritis in pregnancy. In Obstetric and Perinatal Infections. (Charles, D. & Finland, M., Eds). Philadelphia, Lea and Febiger, (1973) pp. 407-46. Klein, J. O. & & Marcy, S. M. Bacterial infections. In Infectious Diseases of the Fetus and Newborn Infant. (Remington, J. S. & & Klein, J. 0., Eds). W. B. Saunders Co. Philadelphia, London and Toronto, (1976) pp. 747-891. 747-89l. Kuhn, J. P. & Lee, S. B. Pneumatoceles associated with Escherichia coli pneumonias in the newborn. Pediatrics 51: 1008-11 (1973). Lee, Y.-H. & Berg, R. B. Cephalhematoma infected with Bacteroides. American Journal of Diseases of Children 121: 77-8 (1971). & Ingall, D. Bacteremia, infected cephalhematoma, and osteoLevy, H. L., O'Connor, J. F. & skuIl in a newborn. American Journal of Diseases of Children 114: 649-51 myelitis of the skull (1967). & Klein, J. O. Sepsis due to Escherichia coli Levy, H. L., Sepe, S. T., Shih, V. E., Vawter, G. F. & in neonates with galactosemia. New England Journal of Medicine 297: 823-5 (1977). Lincoln, K. & Winberg, J. Studies of urinary tract infections in infancy and childhood. II. un selected neonates with special reference to the Quantitative estimation of bacteriuria in unselected occurrence of asymptomatic infections. Acta Paediatrica Scandinavica 53: 307-16 (1964). & Ramsden, C. H. Comparison between microscopical exLittlewood, J. M., Jacobs, S. I. & amination of unstained deposits of urine and quantitative culture. Archives of Disease in Childhood 52: 894-903 (1977).
P. P. A. A. Davies Davies
n.,
Downloaded from http://jac.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 1, 2015
A. Incidence of neonatal urinary tract infection. Archives Littlewood, J. M., Kite, P. & Kite, B. A. of Disease in Childhood 44: 617-20 (1969). Marcy, S. M. Microorganisms responsible for neonatal diarrhea. In Infectious Diseases of the Fetus and Newborn Infant. (Remington, J. S. & Klein, J. J. 0., Eds). W. B. Saunders Co. Philadelphia and London, (1976) Pl'. pp. 892-978. Mathies, A. W., Hodgman, J. & & II vier, vier. .D. D. Henwphilus in/luenzae injiuenzae meningitis in a premature infant. Pediatrics 35: 791-2 (1965). McCartney, E. T. & Stewart, 1. Suppurative orchitis due to Pseudomonas aeruginosa. aerugillosa. Journal of Pediatrics 52: 451-3 (1958). Pediatrics Mparrwe, Mpairwe, Y Y.. .Detection Detection of H. irTjluenzlle injiuenzt1e type bactericidal antibodies (letter). (Jetter), Journal of a/Pediatrics 80: 1064-5 (1972). Nade, S. Choice of antibiotics in management of acute osteomyelitis and acute septic arthritis in children. Archives of Disease in Childhood 52: 679-82 (1977). Naeye, R. L. & & Blanc, W. A. Relation of poverty and race to autenatal antenatal infection. New England ,,~Jedicine 283: 555-60 555--{jO (1970). Journal of "",Jedicine L. & Blanc, W. A. Unfavorable outcome of pregnancy: repeated losses. American Naeye, R. L of Obstetrics and Gynecology 116: 1133-7 (1973). Journal 0/ Naeye, R. L., Tafari, N., Judge, D,., Gilmour, .D. D. & Marboe, C. Amniotic fluid infections in an African city. Journal of Pediatrics 90: 965--70 965-70 (1977). marcescens osteoNelms, .D. D. K., K., Goldman, A. S., O'Donell, A. A. A. & Henry, M. J. Serratia l1Ulrcescens myelitis in an infant. Journal of Pediatrics 72: 222-7 (1968). Infant. Report of the Sixty.Eighth Nelson, J. D. D. III In Necrotizing enterocolitis in the Newborn in/ant. Sixty-Eighth Ross Conference on Pediatric Research (Moore, T. D. Ed.). Columbus, Ohio, Ross Laboratories (1975), Pl'. pp. 80-5. Pre.'Icnt day status and unsolved Neter, E. Enteritis due to enteropathogenic Escherichia coli. Pre.'lent problems. Journal of Pediatrics 55: 223-39 (1959). 0rskov, F. & S0rensen, K. B. Escherichia coli serogroups in breast-fed and bottle-fed infants. Pathologica et Microbialogica Microbiologica Scandinal'ica Sect. B 83: 25-30 (1975). Acta Pathoiogica ca,'le of abortion consequent upon infecPoole, P. M., Whitehouse, .D. D. B. & Gilchrist, M. M. A case Patlwlogy 25: 882-4 (1972). tion with Brucella abortus biotype 2. Journal of Clinical Pathology Robins, D. D. G., White, R. H. R., Rogers, K. B. & Osman, M. S. Urine microscopy as an aid to detection of of bacteriuria. Lancet i: 476-8 (1975). B. Human diarrhea1 Sack, R. B. diarrheal disease caused by enterotoxigenic Escherichia coli. Annual Review of Microbiology 29: 333-53 (1975). Salmon, J. H. Ventriculitis complicating meningitis. American Joumai JVllmal of Diseases of Children Chfldrr!n (1972). 124: 35-40 (1972), Santulli, Heird, W. C., Gongaware, R. R . .D., Santulli. T. V., SchulIinger, SchuIIinger, J. N., Heird, D., Wigger, J., Barlow, B., B.. & Berdan, Berdon, W. E. Acute necrotizing enterocolitis in infancy. A review of 64 Blanc, Blane; W. A. & cases. Pediatrics 55: 376-87 (1975). Schiffer, M. S., Oliveira, E., Glode, M. P., McCracken, G. H., Sarff', Sarff, L. M. & Robbins, J. B. A review: Relation between invasiveness and the KI capsular polysaccharide of Escherichia coli. Pediatric Research 10: 82-7 (1976). ShortJand-Webb, Shortland· Webb, W. R. Proteus and coliform meningoencephalitis in neonates. Journal of Clinical Pathology 21: 422-31 (1968). Smallpeice, V. V. Urinary tract infection in in adult life. SmaUpeice, in chUdhood childhood and its relevance to disease in William Heinemann Medical Books, Ltd. London (1968). Stetler, H., H., Martin. E., Plotkin, S. & Katz, M. Neonatal mastitis due to Escherichia coli. Journal Joumai of Pedlatrics 76: 611-13 611-13 (1970). o/Pedlatrics L,. An epidemic of otitis in newborns due to infection Victorin, L. infection with Pseudomonas aeruginosa. Scandinallica 56: 344-8 Acta Paediatrica Scandinavica 344--8 (1967). Vogel, L. C, Ferguson, L. & Gotoff, S. P. Citrobacter infections of the the central nervous system in early infancy. Journal ofPediatrics 93: 86-8 86--8 (1978). Washburn, T. C., Medearis, D. D. N. Jr. & Childs,B. Childs, B. Sex differences in susceptibility to infections. Pediatrics 35: 57-64 (1965). Winberg, J. & Wessner, G G.. .Does Does breast milk protect against septicaemia in the newborn? Lancet i: 1091-4 (1971).
Infections Infections with with Gram Gram....negath'e negative rods rods
Department Department of ofPaediatrics Paediatricsand andNeo!1atalMedicfne, NeoftatalMedicirte, .lJammersmith .Hammersmith Hospital, Hospital, DuCane W12 DRS, England England DuCane Road, Road, London London WI20HS,
Most Most Gram~negative Gram·negative rods rods have have been been known known to to affect affect the the fetus fetus or or newborn newborn infant infant (see (see Table I), though some of them very rarely compromise the healthy adult host. Table I), though some of them very rarely compromise the healthy adult host. They They may may exert exerttheir their influence influencein in different different ways ways during duringpregnancy pregnancyand andafter afterbirth; birth; and andititseems seems more more relevant to discuss the conditions they induce than each species separately. relevant to discuss the conditions they induce than each species separately.
Pregnancy Pregnancy infectious infections affecting affecting the the fetus fetus In In early earlygestatioll, gestation, aa proportion proportion of ofabortions abortions are are associated associated with with chorioamnionitis, chorjoamnionitis~ and and aa number number of of those those are are very very likely likely due due to to Gram-negative Gram-negative bacilli. bacilli. Later Later in ill pregnancy pregnancy Naeye Naeye and and his his colleagues colleagues (Naeye (Naeye & & Blanc, Blanc, 1970; 1970; 1973; 1973; Naeye, Naeye, Tafari, Tafari, Judge, Judge, Gilmour Gilmour && Marboe, Marboe, 1977) 1977) have have shown shown that that approximately approximately one one third third of ofstillbirths stillbirths and alld early early neonatal neonatal deaths deaths are are associated associated with with an an infected infected intrauterine intrauterine environment environment as as judged judged by by chorio· chorin-amnionitis. proportion rises rises as as socioeconomic socioeconomic status status falls, falls, and and if if there there is is aa family family amniollitis. This This proportion history history of of previously previously unsuccessful unsuccessful pregnancies. pregnancies. Florid Florid maternal maternal infections infections that that cause cause premature premature expUlsion expulsion of ofan an embryo embryo or or fetus fetus are are rare rare now, now, for for bacterial bacterial illness illness is is usually usually recognized recognized promptly promptly and and treated treated with with antimicrobial antimicrobial therapy. therapy. At At the the beginning beginning of of the the century century however however Salmonella Saiinonella typhi typhi was was incriminated incriminated (Hicks (Hicks & & French, French. 1905) 1905) alld and in in certain certain parts parts of ofthe the world world such such as as India India fetal fetal loss loss from from maternal maternal cholera cholera still still contilmes. continues, In In the the latter latter illness illness maternal maternal pyrexia, pyrexia, toxaemia toxaemia and and profound profound acidosis acidosis are are likely likely to to precipitate precipitate miscaniage misc.anlage or or pre~term pre~term labour labour (Hirschhorn, (Hirschhorn, Chowdhury Chowdhury & & Lindenbaum, Lindenbaum, 1969), 1969), rather rather than than the the actual actual transplacental transplacental infection infection which whiCh occurred occurred with with typhoid typhoid fever fever (Hicks (Hicks & & French. French. 1905). 1905). CampyloMeter Campylobacterfetus fetus (Eden, (Eden, 1966) 1966) aud and Brucella Brucella abortus abortus (Poole, (Poole, Whitehouse Whitehouse & & Gilchrist, Gilchrist, 1972) 1972) have have also also been beenincriminated incriminatedin inassociation associationwith withabortion. abortion. A A more more mundane mundane and and often often asymptomatic asymptomatic maternal maternal infection infection which which may may affect affect the the fetus fetus indirectly indirectly isis pregnancy pregnancy bacteriuria. bacteriuria. The The majority majority of ofurinary urinary tract tract infections infections at at any any age ageare afC due dueto to Gram-negative Gram~negative bacilli, bacilli,and and Kass Kass && Zinner Zinner(1973) (1973)have havestated statedthat thatbetween between 33and and 8/~ 8 %of ofpregnant pregnantwomen, women, depending depending on on age, age, parity parity and and socioeconomic socioeconomic status, status~ may may be beinvolved. involved. Controversy Controversyhas hasalways alwayssurrounded surrounded the thequestion questionof ofwhether whetherthere thereisisaa direct direct association association between between such such pregnancy pregnancy bacteriuria bacteriuria and and pre~term pre-term birth, birth, and/or and/or intrauterine intrauterine growth growth retardation, retardation, and andwhether whether effective effective sterilization sterilization of ofthe the urine urine will will reverse reverse this this trend. trend. There ofcourse courseaa known knownassociation associationbetween betweenan anincreased increasedincidence incidenceof ofbacteriuria bacteriuriaand and Thereisisof low low socioeconomic socioeconomic status, status. and and henveen benveen the the latter, latter, low low birth birth weight weight and and intrauterine intrauterine 13 13
0305-7453j79/0AOOl3+08 Q305-1453179fOAOO13 +08$01.00/0 $01.00{0
© © 1979 1979The TheBritish BritishSociety Societyfor for Antimicrobial AntimicrobialChemotherapy Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 1, 2015
Pamela Pamela A. A. Davies Davies
P. P. A. A. Davies Davies
14
Table I. Gram-negative genera which have involved the fetus or newborn Edwardsiella Enterobacter Escherichia Flavobacterium Fusobacterium Haemophilus Klebsiella Moraxella
Pasteurella Proteus Pseudomonas Salmonella Serratia Shigella Vibrio Yersinia
growth retardation. Large numbers are required to discriminate between these variables, and the answers are not yet forthcoming.
Intrapartum infections
The earlier the onset of bacterial sepsis in the infant after birth the greater the certainty that the infection has been maternally derived. Final proof rests on the isolation of the identical organism from the maternal birth canal and from the blood, cerebrospinal fluid (CSF), urine or other infected material of the sick infant. The factors determining intrapartum infection are presumably varied: among them must be bacterial numbers in the birth canal, bacterial virulence, duration of labour, duration of membrane rupture, the need or otherwise for obstetric interference, and gestational age. Lack of specific maternal bactericidal antibody too sounds theoretically important. Such IgG antibody is transferred to the fetus largely in the last trimester of pregnancy, but some authors reporting Haemophilus injluenzae sepsis in newborn infants have been unable to detect the presence of such antibody (Mathies, Hodgman & & Ivler, 1965; Collier, Connor & & Nyhan, 1967). On the other hand, the vast majority of young adults are thought to possess it (Fothergill & & Wright, 1933) and some doubts have been raised about these findings on technical grounds (Mpairwe, 1972). However Feigin & Dodge (1976) have pointed out that possession of such maternal antibody does not necessarily protect against neonatal disease, and evidence for this has been adduced in the experimental animal as well as the human. In a survey of early (~48 h of age) bacteraemia in newborn infants, Jeffery, Mitchison, Wigglesworth & & Davies (1977) found that Gram-negative bacilli were responsible for the condition in 0'4/1000 0·4/1000 births at Hammersmith Hospital between the years 1967 to 1975 inclusive. This incidence compared with that of 0'6/1000 due to Gram-positive organisms. Since the routine for drawing blood culture before starting antimicrobial therapy, or immediately at death may not always have been followed, these figures should be taken as a minimum incidence. The signs of such early infection were the same whether Gram-negative or Gram-positive organisms were involved. Respiratory distress and recurrent apnoea occurred in the majority. The mean age at diagnosis of Gram-negative sepsis however (39 h) was significantly later than that occurring in group-B streptococcal (GBS) bacteraemia (13 h) or in bacteraemia caused by other Gram-positive bacteria (24 h). In the fatal cases, death also occurred later (42 h versus 21 and 33 h respectively). Hyaline membrane formation and/or pneumonia was present in two-thirds of the cases and, as in GBS infection, the hyaline membranes were often infiltrated with masses of
Downloaded from http://jac.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 1, 2015
Acinetobacter Aeromonas Alkaligenes Bacteroides Bordetella Brucella Campylobacter Citrobacter
Infections rods Infections with with Gram-negative Gram-negative rods
15 15
Later neonatal illness Bacterial illness illness which which has has its onset after 48 h of age can still Bacterial still be be maternally maternally derived, derived, but but the environment environment comes comes to to play an increasingly important part the part as as the the infant infant enters enters the the second week of life. second week of life.
Pneumonia Pneumonia Pneumonia isis the the commonest commonest of all neonatal bacterial infections, Pneumonia infections, but but Gram-negative Gram-negative organisms are rarely responsible in the healthy mature infant; the pretorm organisms are rarely responsible infant; the preterm infant infantnursed nursed in neonatal intensive care units however has his upper respiratory tract largely in neonatal intensive respiratory tract largelycolonized colonized byGram-negative Gram-negative organisms organisms (Graham, 1975), and is much by much more more vulnerable. vulnerable.Pseudomonas Pseudomonas aeruginosa is particularly notorious for its ability to flourish in aeruginosa is particularly flourish in the the humidification humidification units units of resuscitation resuscitation aud and suction apparatus, incubators and mechanical of mechanical ventilators ventilators ifif scruscrupulous regular regular cleansing cleansing is is not not carried carried out pulous out (see (see review review by by Davies, Davies, 1971). 1971). Other Otherfreeliving freeliving organisms, all all Gram-negative, Gram-negative, have have also also been been incriminated organisms, incriminated in in what what must must be be considered considered largely hospital-acquired infection (American Journal of Diseases of Chz1dren, 1961; largely hospital-acquired infection (American Journal of Diseases of Children, 1961; Becker, 1962). 1962). Preterm Preterm infants infants with with respiratory Becker, respiratory distress distress syndrome syndrome or or recurrent recurrent apnoea apnoea are those those particularly particularly at at risk. risk. Pneumonia Pneumonia caused are caused by by these these organisms organisms isis often often characcharacof bacteria, necrosis, and a lack of inflammatory terized histologically by large numbers terized histologically by large numbers of bacteria, necrosis, and a lack of inflammatory response, in in contrast contrast to to Gram-positive Gram-positive pulmonary pulmonary infection response, infection (Wigglesworth, (Wigglesworth, J.J. S. S.personal personal communication). Pneumatocele formation, once thought to be characteristic of communication). Pneumatocele formation, once thought to be characteristic ofStaphyloStaphylococcus aureus aureus infection, infection, is is known known to to occur coccus occur with with E. E. coli coli (Levy, (Levy, O'Connor O'Connor && Ingall, Ingall, 1977). 1977). Urinary tract tract infection infection Urinary Escherichia coli coli causes causes over over three-quarters three-quarters of of neonatal neonatal urinary urinary tract tract infections, infections, with with Escherichia Klebsiella and and Proteus Proteus species species involved involved occasionally. Klebsiella occasionally. The The incidence incidence depends depends to to some some extent on on the the gestational gestational age age of of the the populations extent populations examined, examined, but but screening screening surveys surveys of of infants in in maternity maternity units units have have suggested infants suggested one one of of about about l:;'-~ 1 % of of livebirths live births (Lincoln (Lincoln && Winberg, 1964; 1964; Littlewood, Littlewood, Kite Kite & & Kite, Winberg, Kite, 1969). 1969). Craig Craig (1935) (1935) demonstrated demonstrated that that infected infected males outnumbered infected females by 1·9: 1, and several studies since then males outnumbered infected females by 1·9: 1, and several studies since then have havecorrocorroborated this this finding finding (see (see review review by borated by Smallpeice, Smallpeice, 1968). 1968). This This of ofcourse course isis consistent consistentwith withthe the sex incidence of serious neonatal infection in general (Washburu, Medearis & Childs, sex incidence of serious neonatal infection in general (Washburn, Medearis & Childs, 1965), though though quite quite different different from from the 1965), the marked marked female female preponderance preponderance of of urinary urinary tract tract infections at all other ages. This has led to the supposition that where aetiology is coninfections at all other ages. This has led to the supposition that where aetiology is concerned blood stream infections may be more important than ascending jnfections in the cerned blood stream infections may be more important than ascending infections in the first weeks of life.
first weeks of life.
Downloaded from http://jac.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 1, 2015
(Gram-negative) not to say that fulminant Gram-negative Gram-negative infections infections (Gram-negative) organisms. organisms. This This is is not to say that fulminant do injluenzae sepsis sepsis has has been beenseen seen do not not occur occur in in the the first first 12 12 to 24 h of life: rapidly fatal H. influenzae by 1977), and and has has also also been beendescribed describedby by byus uspresenting presenting very very soon after after birth (Jeffery et al., 1977), others very rarely rarely found found in in the the others (Bale (Bale && Watkins, Watkins, 1978). H. H. injluenzae however is only very genital and Bacteroides Bacteroides species speciesare are genital tract tract during during pregnancy; pregnancy; Escherichia coli, Proteus spp., and Stanley, 1975). 1975), the Hurley && Stanley, the Gram-negative Gram-negative bacilli bacilli most commonly present (de Louvois, Hurley and It is perhaps perhaps not not surprising surprising that that and all all have have been been incriminated incriminated in intrapartum infection. It bacterial nearly three three quarters quarters bacterial numbers numbers in in the the blood stream have a bearing on mortality: nearly of than l0000rganisms/ml 1000 organisms/mlwere were ofinfants infants with with E. E. coli coli septicaemia in whom counts of more than found, Presumably those those proven proven cases cases & Schoenknecht, 1974). PresUlnably found, died died (Dietzman, (Dietzman, Fischer & which (Dunham, 1933) 1933) had had low low which recovered recovered in in the preantibiotic and chemotherapy era (Dunham, numbers numbers of of circulating circulating organisms.
16
P. Davies P. A. A. Davies
Meningitis Escherichia coli still appears to be the commonest cause of neonatal meningitis in this country, but a large number of other Gram-negative bacilli, particularly others of the Enterobacteriaceae have also been incriminated over the years. Some of the latter are responsible for a severe vasculitis and extensive cerebral necrosis (Cussen and Ryan, 80% 1967; Shortland-Webb, 1968). About 80 % of the E. coli strains responsible for neonatal meningitis carry the Kl K1 capsular antigen, which is immunochemically similar to the capsular polysaccharide of Neisseria meningitidis (Schiffer et al., 1976). These authors believe that the organism's invasiveness is more likely to be attributable to Kl K1 than to 0a or H antigens. Although infants can present with and die from meningitis in the first of life, a later and often more insidious presentation characterizes many cases, and is 48 h oflife, probably responsible for delayed diagnosis. This in turn may account for the persisting high mortality rates, and the frequency with which survivors may be handicapped. Very occasionally an established hydrocephalus is present before the diagnosis is made (Vogel, Ferguson & & Marcy (1976) in a review of the literature & Gotoff, 1978). Klein & give the three most often recorded presenting signs as a raised temperature (61 % of cases), lethargy (50%) and anorexia or vomiting (49%). Treatment must aim to produce an effective concentration of suitable drug in the CSF. This is less easily achieved in the neonatal period than at other ages because the comparatively high doses of antimicrobial drugs necessary may lead to systemic toxic effects. These occur because there is a relative inefficiency of metabolizing and excretory mechanisms at this period of life. The aminoglycosides, though giving an excellent spectrum for the organisms likely to be involved, do not penetrate CSF well. There is also suggestive evidence that even if given by the lumbar route, the ventricular concentration of the drug may be inadequate, and allow a persisting ventriculitis (Helms, 1977). This complication is frequently found at autopsy, as is some degree of hydrocephalus (Berman & Banker 1966). Thus if the aminoglycosides are to be used, they need to be instilled ventricularly, either by a skilled operator using ventricular puncture, or via a ventriculostomy reservoir (Salmon, 1972). The alternative to this potentially damaging passage of needle or catheter
Downloaded from http://jac.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 1, 2015
The signs of urinary tract infections may be minimal and non-specific or absent though when accompanying blood stream infection or meningitis a much more serious illness occurs, sometimes with unusual jaundice and haemolytic anaemia. Diagnosis rests on the pure growth on culture of 100,000 organisms/ml or more from an uncontaminated urine sample (see review by Davies, 1971 for methods of collection), or on any growth from a suprapubic aspirate. As an emergency bedside measure, the finding of bacteria on microscopy of freshly collected unstained, centrifuged or uncentrifuged urine has been found to correlate well with a significant growth on culture (Robins, White, Rogers & Osman, 1975; Littlewood, Jacobs & Ramsden, 1977). Negative cultures from urine caught in a collecting bag can safely be taken to rule out urinary tract infections at that time, but positive cultures need further corroboration by more meticulous methods of collection, or suprapubic aspiration. Since bacteraemia may be present, the dosage of drugs used for treatment should not be reduced below those normally used for serious neonatal infection, at least initially, even though the majority are excreted entirely by the kidney. Congenital malformations of the urinary tract are not commonly found in neonatal urinary tract infection, but it is now preferred practice to perform radiological investigation in all cases, and to arrange for long term follow-up.
Infections Infections with with Gram-negative Gram-negative rods rods
17 17
through developing brain is the such as as chloramphenicol chloramphenicol or or cothrough developing brain substance substance is the use use of of drugs drugs such cotrimoxazole, both of which penetrate CSF reasonably well. However for some trimoxazole, both of which penetrate CSF reasonably well. However for some of of the the potential Gram-negative potential Gram-negative bacillary bacillary invaders, invaders, such such as as P. P. aeruginosa, aeruginosa, they they would would not not consticonstitute levels in both CSF tute effective effective therapy. therapy. Measurement Measurement of of drug drug levels in both CSF and and blood, blood, whatever whatever the the treatment decided on, is of first importance. treatment decided on, is of first importance. Gastroenteritis Gastroenteritis
Necrotizing Necrotizing enterocolitis enterocolitis
This This illness illness is is characterized characterized clinically clinically by by abdominal abdominal distension distension with with ileus, ileus, bile bile stained stained vomit or gastric aspirate, and the passage of blood per rectum with or without diarrhoea vomit or gastric aspirate, and the passage of blood per rectum with or without diarrhoea (Santulli, radiographically by by signs signs of or more (Santulli, et et at., al., 1975) 1975) and and radiographically of localized localized or more generalized generalized intramural air, with or without perforation and portal vein gas (Berdon, & intramural air, with or without perforation and portal vein gas (Berdon, Grossman Grossman & Baker, 1965). It has occurred frequently in many neonatal intensive care units in recent Baker, 1965). It has occurred frequently in many neonatal intensive care units in recent years. bacilli in in its years. The The role role of of Gram-negative Gram-negative bacilli its development development is is uncertain, uncertain, for for the the condition condition probably has a complex aetiology (Fetterman, 1971). Certain of them, not surprisingly, probably has a complex aetiology (Fetterman, 1971). Certain of them, not surprisingly, have been been cultured from the the blood stream or or peritoneum of established established cases cases (Nelson, (Nelson, have cultured from blood stream peritoneum of 1975), as have Gram-positive organisms, though more rarely. It is probably 1975), as have Gram-positive organisms, though more rarely. It is probably unwise unwise at at present to ascribe ascribe aa primary certain that present to primary role role to to them, them, though though it it seems seems certain that without without colonizacolonization not occur. fact that of the the gut gut the the condition condition would would not occur. The The fact that necrotizing necrotizing enterocolitis enterocolitis tion of occasionally occurs in the presence of established bowel pathogens salmonellae occasionally occurs in the presence of established bowel pathogens such such as as salmonellae (Nelson, 1975), the frequently observed clustering of cases, and the knowledge (Nelson, 1975), the frequently observed clustering of cases, and the knowledge that that strict strict infection control measures may be associated with a reduction in incidence (Book, et al., al., infection control measures may be associated with a reduction in incidence (Book, et 1977), one to to suppose suppose that importance. 1977), lead lead one that an an infective infective element element is is of of prime prime importance. Other Other infections infections
Gram-negative bacilli responsible for number of of other other neonatal Gram-negative bacilli have have been been responsible for aa number neonatal infections. infections. Among 1969), solitary solitary liver Among these these are are cerebral cerebral abscess abscess (Eberhard, (Eberhard, 1969), liver abscess abscess (Kandall, (Kandall, Johnson & Gartner, Gartner, 1974; 1974; Brans, Brans, Ceballos & Cassady, 1974) adrenal adrenal abscess abscess (Favara, (Favara, Johnson & Ceballos & Cassady, 1974) Akers & & Franciosi, Franciosi, 1970), and septic arthritis (Nelms (Nelms et et al., al., 1968; 1968; Berant & Akers 1970), osteomyelitis osteomyelitis and septic arthritis Berant & Kahana, 1969; 1969; Nade, 1977), orchitis & Stewart, 1958) and and otitis Kahana, Nade, 1977), orchitis (McCartney (McCartney & Stewart, 1958) otitis media media (Victorin, 1972). They They have have infected cephalhaematomata (Levy, (Victorin, 1967; 1967; Bland, Bland, 1972). infected cephalhaematomata (Levy, O'Connor O'Connor & Ingall, Ingall, 1967; 1967; Lee Lee & & Berg, Berg, 1971), 1971), scalp scalp abscesses of electrodes electrodes & abscesses secondary secondary to to the the placing placing of (Feder, MacLean MacLean & & Moxon, Moxon, 1976) 1976) and and neonatal neonatal mastitis mastitis (Stetler (Stetler et et al., al., 1970). 1970). Characteristic (Feder, Characteristic skin from indurated indurated erythematous erythematous rashes rashes with with some of the the freeliving freeliving skin lesions lesions have have ranged ranged from some of
Downloaded from http://jac.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 1, 2015
Salmonellae, enteropathogenic E. E. coli coli have have in in the considered to Salmonellae, shigellae shigellae and and enteropathogenic the past past been been considered to be the three Gram-negative Gram-negative organisms organisms responsible responsible for for infective enteritis in the newborn. be the three infective enteritis in the newborn. Recent work, however, by pioneering pioneering veterinary veterinary studies, studies, has Recent work, however, much much of of it it stimulated stimulated by has demonstrated that that certain certain serogroups serogroups of of E. E. coli coli may enterotoxic and demonstrated may be be enterotoxic and cause, cause, as as in in cholera, of fluid fluid into into the the small bowel lumen lumen ;; others others may may be enteroinvasive, cholera, an an outgoing outgoing of small bowel be enteroinvasive, at., 1971). having the ability, ability, like like shigellae, shigellae, to to invade invade the the intestinal mucosa (DuPont (DuPont et having the intestinal mucosa et aI., 1971). The laboratory work needed time consuming The laboratory work needed to to demonstrate demonstrate these these properties properties is is time consuming and and still still essentially It is is also also now now being being realized realized that that enterotoxicity enterotoxicity and and essentially aa research research procedure. procedure. It enteroinvasiveness may be possessed by by other bowel organisms. also enteroinvasiveness may be possessed other bowel organisms. Furthermore Furthermore it it is is also clear that the the older older established established enteropathogenic enteropathogenic serogroups serogroups of of E. E. coli coli (Neter, (Neter, 1959) 1959) clear that may neither enteroinvasive nor enterotoxic, may be be neither enteroinvasive nor enterotoxic, while while some some may may be be either either enteroinvasive enteroinvasive or enterotoxic, both (see (see reviews by Sack, 1975; Marcy, Marcy, 1976). or enterotoxic, and and others others may may be be both reviews by Sack, 1975; 1976).
18
P. A. Davies
Gram-negative rod infections (Foley et al., 1961) to the purplish necrotic lesions of P. aeruginosa. Gram-negative rods may also cause death in infants with inborn errors of metabolism (Levy, et al., 1977) and sepsis due to E. coli may be increased in infants having intramuscular iron (Barry & Reeve, 1977). Prevention
References American Journal of Diseases of Children Water bugs in the bassinet. 101: 273-7 (1961). Bale, J. F. & Watkins, M. Fulminant neonatal Hemophilus in/luenzae pneumonia and sepsis. 233-4 (1978). Journal of Pediatrics 92: 233---4 Barry, D. M. J. & Reeve, A. W. Increased incidence of Gram-negative neonatal sepsis with intramuscular iron administration. Pediatrics 60: 908-12 (1977). Becker, A. H. Infection due to Proteus mirabilis in newborn nursery. American Journal of Diseases of Children 104: 355-9 (1962). Berant, M. & & Kahana, D. Klebsiella osteomyelitis in a newborn. American Journal of Diseases of Children 118: 634-7 (1969). Berdon, W. E., Grossman, H. & Baker, D. H. Necrotizing enterocolitis in the premature infant. Annales de Radiologie 8: 85-9 (1965). Berman, P. H. & Banker, B. Q. Neonatal meningitis: a clinical and pathological study of 29 cases. Pediatrics 38: 6-24 (1966). Bland, R. D. Otitis media in the first six weeks of life: diagnosis, bacteriology and management. Pediatrics 49: 187-97 (1972). Book, L. S., Overall, J. C., Herbst, J. J., Britt, M. R., Epstein, B. & Jung, A. L. Clustering of necrotizing enterocolitis: interruption by infection-control measures. New England Journal of Medicine 297: 984-6 (1977). Brans, Y. W., Ceballos, R. & Cassady, G. Umbilical catheters and hepatic abscesses. Pediatrics 53: 264-6 (1974). Collier, A. M., Connor, J. D. & Nyhan, W. L. Systemic infection with Hemophilus in/luenzae in very young infants. Journal of Pediatrics 70: 539-47 (1967). Craig, W. S. Urinary disorders occurring in the neonatal period. Archives of Disease in Childhood 10: 337-54 (1935). Cussen, L. J. & Ryan, G. B. Hemorrhagic cerebral necrosis in neonatal infants with enterobacterial meningitis. Journal of Pediatrics 71: 771-6 (1967). Davies, P. A. Bacterial infection in the fetus and newborn. Archives of Disease in Childhood 46: 1-27 (1971). de Louvois, J., Hurley, R. & & Stanley, V. C. Microbial flora of the lower genital tract during pregnancy: relationship to morbidity. Journal of Clinical Pathology 28: 731-5 (1975). Dietzman, D. E., Fischer, G. W. & & Schoenknecht, F. D. Neonatal Escherichia coli septicemiabacterial counts in blood. Journal of Pediatrics 85: 128-30 (1974).
Downloaded from http://jac.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 1, 2015
The prevention of neonatal infection is of profound importance, because once established it can be so damaging to rapidly growing organs. As so many of the Gram-negative rods are primary inhabitants of the bowel it follows that faecal-oral transmission has to be prevented whenever possible. This is primarily achieved in neonatal units by conscientious and effective handwashing before and after handling the newborn. Regular disinfection of apparatus and the reduction of organic dirt in such units to an absolute minimum are also essential. Breast feeding is well known to reduce the numbers of E. coli and other Gram-negative organisms in the infant bowel, and there is suggestive evidence that if infants suck liberal amounts in the first week or so of life they may have some protection from infections caused by enteric bacteria (Winberg & Wessner, 1971). E coli strains possessing the Kl K1 antigen are found much less often in faeces of breast fed infants than in those of artiSorensen, 1975). ficially fed infants (0rskov & S0rensen,
Infections with with Gram-negative Gram-negative rods Infections rods
19
Downloaded from http://jac.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 1, 2015
Dunham, E. C. Septicemia in the newborn. American Journal of Diseases of Children 45: 229-53 (1933). DuPont, H. L., Formal, S. B., Hornick, R. B., Snyder, M. J., Libonati, J. P., Sheahan, D. G., La Brec, E. H. & Kalas, J. P. Pathogenesis of Escherichia coli diarrhea. New England Journal of Medicine 285: 1-9 (1971). Eberhard, S. J. Diagnosis of brain abscesses in infants and children. A retrospective study of twenty-six cases. North Carolina Medical Journal 30: 301-13 (1969). Eden, A. N. Perinatal mortality caused by Vibrio fetus. Review and analysis. Journal ofPediatrics 68: 297-304 (1966). Favara, B. E., Akers, D. R. & Franciosi, R. A. Adrenal abscess in a neonate. Journal ofPediatrics 77: 682-5 (1970). Feder, H. M., MacLean, W. C. & Moxon, R. Scalp abscess secondary to fetal scalp electrode. Journal of Pediatrics 89: 808-9 (1976). Feigin, R. D. & Dodge, P. R. Bacterial meningitis: newer concepts of pathophysiology and neurologic sequelae. Pediatric Clinics of North America 23: 541-56 (1976). Fetterman, G. H. Neonatal necrotizing enterocolitis-old pit-faIl pit-falI or new problem? Pediatrics 48: 345-8 (1971). Foley, J. F., GraveIle, & Chin, T. D. Y. Achromobacter septicemiaGravelle, C. R., Englehard, W. E. & fatalities in prematures. I. Clinical and epidemiological study. American Journal of Diseases of Children 101: 279-88 (1961). Fothergill, L. D. & & Wright, J. Influenzal meningitis. The relation of age incidence to the bactericidal power of blood against the causal organism. Journal of Immunology 24: 273-84 (1933). Graham, J. M. An investigation into the aerobic and anaerobic bacterial flora of normal and ill/low birthweight newborn babies. Ph.D. thesis, University of London (1975). Helms, P. J. Relapsing E. coli Kl antigen meningitis in a newborn. Archives of Disease in Childhood 52: 152-4 (1977). Hicks, H. T. & French, H. Typhoid fever and pregnancy, with special reference to foetal infection. Lancet i: 1491-3 (1905). A. & & Lindenbaum, J. Cholera in pregnant women. Hirschhorn, N., Chowdhury, A. K. M. A. Lancet i: 1230-2 (1969). Jeffery, H., Mitchison, R., Wigglesworth, J. S. & Davies, P. A. Early neonatal bacteraemia. Comparison of Group B streptococcal, other Gram-positive and Gram-negative infections. Archives of Disease in Childhood 52: 683-686 (1977). KandaIl, S. R., Johnson, A. B. & Gartner, L. M. Solitary neonatal hepatic abscess. Journal of Kandall, Pediatrics 85: 567-9 (1974). Kass, E. H. and Zinner, S. H. Bacteriuria and pyelonephritis in pregnancy. In Obstetric and Perinatal Infections. (Charles, D. & Finland, M., Eds). Philadelphia, Lea and Febiger, (1973) pp. 407-46. Klein, J. O. & & Marcy, S. M. Bacterial infections. In Infectious Diseases of the Fetus and Newborn Infant. (Remington, J. S. & & Klein, J. 0., Eds). W. B. Saunders Co. Philadelphia, London and Toronto, (1976) pp. 747-891. 747-89l. Kuhn, J. P. & Lee, S. B. Pneumatoceles associated with Escherichia coli pneumonias in the newborn. Pediatrics 51: 1008-11 (1973). Lee, Y.-H. & Berg, R. B. Cephalhematoma infected with Bacteroides. American Journal of Diseases of Children 121: 77-8 (1971). & Ingall, D. Bacteremia, infected cephalhematoma, and osteoLevy, H. L., O'Connor, J. F. & skuIl in a newborn. American Journal of Diseases of Children 114: 649-51 myelitis of the skull (1967). & Klein, J. O. Sepsis due to Escherichia coli Levy, H. L., Sepe, S. T., Shih, V. E., Vawter, G. F. & in neonates with galactosemia. New England Journal of Medicine 297: 823-5 (1977). Lincoln, K. & Winberg, J. Studies of urinary tract infections in infancy and childhood. II. un selected neonates with special reference to the Quantitative estimation of bacteriuria in unselected occurrence of asymptomatic infections. Acta Paediatrica Scandinavica 53: 307-16 (1964). & Ramsden, C. H. Comparison between microscopical exLittlewood, J. M., Jacobs, S. I. & amination of unstained deposits of urine and quantitative culture. Archives of Disease in Childhood 52: 894-903 (1977).
P. P. A. A. Davies Davies
n.,
Downloaded from http://jac.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 1, 2015
A. Incidence of neonatal urinary tract infection. Archives Littlewood, J. M., Kite, P. & Kite, B. A. of Disease in Childhood 44: 617-20 (1969). Marcy, S. M. Microorganisms responsible for neonatal diarrhea. In Infectious Diseases of the Fetus and Newborn Infant. (Remington, J. S. & Klein, J. J. 0., Eds). W. B. Saunders Co. Philadelphia and London, (1976) Pl'. pp. 892-978. Mathies, A. W., Hodgman, J. & & II vier, vier. .D. D. Henwphilus in/luenzae injiuenzae meningitis in a premature infant. Pediatrics 35: 791-2 (1965). McCartney, E. T. & Stewart, 1. Suppurative orchitis due to Pseudomonas aeruginosa. aerugillosa. Journal of Pediatrics 52: 451-3 (1958). Pediatrics Mparrwe, Mpairwe, Y Y.. .Detection Detection of H. irTjluenzlle injiuenzt1e type bactericidal antibodies (letter). (Jetter), Journal of a/Pediatrics 80: 1064-5 (1972). Nade, S. Choice of antibiotics in management of acute osteomyelitis and acute septic arthritis in children. Archives of Disease in Childhood 52: 679-82 (1977). Naeye, R. L. & & Blanc, W. A. Relation of poverty and race to autenatal antenatal infection. New England ,,~Jedicine 283: 555-60 555--{jO (1970). Journal of "",Jedicine L. & Blanc, W. A. Unfavorable outcome of pregnancy: repeated losses. American Naeye, R. L of Obstetrics and Gynecology 116: 1133-7 (1973). Journal 0/ Naeye, R. L., Tafari, N., Judge, D,., Gilmour, .D. D. & Marboe, C. Amniotic fluid infections in an African city. Journal of Pediatrics 90: 965--70 965-70 (1977). marcescens osteoNelms, .D. D. K., K., Goldman, A. S., O'Donell, A. A. A. & Henry, M. J. Serratia l1Ulrcescens myelitis in an infant. Journal of Pediatrics 72: 222-7 (1968). Infant. Report of the Sixty.Eighth Nelson, J. D. D. III In Necrotizing enterocolitis in the Newborn in/ant. Sixty-Eighth Ross Conference on Pediatric Research (Moore, T. D. Ed.). Columbus, Ohio, Ross Laboratories (1975), Pl'. pp. 80-5. Pre.'Icnt day status and unsolved Neter, E. Enteritis due to enteropathogenic Escherichia coli. Pre.'lent problems. Journal of Pediatrics 55: 223-39 (1959). 0rskov, F. & S0rensen, K. B. Escherichia coli serogroups in breast-fed and bottle-fed infants. Pathologica et Microbialogica Microbiologica Scandinal'ica Sect. B 83: 25-30 (1975). Acta Pathoiogica ca,'le of abortion consequent upon infecPoole, P. M., Whitehouse, .D. D. B. & Gilchrist, M. M. A case Patlwlogy 25: 882-4 (1972). tion with Brucella abortus biotype 2. Journal of Clinical Pathology Robins, D. D. G., White, R. H. R., Rogers, K. B. & Osman, M. S. Urine microscopy as an aid to detection of of bacteriuria. Lancet i: 476-8 (1975). B. Human diarrhea1 Sack, R. B. diarrheal disease caused by enterotoxigenic Escherichia coli. Annual Review of Microbiology 29: 333-53 (1975). Salmon, J. H. Ventriculitis complicating meningitis. American Joumai JVllmal of Diseases of Children Chfldrr!n (1972). 124: 35-40 (1972), Santulli, Heird, W. C., Gongaware, R. R . .D., Santulli. T. V., SchulIinger, SchuIIinger, J. N., Heird, D., Wigger, J., Barlow, B., B.. & Berdan, Berdon, W. E. Acute necrotizing enterocolitis in infancy. A review of 64 Blanc, Blane; W. A. & cases. Pediatrics 55: 376-87 (1975). Schiffer, M. S., Oliveira, E., Glode, M. P., McCracken, G. H., Sarff', Sarff, L. M. & Robbins, J. B. A review: Relation between invasiveness and the KI capsular polysaccharide of Escherichia coli. Pediatric Research 10: 82-7 (1976). ShortJand-Webb, Shortland· Webb, W. R. Proteus and coliform meningoencephalitis in neonates. Journal of Clinical Pathology 21: 422-31 (1968). Smallpeice, V. V. Urinary tract infection in in adult life. SmaUpeice, in chUdhood childhood and its relevance to disease in William Heinemann Medical Books, Ltd. London (1968). Stetler, H., H., Martin. E., Plotkin, S. & Katz, M. Neonatal mastitis due to Escherichia coli. Journal Joumai of Pedlatrics 76: 611-13 611-13 (1970). o/Pedlatrics L,. An epidemic of otitis in newborns due to infection Victorin, L. infection with Pseudomonas aeruginosa. Scandinallica 56: 344-8 Acta Paediatrica Scandinavica 344--8 (1967). Vogel, L. C, Ferguson, L. & Gotoff, S. P. Citrobacter infections of the the central nervous system in early infancy. Journal ofPediatrics 93: 86-8 86--8 (1978). Washburn, T. C., Medearis, D. D. N. Jr. & Childs,B. Childs, B. Sex differences in susceptibility to infections. Pediatrics 35: 57-64 (1965). Winberg, J. & Wessner, G G.. .Does Does breast milk protect against septicaemia in the newborn? Lancet i: 1091-4 (1971).
