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MICROBIAL ECOLOGY IN HEALTH AND DISEASE VOL. 3 151-157 (1990) An Intrinsic Pathogenicity Index for Microorganisms Causing Infection in a Neonatal Surgical Unit E. M. LEONARD*?,H. K . F. VAN SAENET, C. P. STOUTENBEEKg?, J. WALKERS AND P. K. H. TAMS Departments of tMedical Microbiology and 1Paediatric Surgery, Royal Liverpool Children’s Hospital, Alder Hey, Liverpool L12 2AP, U K , $Intensive Care Unit, 0 - L - V Gasthuis, 1091 HA Amsterdam, The Netherlands. Received 5 June 1989; revised 22 December 1989 The intrinsic pathogenicity index (IPI) for a particular microorganismis defined as the ratio of the number of patients infected by the microorganismto the number of patients colonised in the digestive tract by identical microorganisms.A microorganism with an IPI of 1 will practically always cause infectionfollowing colonisation (‘high’ pathogen),whilst a microorganism with an IPI of 0 is unlikely to be involved in infection (‘low’ pathogen). IPIs were calculated for microorganisms causing infection in 40 neonates admitted to a neonatal surgical unit. The indices of the predominant organisms involved in infectious problems in this group, Pseudornonas and Candida species, were 0.38 and 0.31 respectively, whilst those for coagulase-negativestaphylococci and enterococci were respectively 0.03 and 0. Possible applications of the IPI are in further assessment of the value of surveillance cultures and as the basis of antibiotic policies in populations with a high risk of infection. KEY WORDS-colonisation; Infection; Pathogenicity index; Neonate; Surgical unit. INTRODUCTION Studies of neonates in intensive care units have shown high rates of nosocomial infection with aerobic Gram-negative bacilli, yeasts, Staphylococcus aureus and coagulase-negative staphyloC O C C ~ . ~ , Little ~ - ~ , ’ published ~ information is available on nosocomial infection in surgical neonates. We recently carried out a prospective inventory study in a neonatal surgical unit to determine rates of colonisation and infection with aerobic bacteria and fungi. High colonisation rates with aerobic Gram-negative bacilli were found, in particular with Klebsiella spp. (55 per cent), Pseudomonas sp. (53 per cent) Escherichia coli (48 per cent) and Enterobacter spp. ( 3 3 per cent). Candida spp. colonised 38 per cent of infants. Most infants were colonised with coagulase-negative staphylococci, alphastreptococci and enterococci (each 98 per cent). The infection rate in the population was 35 per cent. The predominant organisms causing infection were Pseudomonas and Candida spp., microorganisms which colonised infants at rates lower than those for organisms such as coagulase-negative staphylococci *Author to whom correspondence should be addressed. Current address: Department of Medical Microbiology, University College Hospital, Gower Street, London WClE 6BT, UK. 089 l-O6OX/90/030151-07 $05.00 0 1990 by John Wiley & Sons, Ltd. and alpha-streptococci which caused few cases of infection. The results of this study, suggesting apparent differences in pathogenicity of microorganisms, prompted us to investigate why infections in the neonatal surgical population should be caused by certain organisms. Two major factors relating to the chance of infection by a particular microorganism developing in a patient are (i) host-related factors (defence mechanisms, risk factors), and (ii) pathogenicity of the m i c r o o r g a n i ~ m . ’ ~Our ’ ~ ~aim was to study the microbiological factor and quantify the intrinsic potential of an organism to cause infection in this population, by developing an index. PATIENTS AND METHODS Patients The neonatal surgical unit at the Royal Liverpool Children’s Hospital, Alder Hey, admits infants for elective and emergency surgical procedures. Forty infants (26 males, 14 females) admitted to the unit and staying for at least 5 d were studied prospectively over a 3mth period. The mean age on admission was 1 1 d and the average duration of stay 30 d. The mean gestation was 38 wks and mean birthweight was 2.9 kg. The most frequent reason I52 for admission was digestive tract disorder requiring surgery (60 per cent of infants). Other reasons for admission included conditions such as neural tube defect and urological disorders. Specimens and microbiological methods For each baby, swabs were taken from the throat and rectum on admission (baseline cultures) and twice a week thereafter (surveillance cultures). Samples of faeces were collected twice weekly when possible. Urine specimens were collected once a week. Collection of these and other specimens were also performed when considered necessary, for clinical purposes, by surgical staff. All specimens were processed by the microbiologists (E.M.L., H.K.F.v.S.) after collection. Infants were examined daily for clinical evidence of infection. A Gram’s stain preparation was made from each wound swab and examined for the presence of leucocytes and microorganisms. All swabs were qualitatively and semiquantitatively cultured. Four solid media were used: MacConkey agar (Gibco Limited) for evaluation of Enterobacteriaceae, Pseudomonadaceae and Acinetobacter spp., blood agar (Gibco Ltd., Paisley, Scotland) for streptococci and staphylococci, kanamycin aesculin azide agar (Lab M, Salford, UK) for enterococci, and yeast morphology agar (Merck, Darmstadt, FRG) for yeasts. The media were inoculated using the four quadrant method. After each swab had been streaked onto the agar plates, the tip was broken off into 5 ml of brain-heart infusion broth (Lab M). All cultures were incubated aerobically at 37°C. MacConkey and kanamycin agar plates were examined after one night and blood and yeast morphology agar plates after two nights. If the broth was turbid after one night’s incubation, inoculation onto the four media was performed. Semiquantitative estimation of bacterial concentrations was made by grading growth density from the four quadrant method on a scale of 1 + to 5 + : growth only in brain-heart infusion broth = 1 + (comparable to 1-10 microorganisms/ml), growth in the first quadrant of the solid plate=2+ (< lo3), in the second quadrant 3 + ( < lo’), in the third quadrant 4+ (< lo7) and on the whole plate 5+ (> lo7). Faeces, urine and nasopharyngeal aspirates were qualitatively and quantitatively cultured. One millilitre or gram of specimen was suspended in 9 ml of brain-heart infusion broth and ten-fold serial dilutions made. Tubes were cultured overnight at 37°C and those showing turbidity were subcultured E. M. LEONARD ETAL. onto the same four solid media. Incubation and examination of the agar plates were performed in the same way as for swab specimens. Quantitative estimation of bacterial concentrations was made from dilution series results. All morphologically distinct colonies were isolated in pure culture. Microorganisms were identified by standard biochemical and serological methods and typing was performed if necessary, in particular for Pseudomonadaceae, to ascertain whether or not isolates from different patients or sites were identical. In addition, antimicrobial sensitivity patterns were determined for microorganisms using the controlled disc diffusion method. Bacterial charts were made of results obtained and were used to aid assessment of colonisation patterns (Figure 1). Oropharynx and rectum were considered to be part of the same organ system, the digestive tract, and charts for these were used in combination.” Intrinsic pathogenicity index (IFI) For a microorganism, y species, causing infection in a specific population: IPI = number of patients infected by y number of patients colonised in throat/rectum by y Recognised definitions for colonisation and infection were used in the s t ~ d y . ’ ~ ~ ’ ’ Colonisation: a microbiological event, defined as isolation of identical microorganisms from two or more consecutive samples (taken at least 3 d apart) from the same site, in any concentration of c.f.u./ml orgofspecimen, without orwithonlyasmallnumber of leucocytes, aild without signs of infection. Infection: a microbiologically proven clinical event, defined as a clinical diagnosis with microbiological proof (many leucocytes and one type of or predominant microorganism) from the clinical specimen. Endogenous infection: infection caused by potentially pathogenic microorganisms which have first colonised the digestive tract (either part of ‘normal’ resident flora, or newly acquired microorganisms which have colonised the digestive tract). Respiratory tract infection: clinical picture compatible with respiratory tract infection or pneumonia, radiological evidence, positive culture of nasopharyngeal aspirate. 153 A PATHOGENICITY INDEX FOR MICROORGANISMS PPMs’ 1 Day on NSU [ 301 3 I 1321 33 341 35 1361 37 1381 391 401 4 I 142 1431 441 45 ( 4 6 I - Oropharynx Klebsiella sp. - lo9 10 7 Pseudomonas sp. - - to9 to5 S.viridans (07 to9 107 S.faecalis 10 I lo7 to7 - to’ Rectum/faeces Klebsiella sp. I o5 Pseudomonae sp. I o7 S.faecalis I o9 [ I o9 Figure 1. Example of a bacteriological chart used for assessment of colonisation patterns. PPMS =potentially pathogenic microorganisms Meningitis: compatible clinical picture, positive culture of cerebrospinal fluid. Urinary tract infection: turbid urine, pyuria (> 10 leucocytes/microscopic field (400 x ), positive culture of urine with one type of organism (> lo5 organisms/mlof urine). Septicaemia: compatible clinical picture, haematological abnormalities (leucocytcosis, leucopenia, ‘left shift’, toxic granulation of leucocytes) and positive blood culture. Woundlsurface infection: erythma and/or pus at site, purulence on Gram’s stain, isolation of one/ predominant organism. RESULTS Most babies in the study group were colonised in the digestive tract with coagulase-negative staphylococci (98 per cent), enterococci (95 per cent) and alpha-streptococci (95 per cent), microorganisms characteristic of the indigenous flora (Table 1). Aerobic Gram-negative bacilli (AGNB) frequently colonised the throat/rectum, predominant organisms being Pseudomonas spp. (53 per cent of babies Table 1. Rates of colonisation and infection in surgical neonates Microorganism Coagulase-negative staphylococci Enterococci Alpha-streptococci Pseudomonas spp. Klebsiella spp. Escherichia coli Staphylococcus aureus Candida spp. Enterobacter spp. Proteus spp. Citrobacter spp. Acinetobacter spp. Serratia spp. Morganella spp. Patients colonised in throat/rectum (no.) 39 (98) 38 (95) 38 (95) 21 (53) 19 (48) 19 (48) 17 (43) 13 (33) 12 (30) 605) 6 (15) 4(10) 2 (5) 1 (3) Figures in parentheses indicate percentages Patients infected (no.) 154 E. M. LEONARD ET AL. E.coli Klebsiella rpp. colonised), Klebsiella spp., Escherichia coli (43 per cent) and Enterobacter spp. (30 per cent). Other AGNB such as Proteus, Acinetobacter and Serratia spp. were found to colonise the digestive tract of 15 per cent or less of children. Forty-three per cent of babies carried Staphylococcus aureus, and one-third were colonised by Candida spp. The infection rate in this population was 35 per cent; the predominant microorganisms causing infection were Pseudomonus spp., with 8/40 (20 per cent) children developing one or more infections. Candida spp. caused infection in 10 per cent of children. Other organisms which caused infection were Enterobacter sp., S. aureus, E. coli,Klebsiella sp. and coagulase-negative staphylococci, each causing a single episode of infection. These results were applied in the formula previously described to calculate the intrinsic pathogenicity indices of various microorganisms isolated from the study group (Figure 2). The range of the index is 0-1. In the surgical neonates, the highest indices were found for Pseudomonas and Candida spp. (0.38 and 0-31 respectively). Much lower indices were found for other microorganisms, including S. aureus (0-06), coagulase-negative staphylococci (0.03) and enterococci (0). DISCUSSION The derivation of the formula for an intrinsic pathogenicity index (IPI) is based on our observation that the pathogenesis of nosocomial infection in a population of surgical neonates was endogeno~s.’~ The denominator used, ‘number of patients colonised in throat/rectum’, is crucial to the formula. Several studies of compromised patient populations, such as long-term ventilated ICU patients, have shown that three distinct stages in the development of endogenous infection can be identified: (i) colonisation of the oropharynx/gastrointestinaltract, (ii) colonisation of major organ systems (respiratory tract, urinary tract, skin), and (iii) infection by identical microorganisms.’ 220,24 This sequence was identified in the surgical neonatal population; infection caused by microorganisms was always preceded by colonisation of the digestive tract by identical organisms, the average time interval between identification of colonisation and subsequent infection being 1 week. Since digestive tract colonisation was considered to be a crucial stage in the development of infection in these populations, rates for this rather than for colonisation of body surfaces were used for the IPI formula. The term ‘colonisation of body surfaces’ includes colonisation of systems other than the digestive tract,’ and use of this term in the IPI formula would encompass both first and second stages in development of infection. In addition, colonisation of another system occurred occasionally without previous colonisation of the digestive tract having been identified, but never resulted in infection in the neonatal group; use of ‘digestive tract colonisation’ in the formula excludes these cases. A PATHOGENICITY INDEX FOR MICROORGANISMS The formula gives an indication of the capacity of a microorganism which first colonises the digestive tract of a patient to cause infection in that patient. The index derived for a particular microorganismis applicable to a specific patient population. The range of the IPI is 0-1. An IPI of 1 denotes a microorganism which, after colonising a patient, will always cause infection. Such an organism may be described as highly virulent.22No such organism was identified in the surgical neonatal population, but it might be antipicated that an organism such as Salmonella typhimurium would have a high index. Conversely, in the case of an organism with an IPI close to 0, colonisation will seldom be followed by infection. Such an organism is described as poorly virulent; this index would be characteristic of the indigenous flora. Examples from the surgical neonatal population are coagulase-negative staphylococci (IPI 0.03) and enterococci (IPI 0). An index of 0.5 implies that colonisation by the organism will be followed by infection in half the cases. Organisms with indices in this region are described as potential pathogens. The indices of the predominant organisms causing infection in the neonatal surgical population, Pseudomonas and Candida spp., came into this category at 0.38 and 0.31 respectively. The accuracy of the applied IPI formula must depend on the accuracy of detection of colonisation and infection. (These terms themselves still need to be clearly defined and agreed by clinical and microbiological workers.) Several techniques were used in our study to increase the sensitivity and accuracy of detection of colonisation. Collection of baseline and surveillance cultures from both oropharynx and rectum was found to be of great use. These sites were considered to be part of the same organ system and results were considered in combination, using the chart system previously mentioned. Use of the broth incubation technique (‘enrichment’step)2 enabled us to detect small numbers of microorganisms, which is particularly important for oropharyngeal samples. More detailed colonisation patterns that might otherwise have been missed were thus detected and, in addition, insight was gained into the inadequacies of considering samples from each site in isolation. For example, in some cases microorganisms were never isolated from the oropharynx or were found at irregular intervals, but when results of rectal swab or faecal cultures were also considered,it was apparent that the digestive tract had become colonised with these organisms. An explanation for these findings is that Gram-negative bacilli may be present 155 only transiently in the oral cavity because of lack of adherence to surfaces and the actions of chewing, sucking and swallowing,’6 but may be detected later, after overgrowth at intestinal level, in faecal samples. A further factor is that the quality of samples, particularly from the oropharynx, is likely to vary in populations of infants and children. We consider that the IPI concept needs to be developed, but at this stage would like to suggest possible applications. A practical application is in predicting which of those organisms isolated from a surveillance swab is most likely to cause infection. The value of surveillance cultures, in particular as predictors of infection, is still subject to debate.1.3*9.18 For such cultures to be of clinical use, detectable colonisation must either precede infection or not be followed by infection; the more reliable the prediction, the greater the value. This raises the crucial point that the basic stage of detection of colonisation is itself dependent on several factors, such as sites chosen for surveillance,criteria used for definition of colonisation, interpretation of results and microbiological techniques used. These factors have not been constant among different investigators, and this may have influenced results. Apart from technical aspects, it is well established that if the infection rate in a population is low, the positive predictive value of even an excellent test will also be low.’ Results obtained by using standardised sensitive techniques could be applied in a formula such as that described, relating to pathogenicity of microorganisms, to aid assessment of the value of surveillancecultures in specific populations at high risk of infection. Another application for the IPI is in aiding construction of antibiotic policies, both prophylactic and therapeutic. After calculation of IPI values for microorganisms in different patient populations, those most likely to cause infection in that population might be identified and appropriate antibiotic usage recommended. Apparent differences in pathogenicity of microorganisms have also been noted in adult neutropenic patients by various worker^.^^,^','^.^^ It has been shown that, once the blood neutrophil count has fallen below 100/mm3, Pseudomonas spp. are the bacteria most likely to translocate from gut lumen into the bloodstream. This illustrates how development of infection depends on the balance between intrinsic pathogenicity of microorganisms and defencecapacity of the host. Our index envelops both factors, but does not differentiate between them. Host defences may be reduced by many 156 factors such a s underlying disease, surgical trauma, medical intervention and use of chemotherapeutic agents and antibiotics. When resistance to colonisation is lowered by such factors, colonisation of the digestive tract by potentially pathogenic microorganisms may occur more readily. Both host defence and microbial pathogenicity should be taken into consideration, therefore, when predicting the likelihood of infection in a particular patient. We suggest that a separate index for host defence, a ‘host colonisation index’, might be developed to advantage, to predict which patients in a given population are most likely to become infected. ACKNOWLEDGEMENTS We are very grateful to Mr R. C. M. Cook, Mr R. E. Cudmore and Mr A. M. K. Rickwood for allowing us to study their patients, the nursing and medical staff of the Neonatal Surgical Unit, the infants and their parents, Dr J. Green for statistical advice, Mr J. Duitsch for drawing the figures, Professors C. A. Hart and D. A. Lloyd for critically reviewing the paper, and to Liverpool Health Authority. REFERENCES 1. Evans ME, SchaffnerW, Federspiel CF, Cotton RB, McKee KT Jr, Stratton CW. (1988). Sensitivity, specificity, and predictive value of body surface cultures in a neonatal intensive care unit. 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