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Prevention of Preterm Delivery and Low Birth Weight Associated with Asymptomatic Bacteriuria Robert Mittendorf, Michelle A. Williams, and Edward H. Kass*
From the Department of Epidemiology, Harvard School of Public Health, the Departments of Obstetrics and Gynecology and Community Health, Tufts University School of Medicine and New England Medical Center Hospitals, Boston, Massachusetts; and the Department of Epidemiology, University of Washington, Seattle, Washington
The association between asymptomatic bacteriuria and preterm delivery (5 white blood cells [WBCs] per high-power field [HPF] is not a reliable marker of bacteriuria. About one-half of patients with bacteriuria have 5 inflammatory cells/HPF. Thus, pyuria is not an acceptable screening device because of the elevated rate of both false-negative results and false-positive results, although the secretion of large numbers of WBCs may indicate significant renal invasion and increased risk of perinatal morbidity.
Although E. colt and closely related coliforms most commonly cause acute uncomplicated UTIs in both the pregnant and the nonpregnant woman, McFadyen and Eykyn [17] have reported the isolation of Gardnerella vaginalis from 15.9% of suprapubic aspirates taken from 1,000 asymptomatic paras. In addition, Fairley and Birch [18] recovered G. vaginalis more often from the urine of women with pregnancy-induced hypertension than from the urine of controls. The relative frequency of staphylococci, enterococci, and certain species of Proteus and Pseudomonas, less common pathogens than E. colt, increases among patients who have received prior antibiotic treatment. Coleman and Taylor [19] found E. colt in 82% of patients with uncomplicated infections but in only 18% of those with complicated infections. Proteus species was found in only 5% of patients with uncomplicated infections but in more than one-third of those with complicated UTIs. Pseudomonas species, an organism that had never been recovered from patients with simple infections, was isolated in 7% of cases of complicated disease.
Griess Test
Many methods for the quick estimation of the number of bacteria have been developed, including the detection of bacteria by means of their enzymatic activity or metabolic products. Griess test depends on the ability of most enteric bacteria to reduce nitrates to nitrites. However, some uropathogens cannot reduce nitrates, and others convert nitrates to ammonia so efficiently that appreciable levels of nitrites do not accumulate during reduction. The test is sensitive only to the presence of nitrites and thus is useful only when positive. An absence of nitrites in the urine may be due to an absence of infection, an absence of nitrate substrate despite infection, or a reduction of nitrates beyond the nitrite stage. Thus, because Griess test yields many false-negative results, it is unacceptable as a screening test.
Virulence Factors in E. coli
O Surface Antigen Strains of E. colt, the most common pathogen of the urinary tract, are identified by three different surface antigens0, K, and H—as well as by pili or fimbriae (also known as adhesins) [20] and their cytoplasmic enzymes. The 0 antigen or endotoxin, known to exist in >150 different antigenic forms, is the unique lipopolysaccharide of the cell wall. In a survey from British antenatal clinics [21], about 55% of >300 E. colt urinary tract isolates belonged to 0 groups 1, 2, 4, 6, 7, 11, 18, and 75. In the United States, Maiztegue and Kass [22] found that 0 groups 4, 6, 62, and 75 were most prevalent. Furthermore, Stenqvist et al. [23] reported that 0 anti-
Downloaded from http://cid.oxfordjournals.org/ at Yale University on July 1, 2015
Kass [16] also found that clean-voided urine specimens with bacterial counts >10 5 organisms/mL had a 95% correlation with urine specimens obtained from a catheter from the same patient. Furthermore, the detection of >10 5 organisms/ mL in one clean-voided specimen of urine had an 85% probability of indicating true infection. The same finding in successive specimens increased the probability of infection to 96%. The gram stain, another easily performed quantitative screening test for bacteriuria, was also found to have a high correlation with true infection. The gram-stained smears of uncentrifuged urine were found to be positive for 80% of patients whose colony counts of bacteria in urine specimens obtained from a catheter were >10 5 organisms/mL, although the gram-stained smears of 20% of the patients with between 10 2 and 10 5 organisms/mL of urine were also positive [16]. Thus, quantification by colony counting or gram stain became the standard for defining true UTI.
929
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Mittendorf, Williams, and Kass
gens 1, 2, 6, 16, 21, and 75 accounted for 71% of all isolates from, a group of Swedish patients with pyelonephritis. However, these same 0 antigens were expressed by only 19% of the cfu in patients with cystitis or asymptomatic bacteriuria (P < .001). Thus, not only are isolates of E. coli with certain 0 serotypes more likely than other isolates to be associated with infections of the urinary tract, but certain 0 antigens have a higher probability of causing acute pyelonephritis rather than less significant disease of the lower urinary tract. Because there is a marked antibody response to 0 surface antigens within 2 weeks of exposure in those patients with pyelonephritis [24], serotyping can be used for predicting which strains of E. coli are more likely to be nephritogenic [25] and require increased surveillance during pregnancy.
Although 0 antigens are important predictors of nephritogenicity, certain pili of E. coli are more specific determinants of bacterial virulence. Since cell-membrane glycolipids Galal –0- 4Gali3—which function as receptors for the pili of pyelonephritogenic E. coli [26]—are also antigens in the P blood group system [27], the ability of bacteria to attach to human uroepithelial cells correlates with their ability to agglutinate human erythrocytes containing the P k , P, and P I antigens [28]. It follows that infections with strains of E. coli possessing P blood group–specific adhesins can be diagnosed in vitro by simple hemagglutination inhibition testing [29] or by immunofluorescence of infected urine—two immunologic tests that permit identification of virulent strains requiring increased surveillance during pregnancy. Applying the fact that these pili and their bacteria remain attached to exfoliated uroepithelial cells [30], Kallenius et al. [31] discovered that P fimbriae were present in 91% of the urinary bacterial strains causing acute pyelonephritis in children. Among strains causing cystitis and asymptomatic bacteriuria, these pili were found in only 19% and 14% of cases, respectively. A previous investigation had shown that bacterial adherence to uroepithelial cells is important in establishing infection and that strains of E. coli causing pyelonephritis adhere better in vitro to epithelial cells than do strains causing lower UTI [32]. Svanborg Eden et al. [33] observed that five nonadhering strains of E. coli failed to multiply on the surface of uroepithelial cells, whereas the number of four adhering strains increased. However, the increase was mostly due to adhesion of new bacteria and not to cell division of the bacteria that was already attached. Squamous and transitional epithelial cells were found in all specimens studied, but columnar epithelial cells were uncommon. None of the tested strains adhered selectively to any uroepithelial cell type [33]. Moreover, Márild et al. [34], in their prospective study of first-episode UTI in children, demonstrated that epitheliumattaching strains of E. coli induced significantly greater host inflammatory responses than did nonattaching strains.
Management of UTIs during Pregnancy Renal Concentrating Ability
Bacteriuric women are more likely than nonbacteriuric women to have defective renal concentrating ability. This deficiency is correlated with presumed evidence of kidney infection, namely, pyelographic changes, biopsy-proven pyelonephritis, or culture of ureteral urine positive for bacteria. Norden et al. [35] found that 22 (15%) of 147 bacteriuric women in the prenatal clinic at the Boston City Hospital had renal concentrating abilities of
Prevention of Preterm Delivery and Low Birth Weight Associated with Asymptomatic Bacteriuria Robert Mittendorf, Michelle A. Williams, and Edward H. Kass*
From the Department of Epidemiology, Harvard School of Public Health, the Departments of Obstetrics and Gynecology and Community Health, Tufts University School of Medicine and New England Medical Center Hospitals, Boston, Massachusetts; and the Department of Epidemiology, University of Washington, Seattle, Washington
The association between asymptomatic bacteriuria and preterm delivery (5 white blood cells [WBCs] per high-power field [HPF] is not a reliable marker of bacteriuria. About one-half of patients with bacteriuria have 5 inflammatory cells/HPF. Thus, pyuria is not an acceptable screening device because of the elevated rate of both false-negative results and false-positive results, although the secretion of large numbers of WBCs may indicate significant renal invasion and increased risk of perinatal morbidity.
Although E. colt and closely related coliforms most commonly cause acute uncomplicated UTIs in both the pregnant and the nonpregnant woman, McFadyen and Eykyn [17] have reported the isolation of Gardnerella vaginalis from 15.9% of suprapubic aspirates taken from 1,000 asymptomatic paras. In addition, Fairley and Birch [18] recovered G. vaginalis more often from the urine of women with pregnancy-induced hypertension than from the urine of controls. The relative frequency of staphylococci, enterococci, and certain species of Proteus and Pseudomonas, less common pathogens than E. colt, increases among patients who have received prior antibiotic treatment. Coleman and Taylor [19] found E. colt in 82% of patients with uncomplicated infections but in only 18% of those with complicated infections. Proteus species was found in only 5% of patients with uncomplicated infections but in more than one-third of those with complicated UTIs. Pseudomonas species, an organism that had never been recovered from patients with simple infections, was isolated in 7% of cases of complicated disease.
Griess Test
Many methods for the quick estimation of the number of bacteria have been developed, including the detection of bacteria by means of their enzymatic activity or metabolic products. Griess test depends on the ability of most enteric bacteria to reduce nitrates to nitrites. However, some uropathogens cannot reduce nitrates, and others convert nitrates to ammonia so efficiently that appreciable levels of nitrites do not accumulate during reduction. The test is sensitive only to the presence of nitrites and thus is useful only when positive. An absence of nitrites in the urine may be due to an absence of infection, an absence of nitrate substrate despite infection, or a reduction of nitrates beyond the nitrite stage. Thus, because Griess test yields many false-negative results, it is unacceptable as a screening test.
Virulence Factors in E. coli
O Surface Antigen Strains of E. colt, the most common pathogen of the urinary tract, are identified by three different surface antigens0, K, and H—as well as by pili or fimbriae (also known as adhesins) [20] and their cytoplasmic enzymes. The 0 antigen or endotoxin, known to exist in >150 different antigenic forms, is the unique lipopolysaccharide of the cell wall. In a survey from British antenatal clinics [21], about 55% of >300 E. colt urinary tract isolates belonged to 0 groups 1, 2, 4, 6, 7, 11, 18, and 75. In the United States, Maiztegue and Kass [22] found that 0 groups 4, 6, 62, and 75 were most prevalent. Furthermore, Stenqvist et al. [23] reported that 0 anti-
Downloaded from http://cid.oxfordjournals.org/ at Yale University on July 1, 2015
Kass [16] also found that clean-voided urine specimens with bacterial counts >10 5 organisms/mL had a 95% correlation with urine specimens obtained from a catheter from the same patient. Furthermore, the detection of >10 5 organisms/ mL in one clean-voided specimen of urine had an 85% probability of indicating true infection. The same finding in successive specimens increased the probability of infection to 96%. The gram stain, another easily performed quantitative screening test for bacteriuria, was also found to have a high correlation with true infection. The gram-stained smears of uncentrifuged urine were found to be positive for 80% of patients whose colony counts of bacteria in urine specimens obtained from a catheter were >10 5 organisms/mL, although the gram-stained smears of 20% of the patients with between 10 2 and 10 5 organisms/mL of urine were also positive [16]. Thus, quantification by colony counting or gram stain became the standard for defining true UTI.
929
930
Mittendorf, Williams, and Kass
gens 1, 2, 6, 16, 21, and 75 accounted for 71% of all isolates from, a group of Swedish patients with pyelonephritis. However, these same 0 antigens were expressed by only 19% of the cfu in patients with cystitis or asymptomatic bacteriuria (P < .001). Thus, not only are isolates of E. coli with certain 0 serotypes more likely than other isolates to be associated with infections of the urinary tract, but certain 0 antigens have a higher probability of causing acute pyelonephritis rather than less significant disease of the lower urinary tract. Because there is a marked antibody response to 0 surface antigens within 2 weeks of exposure in those patients with pyelonephritis [24], serotyping can be used for predicting which strains of E. coli are more likely to be nephritogenic [25] and require increased surveillance during pregnancy.
Although 0 antigens are important predictors of nephritogenicity, certain pili of E. coli are more specific determinants of bacterial virulence. Since cell-membrane glycolipids Galal –0- 4Gali3—which function as receptors for the pili of pyelonephritogenic E. coli [26]—are also antigens in the P blood group system [27], the ability of bacteria to attach to human uroepithelial cells correlates with their ability to agglutinate human erythrocytes containing the P k , P, and P I antigens [28]. It follows that infections with strains of E. coli possessing P blood group–specific adhesins can be diagnosed in vitro by simple hemagglutination inhibition testing [29] or by immunofluorescence of infected urine—two immunologic tests that permit identification of virulent strains requiring increased surveillance during pregnancy. Applying the fact that these pili and their bacteria remain attached to exfoliated uroepithelial cells [30], Kallenius et al. [31] discovered that P fimbriae were present in 91% of the urinary bacterial strains causing acute pyelonephritis in children. Among strains causing cystitis and asymptomatic bacteriuria, these pili were found in only 19% and 14% of cases, respectively. A previous investigation had shown that bacterial adherence to uroepithelial cells is important in establishing infection and that strains of E. coli causing pyelonephritis adhere better in vitro to epithelial cells than do strains causing lower UTI [32]. Svanborg Eden et al. [33] observed that five nonadhering strains of E. coli failed to multiply on the surface of uroepithelial cells, whereas the number of four adhering strains increased. However, the increase was mostly due to adhesion of new bacteria and not to cell division of the bacteria that was already attached. Squamous and transitional epithelial cells were found in all specimens studied, but columnar epithelial cells were uncommon. None of the tested strains adhered selectively to any uroepithelial cell type [33]. Moreover, Márild et al. [34], in their prospective study of first-episode UTI in children, demonstrated that epitheliumattaching strains of E. coli induced significantly greater host inflammatory responses than did nonattaching strains.
Management of UTIs during Pregnancy Renal Concentrating Ability
Bacteriuric women are more likely than nonbacteriuric women to have defective renal concentrating ability. This deficiency is correlated with presumed evidence of kidney infection, namely, pyelographic changes, biopsy-proven pyelonephritis, or culture of ureteral urine positive for bacteria. Norden et al. [35] found that 22 (15%) of 147 bacteriuric women in the prenatal clinic at the Boston City Hospital had renal concentrating abilities of
