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Moxalactam therapy to neonatal meningitis due to gram-negative enteric bacilli. A prospective controlled evaluation
... Hemolysin-coregulated protein (Hcp) and valine glycine repeat (VgrG) are both considered to be the hallmarks of T6SS and show considerable homology to essential proteins that form the punctuating injector of a typical bacteriophage (Brunet et al., 2014). Since the discovery of its first member in V. cholerae as part of the T6SS machinery (McCracken et al., 1984;Ishikawa et al., 2009), the Hcp family proteins have been identified in a variety of bacterial species. An Hcp1/Hcp2 double knockout of V. cholerae V52 was generated by transposon mutagenesis and showed no virulence on Dictyostelium discoideum (Pukatzki et al., 2006). ...
Escherichia coli-induced meningitis remains a life-threatening disease despite recent advances in the field of antibiotics-based therapeutics, necessitating continued research on its pathogenesis. The current study aims to elucidate the mechanism through which hemolysin-coregulated protein 1 (Hcp1) induces the apoptosis of human brain microvascular endothelial cells (HBMEC). Co-immunoprecipitation coupled with mass spectrometric (MS) characterization led to the identification of IQ motif containing GTPase activating protein 1 (IQGAP1) as a downstream target of Hcp1. IQGAP1 was found to be up-regulated by Hcp1 treatment and mediate the stimulation of HBMEC apoptosis. It was shown that Hcp1 could compete against Smurf1 for binding to IQGAP1, thereby rescuing the latter from ubiquitin-dependent degradation. Subsequent study suggested that IQGAP1 could stimulate the MAPK signaling pathway by promoting the phosphorylation of ERK1/2, an effect that was blocked by U0126, an MAPK inhibitor. Furthermore, U0126 also demonstrated therapeutic potential against E. coli meningitis in a mouse model. Taken together, our results suggested the feasibility of targeting the MAPK pathway as a putative therapeutic strategy against bacterial meningitis.
Human Meningitis-Associated Escherichia coli, Page 1 of 2
Abstract
Escherichia coli is the most common Gram-negative bacillary organism causing meningitis, and E. coli meningitis continues to be an important cause of mortality and morbidity throughout the world. Our incomplete knowledge of its pathogenesis contributes to such mortality and morbidity. Recent reports of E. coli strains producing CTX-M-type or TEM-type extended-spectrum β-lactamases create a challenge. Studies using in vitro and in vivo models of the blood-brain barrier have shown that E. coli meningitis follows a high degree of bacteremia and invasion of the blood-brain barrier. E. coli invasion of the blood-brain barrier, the essential step in the development of E. coli meningitis, requires specific microbial and host factors as well as microbe- and host-specific signaling molecules. Blockade of such microbial and host factors contributing to E. coli invasion of the blood-brain barrier is shown to be efficient in preventing E. coli penetration into the brain. The basis for requiring a high degree of bacteremia for E. coli penetration of the blood-brain barrier, however, remains unclear. Continued investigation on the microbial and host factors contributing to a high degree of bacteremia and E. coli invasion of the blood-brain barrier is likely to identify new targets for prevention and therapy of E. coli meningitis.
Bacterial sepsis in the neonate is a clinical syndrome characterized by systemic signs of infection and accompanied by bacteremia in the first month of life. Meningitis in the neonate usually is a sequela of bacteremia and is discussed in this chapter because meningitis and sepsis typically share a common cause and pathogenesis. Infections of the bones, joints, and soft tissues and of the respiratory, genitourinary, and gastrointestinal tracts can be accompanied by bacteremia, but the cause, clinical features, diagnosis, and management of these infections are sufficiently different to warrant separate discussions. Sepsis and meningitis caused by group B Streptococcus, Staphylococcus aureus, Neisseria gonorrhoeae, Listeria monocytogenes, Salmonella species, and Mycobacterium tuberculosis are described in other chapters.
Meningitis-Associated Escherichia coli, Page 1 of 2
Abstract
Escherichia coliis the most common Gram-negative organism causing neonatal meningitis. Neonatal E. colimeningitis continues to be an important cause of mortality and morbidity throughout the world. Our incomplete knowledge of its pathogenesis and pathophysiology contributes to such mortality and morbidity. Recent reports of neonatal meningitis caused by E. coli strains producing CTX-M-type or TEM-type extended-spectrum β-lactamases create a challenge. E. colipenetration into the brain, the essential step in the development of E. coli meningitis, requires a high-degree of bacteremia and penetration of the blood-brain barrier as live bacteria, but the underlying mechanisms remain incompletely understood. Recent functional genomic approaches of meningitis-causing E. coli in both in vitro and in vivo models of the blood-brain barrier (e.g., human brain microvascular endothelial cells and animal models of experimental hematogenousE. colimeningitis, respectively) have identified several E. coli factors contributing to a high-degree of bacteremia, as well as specific microbial factors contributing to E. coli invasion of the blood-brain barrier. In addition, E. coli penetration of the blood-brain barrier involves specific host factors as well as microbe- and host-specific signaling molecules. Blockade of such microbial and host factors and host cell signaling molecules is efficient in preventing E. coli penetration into the brain. Continued investigation of the microbial and host factors contributing to E. colibacteremia andinvasion of the blood-brain barrier is likely to identify new targets for prevention and therapy of E. coli meningitis, thereby limiting the exposure to emerging antimicrobial-resistant E. coli.
E. coli is the most common Gram-negative bacteria causing neonatal meningitis, and E. coli meningitis continues to be an important cause of mortality and morbidity throughout the world. Recent reports of E. coli meningitis caused by antimicrobial resistant strains are a particular concern. These findings indicate that a novel strategy is needed to identify new targets for prevention and therapy of E. coli meningitis. Cytotoxic necrotizing factor 1 (CNF1) is a bacterial virulence factor associated principally with E. coli strains causing urinary tract infection and meningitis. We have shown that CNF1 contributes to E. coli invasion of the blood-brain barrier and penetration into the brain, the essential step in the development of E. coli meningitis, and identified the host receptor for CNF1, 37-kDa laminin receptor precursor (37LRP). CNF1, however, is a cytoplasmic protein and its contribution to E. coli invasion of the blood-brain barrier requires its secretion from the bacterial cytoplasm. No signal peptide is found in the CNF1 sequence. CNF1 secretion is, therefore, a strategy utilized by meningitis-causing E. coli to invade the blood-brain barrier. Elucidation of the mechanisms involved in CNF1 secretion, as shown in this report with the involvement of Fdx and YgfZ provides the novel information on potential targets for prevention and therapy of E. coli meningitis by virtue of targeting the secretion of CNF1.
Salmonella infect humans and animals world-wide causing a spectrum of diseases including enteric fever, gastroenteritis and septicaemia. A number of mechanisms of host resistance to salmonellosis have been identified in the mouse typhoid model. In mice, salmonellae usually reside inside phagocytes and dendritic cells localized within discrete pathological lesions surrounded by normal tissue. Bacterial growth in the tissues is controlled by NADPH oxidase-dependent and iNOS-dependent anti-microbial functions of resident and inflammatory phagocytes and is under the control of H-2 genes and the Nramp1 gene. The concerted action of a number of cytokines (TNFα, IFNγ, IL-12, IL-18, IL-15), the contribution of CD4 TCR-α/β T-cells, the presence of B-cells and antibodies are essential for host resistance to this bacterium. Observations on the increased incidence of Salmonella infections in immunocompromised patients have revealed some effector mechanisms that control these infections in humans. Deficiencies in components of the innate immune system including gastric secretion, neutrophil and macrophage functions predispose individuals to salmonellosis. A higher incidence of salmonellosis is seen also in patients with antibody deficiencies, defects in cell-mediated immunity and deficiencies in Th1 cytokines (IL-12, IFNγ) or cytokine receptors (IL-12R β1 subunit, IFNγR chains 1 and 2).
The combination of ampicillin with either gentamicin or chloramphenicol, which is currently the initial chemotherapy for purulent meningitis, has lost its effectiveness in recent years because of an increase in the incidence of ampicillin-resistant strains. This has made it necessary to search for a suitable substitute therapy.
Twenty-two new β-lactam agents were compared with penicillin G and ampicillin in terms of their antibacterial activity in relation to the principal causative microbes of meningitis and their ability to transfer into the cerebrospinal fluid (CSF) of rabbits with experimental staphylococcal meningitis. In addition, a survey was conducted of the therapeutic efficacy achieved by these drugs in cases seen by the authors and in other domestic and overseas cases. Finally, an investigation was made as to whether or not the transfer of the drug into the CSF was suppressed when it was administered simultaneously with ampicillin.
From the results, it was surmised that in future the most appropriate initial chemotherapy for purulent meningitis will be a combination of cefotaxime, or perhaps ceftriaxone, plus ampicillin.
It can be concluded that bacterial meningitis is an important cause of childhood morbidity and mortality. Isolation of causative
pathogenes is poor in our country. A routine gram staining of CSF and use of rapid diagnostic kits with better culture facilities
would be helpful in improving the outcome. In first 3 months of life, therapy should include one of the 3rd generation cephalosporins
with an aminoglycoside. For meningitis in age groups between 3 months to 12 years, chloramphenicol and ampicillin should be
the first line empirical therapy. If gram-ve organisms are suspected or isolated, one of the 3rd generation cephalosporins
with or without an aminoglycoside is good alternative. The treatment can be stopped in uncomplicated case after 7–10 days
(5 days of afebride period) in meningitis caused by meningococcus, pneumococcus andH. infuenzae. For BM caused by gram-ve bacilli treatment for 21 days is recommended. There is no need to perform CSF examination at the
conclusion of therapy in cases of bacterial meningitis beyond neonatal period. There is a need to further evaluate therapeutic
regimens like chloramphenicol alone, ceftriaxone home therapy, especially for rural areas etc. to decrease the cost of hospitalisation
in referral hospitals.
The basic principles of rational antimicrobial therapy and details about the major classes of antibiotics as they apply to the treatment of pediatric infections are reviewed. A primary focus is on the chemistry, mechanism of action, antimcrobial spectrum, adverse effects of antimicrobial agents, and how these factors affect clinical use. The factors reviewed that affect antimicrobial selection include microbiological and anatomic, host, and pharmaceutical considerations. In addition, examples pertinent to the treatment of specific pediatric infections are given.
Pediatric Research publishes original papers, invited reviews, and commentaries on the etiologies of diseases of children and disorders of development, extending from molecular biology to epidemiology. Use of model organisms and in vitro techniques relevant to developmental biology and medicine are acceptable, as are translational human studies.
Neonatal patients are surviving longer due to the rapid advances in medical knowledge and technology. Our understanding of the developmental physiology of both preterm and full term neonates has also increased. It is now apparent that differences in body composition and organ function significantly affect the pharmacokinetics of antibacterial drugs in neonates, and dosage modifications are required to optimise antimicrobial therapy.
The penicillins and cephalosporins are frequently used in neonates. Although ampicillin has replaced benzylpenicillin (penicillin G) for empirical treatment of neonatal sepsis, many of the other penicillins may be used in neonates for the management of various infections. Increased volume of distribution (Vd) and decreased total body clearance (CL) affect the disposition of penicillins and cephalosporins. Decreased renal clearance (CLR) due to decreased glomerular filtration and tubular secretion is responsible for the decreased CL for most of the β-lactams.
Aminoglycoside Vd is affected by the increased total body water content and extracellular fluid volume of neonates. The increased Vd, in part, accounts for the extended elimination half-life (t½) observed in neonates. Aminoglycoside CL is dependent on renal glomerular filtration which is markedly decreased in neonates, especially those preterm. These drugs appear to be less nephrotoxic and ototoxic in neonates than in older patients, and the role of serum concentration monitoring should be limited to specific neonatal patients.
Other antibiotics such as vancomycin, teicoplanin, chloramphenicol, rifampicin, erythromycin, clindamycin, metronidazole and cotrimoxazole (trimethoprim plus sulfamethoxazole) may be used in certain clinical situations. The emergence of staphylococcal resistance to penicillins has increased the need for vancomycin. With the exceptions of vancomycin and chloramphenicol, the efficacy and safety of these other agents in neonates have not been established. The need for serum vancomycin concentration monitoring may be limited, as with aminoglycosides, while safety concerns warrant the routine monitoring of serum chloramphenicol concentrations in neonates.
Dosing guidelines are provided, based on the pharmacokinetics of the drugs and previously published recommendations. These dosing guidelines are intended for initial therapy, and close therapeutic monitoring is recommended for maintenance dose requirements to optimise patient outcome.
There has been an enormous increase in our knowledge of neonatal physiology and drug disposition. Fortunately, many of the antibacterial drugs used in neonates (e.g. penicillins and cephalosporins) are relatively safe. It will be important to evaluate all newly developed antibiotics in neonates to assure their maximum efficacy and safety.
We reviewed cases of Gram-negative enteric bacillary meningitis in infants and children treated with cefotaxime at Texas Children's Hospital from January, 1984, through June, 1989. Seventeen of 20 children had an underlying condition predisposing to the development of meningitis. The etiologic organisms in these 20 children (2 days to 12 years old; median, 12 days old) were Klebsiella sp, 9; Escherichia coli, 4; Enterobacter cloacae, 3; Citrobacter diversus, 2; other, 2. With the exception of one isolate of Acinetobacter, all isolates were susceptible to cefotaxime. In addition to cefotaxime 17 children received an aminoglycoside intravenously. Children with meningitis caused by Klebsiella sp. or non-Klebsiella organisms received cefotaxime for 31 +/- 14 and 37 +/- 17 days, respectively. Aminoglycosides were administered for 16 +/- 10 days in both groups. Five children in each group also received intraventricular doses (1 to 25) of an aminoglycoside (9) or colistimethate (1). The mean durations of positive lumbar, ventricular cerebrospinal fluid or brain abscess cultures were 5.8 +/- 4.7 and 7.2 +/- 5.0 days after start of therapy in the Klebsiella and non-Klebsiella meningitis patients, respectively. Only three children were normal at the time of discharge or follow-up. Gram-negative enteric meningitis remains difficult to treat despite the excellent in vitro activity of cefotaxime against Gram-negative enterics, in part as a result of the predisposing conditions resulting in the development of this infection.
Over the past 5 yr, we have conducted two clinical and two pharmacokinetic investigations of cefotaxime (CTX) and desacetylcefotaxime (dCTX) in neonates, infants, and children. A total of 50 children with culture-proven bacterial meningitis were randomized to receive either 200 mg/kg/day of CTX (n = 23, mean age 24.4 mo) or standard doses of ampicillin (AMP) and chloramphenicol succinate (CAPS; n = 27, mean age 16.6 mo). Results were similar between the CTX and Amp/CAPS groups for clinical/microbiological cures (100% versus 96%, respectively) and for survival without sequelae (78% vs. 77%, respectively). All bacterial isolates were sensitive to CTX, and the comparison of the MIC/MBC values for CTX to the CSF bactericidal titers suggested antimicrobial activity for dCTX. In a second clinical trial, 20 infants (1 wk-3 mo) were treated with 200 mg/kg/day of CTX for Gram-negative enteric bacillary meningitis. Cultures of CSF obtained 24 hr after the initiation of treatment were sterile in all subjects. Survival and complication rates of 95% and 21%, respectively, were observed. This compared favorably to previously published experiences with alternate treatment regimens for Gram-negative meningitis in the newborn. In both meningitis studies, the safety profile for CTX was excellent.(ABSTRACT TRUNCATED AT 250 WORDS)
The outcome of neonatal septicemia in 320 infants seen during 1969-83 has been evaluated. Mortality decreased from 27% to 12%. The incidence of moderate to severe handicaps in survivors remained unchanged at around 20%. Sixty percent of these handicapped children had meningitis or osteomyelitis, and many of these were healthy prior to onset. All handicapped infants without osteomyelitis or meningitis had several other risk factors that may have contributed to the final outcome.
Le Citrobacter (notamment diversus) est une cause de frequence croissante de meningite epidemique ou sporadique du nouveau-ne ou du jeune nourrisson, compliquee dans 77% des cas d'abces du cerveau. L'experimentation sur le rat pourrait aider a expliquer cette frequence et avoir des implications pour l'epidemiologie, la prevention et le traitement de ces meningites
The introduction of several cephalosporins into pediatric practice has provided the physician with a number of choices in the treatment of neonatal and childhood meningitis. Adequate studies are available to indicate that these new drugs are as effective as traditional treatments in terms of survival and major neurologic sequelae but it is not known whether the results are worse or better as far as the incidence of more subtle neurologic changes is concerned. The advantages of the cephalosporins in treatment of childhood meningitis are that they permit single drug therapy, the risks of drug toxicity are reduced, and the problems of penicillin-tolerant pneumococci and ampicillin/chloramphenicol-resistant H. influenzae are avoided. When used in the treatment of neonatal disease, the cephalosporins have the advantage of lower toxicity than the aminoglycosides, generally making blood drug level determinations unnecessary, and are effective against strains of bacteria that have become resistant to the latter drugs.
Despite immunization and antimicrobial prophylaxis strategies aimed at decreasing bacterial meningitis, approximately 20,000 cases still occur annually in the United States in children under 16 years of age. The mortality of this infection remains approximately 5 percent in older children and 15-20 percent in neonates, despite increasingly potent antimicrobial agents and significant advances in adjunctive medical therapies. Furthermore, the rate of sequelae, most commonly neurologic, remains between 30-40 percent. In this paper, we review some recent advances in the assessment and treatment of children with suspected or proven bacterial meningitis.
The cephalosporins have been available for clinical use for nearly 20 years and a large number is presently marketed, including drugs with a wide range of different pharmacokinetic and microbiologic properties. While some of these agents have certain specific uses in which they excel, the cephalosporins have not replaced older antibiotics but do provide the physician with a broader range of choices for the treatment of many infections, allowing greater individualization of therapy.
Eighty-five infants and children were prospectively randomized to receive cefotaxime or ampicillin and chloramphenicol for therapy of bacterial meningitis. The two therapy groups of patients were comparable as to sex, age, clinical status on admission, prior administration of antibiotics and etiology. Three infants (7%) died in each therapy group. Mean number of days of positive cerebrospinal fluid cultures, time to defervescence and duration of treatment and of hospital stay and complications developing during treatment were similar for the two treatment regimens. Median cerebrospinal fluid bactericidal titers against the patients' pathogens in cefotaxime-treated patients (1:64) were larger than those in patients who received conventional therapy (1:8). Mild to moderate motor sequelae were more frequent in those given conventional therapy at the time of discharge only, and not at 4 months or longer of follow-up. We conclude that cefotaxime has similar efficacy when compared with conventional therapy for the management of bacterial meningitis in pediatric patients.
Collection of fluid in the subdural space during the course of acute bacterial meningitis is common in infants and is generally referred to as subdural effusion. The factors that influence formation of subdural effusion remain unclear. Large white blood cell counts (WBC) combined with an increased percentage of neutrophils and low glucose content, even when the culture is negative, are considered indicative of infected effusions. When grossly purulent material is encountered in the subdural space, the term subdural empyema is used.
Ceftriaxone has a very long serum half-life and enhanced in vitro activity against common pediatric pathogens. Therefore we evaluated the efficacy and safety of once daily ceftriaxone therapy in 57 children with serious infections including: meningitis (26 patients); ventriculitis (3); pyelonephritis (7); osteomyelitis (6); abscess (4); septic arthritis (3); sepsis (2); and miscellaneous infections (6). The most common isolates were Haemophilus influenzae (23), Escherichia coli (9) and Staphylococcus aureus (8). Ceftriaxone was given intravenously or intramuscularly in a dose of 50 mg/kg for non-central nervous system (CNS) infections. Patients with CNS infections received an initial dose of 100 mg/kg followed by 80 mg/kg 12 hours later and once daily thereafter. In a limited number of patients no major differences in serum ceftriaxone concentrations were found after intravenous or intramuscular injection. Of 57 patients with pathogens isolated 55 were completely cured; in one patient with Klebsiella pneumoniae ventriculitis, intraventricular gentamicin was briefly added to the regimen. Another patient with an anaerobic liver abscess recovered after metronidazole was administered. In three patients a delayed response to ceftriaxone was noted. One patient with previous recurrent infections had a second episode of H. influenzae meningitis 22 days after cessation of therapy. Clinical side effects were noted in 10 of 71 patients (including 14 treated patients who had negative cultures). Seven patients had diarrhea, one each had fever or rash and one had fever, rash and arthralgia. Laboratory side effects in 16 of 71 patients included eosinophilia (7), thrombocytosis (7), elevated liver enzymes (4) and leukopenia and neutropenia (2).(ABSTRACT TRUNCATED AT 250 WORDS)
The long-term outcome and admission features predictive of outcome were determined for 61 patients with group B streptococcal meningitis treated between 1974 and 1979. Infection was rapidly fatal in 13 patients (21%). Among the 48 survivors, 38 (79%) 3 years of age or older were available for comprehensive evaluation. Excluding five who had died before age 3 years, the mean age at evaluation was 6.0 years (range 3.3 to 9.0 years). Among survivors, 11 (29%) had severe neurologic sequelae, eight (21%) had mild to moderate deficits, and 19 (50%) were functioning normally. Analysis of predictive features revealed a significant risk of death or severe impairment among infants who at hospital admission were comatose or semicomatose, had decreased perfusion, total peripheral WBC less than 5,000/mm3, absolute neutrophil count less than 1000/mm3, and CSF protein greater than 300 mg/dl (P less than or equal to 0.05). These data indicate that, although mortality from group B streptococcal meningitis has declined, approximately half of the survivors of acute infection have some degree of morbidity when evaluated at ages permitting the detection of language delay and borderline or mild mental retardation.
Seven neonates were treated with cefotaxime during eight episodes of Gram-negative bacillary meningitis and sepsis. The causative organisms were Escherichia coli in six cases and Klebsiella pneumoniae and Enterobacter sakazakii in one each. After identification of the pathogen cefotaxime was used alone in six instances. Two patients with brain abscesses received adjunctive therapy with another antibiotic. The sterility of cerebrospinal fluid was documented after a mean of 3.3 days of therapy. Mean cerebrospinal fluid bactericidal titer was 1:64. All patients recovered with good neurologic outcome. Cefotaxime in a dosage of 150 mg/kg/day divided every 6 hours intravenously seems safe and effective therapy for neonatal Gram-negative bacillary meningitis.
The conventional antimicrobial therapy of gram-negative infection in the newborn is the combination of ampicillin and an aminoglycoside, usually gentamicin or kanamycin. Although gentamicin and kanamycin have been used interchangeably, efficacies of the two drugs have not been carefully compared. In addition, the contribution of ampicillin to the outcome of neonatal gram-negative meningitis is controversial. We evaluated the activity of gentamicin and kanamycin alone and in combinations with ampicillin in vitro and in vivo against a K1 Escherichia coli strain. In vitro, the E. coli strain was relatively sensitive to ampicillin, gentamicin, and kanamycin, with the minimal inhibitory and minimal bactericidal concentrations of 2 and 4, 2 and 2, and 4 and 8 micrograms/ml, respectively. Checkerboard determinations of minimal inhibitory and minimal bactericidal concentrations of drug combinations exhibited an indifferent response for both ampicillin + gentamicin and ampicillin + kanamycin. However, in vivo studies using an experimental E. coli bacteremia and meningitis model in newborn rats suggested that gentamicin was more effective than kanamycin. This was shown by more rapid bacterial clearance from the blood, a decreased incidence of meningitis in bacteremic animals, and improved survival. Furthermore, the addition of ampicillin improved the outcome of kanamycin, but not gentamicin, suggesting that the contribution of ampicillin may vary depending on the type of aminoglycoside used. These findings suggest that kanamycin is less effective than gentamicin in vivo against E. coli and should be used in combination with ampicillin to achieve an outcome comparable to that of gentamicin in this model of E. coli infection.
The spectrum of neonatal infections continues to evolve with changes in the types and antibiotic susceptibilities of bacterial pathogens and the prominent appearance of new clinical syndromes of infection in the newborn intensive care unit. Fortunately with the development of new antibiotics and thorough reevaluation of older antibiotics in the neonate, effective antimicrobial therapy is still available. With the knowledge of national and local trends of infecting organisms, it is possible to select an accurate empiric antibiotic regimen for neonatal sepsis.
New products, new procedures, new information, and new legislation will have a significant impact on management and prevention of respiratory infections in children. Current areas of investigation include the changing epidemiology (increased number of children in day care), concern about morbidity of common infections (hearing impairment and effect on development of speech and language due to otitis media), and new modes of microbiologic diagnosis (antigen detection). New antimicrobial agents have wider spectrums of activity, increased concentrations in body fluids, and lesser toxicity than available drugs. New uses of old drugs are identified (value of erythromycin for Legionella pneumophila, Chlamydia trachomatis, and Mycoplasma pneumoniae). Increased usage of chemoprophylaxis for prevention of recurrences of acute otitis media follows publication of impressive results of recent studies. New conjugate polysaccharide vaccines are immunogenic in young infants. Finally, and of major importance to children, physicians, and manufacturers, is vaccine liability legislation, now in congressional committee.
Because of increased aminoglycoside resistance of hospital bacterial isolates, aminoglycoside sensitivity patterns of isolates in a large children's hospital were assessed before and during a 33-month period of almost exclusive amikacin use. There was no significant change in overall resistance rates of gram-negative enteric bacteria to gentamicin (4.8 percent and 4.6 percent), tobramycin (2.5 percent and 3.6 percent), and amikacin (1.2 percent and 1.8 percent) from the pre-amikacin period to the amikacin usage period, respectively. No significant differences were observed for isolates of Escherichia coli, Klebsiella, Serratia, Acinetobacter, and Pseudomonas species. In contrast, significant decreases in gentamicin and tobramycin resistance rates for Enterobacter, Citrobacter, and Pseudomonas aeruginosa and in gentamicin resistance of Proteus were found. Very little change in resistance of staphylococcal isolates was seen during a shorter evaluation period. Pediatric aminoglycoside usage includes therapy of neonatal infections, cystic fibrosis, febrile neutropenic episodes in patients with cancer, abdominal surgery, bacterial endocarditis, and gram-negative central nervous system infections. Amikacin has also been used successfully as single-dose therapy of urinary tract infections, and acceptable cerebrospinal fluid levels of amikacin have been documented in hydrocephalic patients with ventriculitis. In vitro studies of 22 bacterial isolates demonstrated synergy between amikacin and penicillin or newer cephalosporins in 13, an additive effect in seven and indifference in two. No antagonism was found. In addition, in vivo synergy between imipenem and amikacin was found in neutropenic infant rats with P. aeruginosa sepsis using a strain with which no synergy was demonstrable in vitro. Amikacin is effective in pediatric infections and is well tolerated by children. Because excessive or inadequate levels are frequent with usually recommended doses, particularly in neonates and patients with compromised renal function or cystic fibrosis, serum levels should be monitored to minimize risk and to ensure therapeutic levels.
We reviewed our experience with gram-negative enteric bacillary meningitis in neonates and infants from 1969 through 1989. Ninety-eight patients were identified. Their ages were from 1 day to 2 years with a median of 10 days. In 25 patients (26%), predisposing factors were identified, the most common of which were neural tube defects and urinary tract anomalies. The causative agents were Escherichia coli (53%), Klebsiella-Enterobacter species (16%), Citrobacter diversus (9%), Salmonella species (9%), Proteus mirabilis (4%), Serratia marcescens (3%), Bacteroides fragilis (3%), and Aeromonas species (2%). At the time of diagnosis, Gram-stained smears of cerebrospinal fluid revealed gram-negative bacilli in 61% of patients. The causative organism was cultured from blood obtained from 55% of patients, and 21% had positive urine culture results. The cerebrospinal fluid leukocyte counts ranged from 0 to 80,600 cells/mm3, and the cerebrospinal fluid/serum glucose concentration ratio was less than 0.5 in 72% of patients. Antimicrobial regimens varied greatly. After initiation of antibiotic therapy, an average of 3 days was needed for eradication of bacteria from cerebrospinal fluid. The case-fatality rate was 17%, and 61% of survivors had long-term sequelae that included seizure disorders, hydrocephalus, physical disability, developmental delay, and hearing loss.
We evaluated 22 paired maternal and cord sera regarding the presence of IgG and IgG subclasses against purified Escherichia coli LPS O6, O16 and O111 employing ELISA for titre and avidity analysis, isoelectric focusing associated with affinity-blotting for spectrotypic analysis, and the Western-blotting technique for recognition of the various bands in lipopolysaccharide (LPS). Levels of anti-LPS IgG antibodies in cord sera were equivalent to their respective maternal sera, showing a significant correlation (P < 0.0001). IgG1 antibody levels were higher in cord sera than in maternal sera (P < 0.005 for anti-O111, P < 0.05 for anti-O16 and P < 0.02 for anti-O6). Cord IgG2 antibody levels were not different from the maternal levels (P > 0.1). The levels of IgG3 and IgG4 were undetectable. The avidity of anti-O6 and anti-O111 IgG in 10 cord sera showed an extremely significant correlation with maternal antibody avidity (P < 0.0001). Identical patterns of recognition were found in the paired samples analysed by Western blotting. Most of the serum samples recognized the O-repetitive chains and also the region corresponding to core and lipid A. Although the antibody spectrotypes varied among individuals, paired cord and maternal serum samples showed identical patterns. Our findings suggest the occurrence of placental transfer of IgG antibodies against LPS O6, O16 and O111, mainly involving the IgG1 or IgG2 subclasses.
Various species of Citrobacter may cause infections in neonates and immunocompromised hosts. Citrobacter koseri (formerly Citrobacter diversus) is best known as the cause of sepsis and meningitis leading to central nervous system (CNS) abscesses in neonates and young
infants. Early onset and late-onset infections occur as for other neonatal bacterial infections. The majority of cases are
sporadic, with no clear source of infection. A few have been confirmed to be vertically transmitted, and nosocomial outbreaks
have occurred in neonatal care units. The pathophysiology is not well understood, but a surface protein has been identified
as a possible virulence factor among strains that cause citrobacter brain abscesses in neonates. Despite improvements in diagnostic
imaging techniques, surgery, and antibiotic therapy, approximately one-third of infants with abscesses die, and one-half sustain
CNS damage. In this article, the taxonomy, epidemiology, pathogenesis, diagnosis, treatment, and outcome of citrobacter disease
in children are reviewed.
The aim of this study was to analyze the epidemiological evolution of causal germs in meningitis in children aged 1 day to 15 years and determine the relationship between pretreatment concentrations of bacteria in cerebral spinal fluid (CSF), patient age, bacterial species and bacteriological eradication.
A quantitative analysis of germs was performed in 212 children with bacterial meningitis (mean age 19.8 months).
Bacterial counts ranged from 2.10(1) to 4.10(9) CFU/ml in CSF. Among the 212 patients, 52 (24.5%) had counts 10(7)/ml. Infants had significantly higher counts than the other age groups. Mean counts for Hoemophilus influenzoe serotype B were not different from those for Streptococcus pneumoniae but were significantly higher than for Neisseria meningitidis. Compared with initial germ counts, 98.5% of the CSF specimens were sterile at 24 and 48 hours and 100% at 72 hours.
Germ counts were higher in infants.
Escherichia coli meningitis commonly occurs in the neonatal period, but the basis of this age dependency is unclear. We have previously identified two types of E. coli-brain microvascular endothelial cell (BMEC) interactions contributing to E. coli traversal of the blood-brain barrier (i.e., binding and invasion). The present study examined whether the age dependency of E. coli meningitis stemmed from differences in the capacities of neonatal and adult BMECs to interact with E. coli. BMECs were isolated from rats of different ages (10 days, 20 days and 3 months) as well as from humans of different ages (fetuses, 4- to 7-year-old children, and a 35-year-old adult, and 60- to 85-year-old geriatrics). The bindings of E. coli to young and old rat BMECs were similar. Also, the abilities of E. coli to invade BMECs were similar for BMECs derived from young and old rats and from human fetuses, children, adults, and geriatrics. These findings suggest that the predominance of E. coli meningitis in neonates is not likely due to greater binding and invasion capacities of newborn compared to adult BMECs.
A high prevalence of systemic infections caused by enterobacteria such as Escherichia coli is observed during the neonatal period. Lipopolysaccharide (LPS) is one of the major factors responsible for septic shock caused by these Gram-negative bacteria. We have recently demonstrated the presence of anti-LPS immunoglobulin (Ig)G antibodies in cord blood with a repertoire identical to that found in maternal serum. In the present study, we analyzed anti-LPS O111 antibody isotypes in maternal serum and colostrum from mothers and in cord serum from their respective full-term (n = 30) and preterm (n = 13) neonate infants. The main isotype found in serum samples from mothers of term infants was IgM (range between 28 and 54 mg/l), followed by IgA (1-2 mg/l) and IgG (2-3 mg/l). The range of IgG antibody concentrations in cord blood was between 2 and 3 mg/l, as a result of placental transfer. A novel observation in our study was that the LPS bands recognized by colostral antibodies were completely different from those recognized by IgG in serum. Colostral IgA antibodies recognized several bands not bound by serum IgG antibodies from the respective maternal serum, independently of the antibody quantity. In addition, we verified the pattern of LPS recognition by serum IgA and colostral IgA antibodies was identical, what suggested that the antibody isotype found in serum could probably be derived from differentiated IgA-positive cells which were homing to the mucosa through the mucosal homing mechanism. Identical pattern of recognition was obtained comparing the IgA and IgM isotypes in colostrum. Slight differences in the pattern of recognition were found between colostral and serum IgM antibodies. The fact that colostral antibodies recognize much more bands than serum antibodies may be important for the host to mount an effective immune response in the intestinal lumen, in order to prevent excessive absorption of LPS, reducing possible systemic effects caused by the molecule.
Group B beta-hemolytic streptococci and Escherichia coli strains account for approximately two thirds of all cases of neonatal meningitis, while bacteria that typically account for meningitis in older age groups (Haemophilus influenzae type B, Neisseria meningitidis, and Streptococcus pneumoniae) are infrequent causes of meningitis in the neonatal population.
As with other medical problems in neonates, signs and symptoms of bacterial infection of the central nervous system are generally few in number and nonspecific in nature. Manifestations that can suggest meningitis, as well as other serious illnesses, include temperature instability, lethargy, respiratory distress, poor feeding, vomiting, and diarrhea. Signs suggestive of meningeal irritation, including stiff neck, bulging fontanelle, convulsions, and opisthotonus, occur only in a minority of neonates with bacterial meningitis and cannot be relied on solely to identify such patients.
Ampicillin and either gentamicin or cefotaxime are recommended for initial empiric therapy of neonatal meningitis.
When the results of the cerebrospinal fluid (CSF) culture and susceptibilities are known, therapy can be narrowed to cover the specific pathogen identified.
In general, penicillin G or ampicillin is preferred for group B streptococcal meningitis, ampicillin for Listeria monocytogenes meningitis, and ampicillin plus either an aminoglycoside or cefotaxime for gram-negative meningitis.
For the very low birth weight neonate who has been in the nursery for a prolonged period of time, organisms such as enterococci and gentamicin-resistant gram-negative enteric bacilli must also be considered. In patients with long-term vascular catheters, Staphylococcus aureus or coagulase-negative staphylococci must also be considered. Empiric combinations of antibiotics for such patients would include ampicillin or vancomycin, plus amikacin or cefotaxime.
All neonates should undergo repeat CSF examination and culture at 48 to 72 hours after initiation of therapy. If organisms are observed on gram stain, modification of the therapeutic regimen should be considered, and neuroimaging should be performed.
In general, therapy should be continued for 14 to 21 days for neonatal meningitis caused by group B streptococci or L. monocytogenes, and for at least 21 days for disease caused by gram-negative enteric bacilli.
All patients with neonatal meningitis should have hearing and development monitored serially. The first audiologic evaluation should occur 4 to 6 weeks after resolution of the meningitis.
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