Imad Kassis

Carbapenem Resistance Among Klebsiella pneumoniae Isolates: Risk Factors, Molecular Characteristics, and Susceptibility Patterns

BACKGROUNDnCarbapenem resistance among isolates of Klebsiella pneumoniae has been unusual.nnnOBJECTIVESnTo identify risk factors for infection with carbapenem-resistant K. pneumoniae (CRKP) and to characterize microbiological aspects of isolates associated with these infections.nnnDESIGNnRetrospective case-control study.nnnSETTINGnA 900-bed tertiary care hospital.nnnRESULTSnFrom January 2006 through April 2007, K. pneumoniae was isolated from 461 inpatients; 88 had CRKP infection (case patients), whereas 373 had carbapenem-susceptible K. pneumoniae infection (control subjects). The independent risk factors for infection with CRKP were prior fluoroquinolone use (odds ratio [OR], 1.87 [95% confidence interval [CI], 1.07-3.26]; P=.026), previous receipt of a carbapenem drug (OR, 1.83 [95% CI, 1.02-3.27]; P=.042), admission to the intensive care unit (OR, 4.27 [95% CI, 2.49-7.31]; P<.001), and exposure to at least 1 antibiotic drug before isolation of K. pneumoniae (OR, 3.93 [95% CI, 1.15-13.47]; P=.029). All CRKP isolates carried the bla(KPC) gene. Approximately 90% of the tested isolates carried the bla(KPC-2) allele, suggesting patient-to-patient transmission. Almost all CRKP isolates were resistant to all antibiotics, except to colistin (resistance rate, 4.5%), gentamicin (resistance rate, 7%), and tigecycline (resistance rate, 15%).nnnCONCLUSIONSnCRKP should be regarded as an emerging clinical threat. Because these isolates are resistant to virtually all commonly used antibiotics, control of their spread is crucial.

Invasive pediatric Kingella kingae infections: a nationwide collaborative study.

Background: Kingella kingae is a gram-negative coccobacillus, increasingly recognized as an invasive pediatric pathogen. To date, only few small series of invasive K. kingae infections have been published, mostly from single medical centers. A nationwide multicenter study was performed to investigate the epidemiologic, clinical, and laboratory features of children with culture-proven K. kingae infections. Methods: Clinical microbiology laboratories serving all 22 medical centers in Israel were contacted in a search for children aged 0 to 18 years from whom K. kingae was isolated from a normally sterile site, dating from as far back as possible until December 31, 2007. Medical records of identified patients were reviewed using uniform case definitions. Results: A total of 322 episodes of infection were identified in 321 children, of which 96% occurred before the age of 36 months. The annual incidence in children aged <4 years was 9.4 per 100,000. Infections showed a seasonal nadir between February and April. Skeletal system infections occurred in 169 (52.6%) children and included septic arthritis, osteomyelitis, and tenosynovitis. Occult bacteremia occurred in 140 children (43.6%), endocarditis in 8 (2.5%), and pneumonia in 4 (1.2%). With the exception of endocarditis cases, patients usually appeared only mildly ill. About one-quarter of children had a body temperature <38°C, 57.1% had a blood white blood cell count <15,000/mm3, 22.0% had normal C-reactive protein values, and 31.8% had nonelevated erythrocyte sedimentation rate. Conclusions: K. kingae infections usually occur in otherwise healthy children aged 6 to 36 months, mainly causing skeletal system infections and bacteremia, and occasionally endocarditis and pneumonia. Clinical presentation is usually mild, except for endocarditis, necessitating a high index of suspicion.

Early Emergence of Ganciclovir-Resistant Human Cytomegalovirus Strains in Children with Primary Combined Immunodeficiency

Children with primary combined immunodeficiency (CID) and human cytomegalovirus (HCMV) infection often deteriorate despite antiviral therapy. In this study, the emergence of ganciclovir-resistant strains was examined in 6 children with CID and HCMV infection, using sequence analysis of the HCMV UL97 gene and virus susceptibility assays. Mutations in the proposed ATP binding site associated with ganciclovir resistance were found in 4 of the 6 children. In 1 patient with B severe CID, an unusual multiplicity of mutations was found in the UL97 substrate binding domain between aa 590-606. All mutations were detected within 10 days to 3 weeks from initiation of therapy. The emergence of resistant strains in children with CID appears earlier than in other groups of HCMV-infected patients. These findings may have relevance to the cellular pathways involved in viral DNA repair and mutagenesis, and they indicate the need for early and frequent genotypic monitoring and prompt therapeutic modification in this patient population.

Sole pathogen in acute bronchiolitis: is there a role for other organisms apart from respiratory syncytial virus?

Background: Acute bronchiolitis (AB) is a common disease of young children with peak incidence during the winter season. Respiratory syncytial virus (RSV) is a major causative organism, yet recent relatively small sized studies have suggested an increased role of other organisms as sole or codetected organisms. The aim of this study was to assess the prevalence of sole- and mixed-organisms infections in hospitalized children with AB, using combined antigen-based and polymerase chain reaction assays (PCR). Methods: Sputum or nasal wash specimens obtained from 490 previously healthy children ≤2 years of age hospitalized with AB between December 1, 2005 and March 31, 2006 were tested: (1) For RSV, by rapid antigen detection test; (2) For RSV, influenza A, B, Parainfluenza 1 to 3, and adenovirus antigens by direct fluorescent assay; (3) For influenza A and B, RSV, Parainfluenza 1 to 3 viruses RNA by reverse transcription (RT) PCR assay; (4) For human metapneumovirus and rhinovirus RNA by RT real-time PCR assay; (5) For adenovirus, and Bordetella pertussis DNA by conventional PCR assays; (6) For human bocavirus DNA by real-tine PCR assays. Results: At least 1 organism was detected in 465 (91%) children. In 283 (61%), 117 (25%), and 23 (5%) children, 1, 2, and 3/4 organisms were detected, respectively. The most commonly detected organism was RSV, detected in 76%, and as a sole organism in 49%. Rhinovirus, human metapneumovirus, influenza virus A, bocavirus, Bordetella pertussis, and adenovirus were detected as a sole organism in 7%, 2.1%, 1%, 0.6%, 0.6%, and 0.2% of the children, respectively. Conclusions: Respiratory organisms were detected in the majority of the children, of whom about one third suffered from mixed organism infection. RSV was the most prevalent sole detected organism. The relevance of all other organisms may be much less than previously suggested.

Effectiveness of a nationwide infant immunization program against Haemophilus influenzae b

An ongoing nationwide prospective surveillance program for invasive H. influenzae b (Hib) disease in Israel enabled us to study the effectiveness of a national infant Hib immunization program, which included all infants born since January 1994. The vaccine used was Hib polysaccharide conjugated to outer membrane protein complex of Neisseria meningitidis b (PRP-OMPC). For the cohort born during the 3 years since January 1994, the vaccine effectiveness was 94.9% for all invasive Hib diseases and 96.6% for meningitis. The efficacy in fully immunized subjects was 98.7 and 99.5%, respectively. A herd immunity effect could be observed, since a reduction in cases also occurred among infants too young to be immunized. No increase in invasive cases caused by S. pneumoniae and N. meningitidis was observed during the study period. This is the first report outside North America and Western Europe that demonstrates a nationwide extensive reduction of invasive Hib disease within a short time of the introduction of Hib conjugate vaccines to the infant immunization program.

Outpatient treatment of serious community-acquired pediatric infections using once daily intramuscular ceftriaxone.

Pediatric patients with serious infections are usually hospitalized for parenteral antibiotic treatment. We studied prospectively 74 pediatric patients with community-acquired serious infections and used once daily intramuscular ceftriaxone. Seventeen patients (23%) were initially hospitalized and 57 (77%) patients were treated entirely as outpatients. An initial intramuscular dose of 75 mg/kg was followed by daily doses of 50 mg/kg (maximum, 1.5 g). Infections treated included periorbital/buccal cellulitis, other cellulitis, urinary tract infections, pneumonia, osteomyelitis, mastoiditis, suppurative arthritis and orbital cellulitis. Organisms were recovered from cultures of 37 (50%) patients and 6 (8%) patients were bacteremic. Bacteria included Gram-positive (mostly Staphylococcus aureus) and Gram-negative (mostly enteric bacilli and Haemophilus influenzae organisms). No serious side effects were observed. Of 74 patients 72 (97%) were cured and improvement was usually observed within 24 hours. Two patients did not improve: one with chronic Pseudomonas mastoiditis; and one with lung abscess. Based on previous experience it is estimated that 376 hospitalization days were saved. All 72 successfully treated patients and their parents resumed normal activity within 72 hours of starting therapy. Our data suggest that ceftriaxone can be used for outpatient treatment of some infectious diseases.

An outbreak of Mycobacterium mucogenicum bacteremia in pediatric hematology-oncology patients.

Background and Aims: Mycobacterium mucogenicum (MM) is a rapidly growing nontuberculous mycobacterium that is commonly identified in tap water that can rarely cause bacteremia. We describe an outbreak of MM bacteremia among pediatric hematology-oncology patients. Methods: Charts of children with MM bacteremia were retrospectively reviewed. Demographic data, underlying conditions, central venous catheter (CVC) type, duration of bacteremia, and treatment were retrieved. Epidemiologic investigation was conducted during the outbreak including environmental sampling. Results: During an 8-month period (September 2005–May 2006), 8 patients aged 1.5 to 17 years had MM bacteremia. Seven patients had underlying malignancy and 1 with thalassemia major had bone marrow transplantation. The mean number of positive blood cultures was 4.2 (1–11) per patient. Two patients received antibiotic treatment in addition to removal of CVC. All patients were cured. Almost 60 environmental samples were obtained from surfaces, ice, and municipal water supply. All were negative and no source was documented. Infection control measures included emphasis on guidelines for prevention of CVC-associated infections. No cases occurred before and after this outbreak. Conclusions: MM is a rare agent of CVC-associated bacteremia. Removal of the CVC may be sufficient for management of bacteremia. In the absence of definite source identification, reinforcement of standard infection control measures can be successful in containing outbreaks.

Treatment with oral ribavirin and IVIG of severe human metapneumovirus pneumonia (HMPV) in immune compromised child

To the Editor: Pneumonia in an immunocompromised host poses a diagnostic and treatment challenge, especially in light of emerging pathogens. Human metapneumovirus (HMPV) has recently emerged as a new pathogen associated with bronchiolitis in infants, which can cause severe pneumonia and respiratory failure among compromised hosts. An 8-year-old malewith abdominal Burkitt lymphoma and bone marrow involvement diagnosed 2months previously, presentedwith fever, general fatigue, mild cough, and oral ulcers. On admission he had a temperature of 39.48C, and no obvious source of infection. His total leukocyte count was 100 cells/ml and he was treated with piperacillin/tazobactam and amikacin. By day 4, he had a nasal discharge and worsened cough, with rales, severe dyspnea, and oxygen desaturation (88% on ambient air). A nasal wash was taken for respiratory pathogens (respiratory syncytial virus, adenovirus, influenza A and B, parainfluenza 1, 2, 3, H1N1, HMPV), in addition to sputum culture and urine for legionella antigen. Chest X-ray (Fig. 1A) and computerized tomography, demonstrated bilateral infiltrates. He developed low blood pressure and severe respiratory distress, such that bronchoalveolar lavage (BAL) could not be done. Antibiotic treatment was changed to meropenem, vancomycin, levofloxacin, and caspofungin. Cultures and urinary legionella antigen were negative. Respiratory secretions were positive for HMPV (IFA). Because of severe immunosuppression and his poor clinical condition, the patient was given oral ribavirin and a single dose of IVIG. Four days later he was afebrile with no respiratory effort, and his WBC rose to 12,000 cells/ml while on G-CSF. Repeat test for HMPVwas negative after 8 days and hewas discharged. The patient was treated for three more days with ribavirin (total of 12 days) and 7 days with levofloxacin, and had a complete remission (Fig. 1B). Polymicrobial pneumonia could not be excluded, sinceBALwas not done although sputum was negative for other pathogens. Therefore, he was treated with antibacterial agents as well. HMPVisaparamyxovirus,firstdescribed in2001inchildrenwith respiratory disease [1].Most healthy children are seropositive by the age of 5 years, with reinfections throughout life [2]. Normal hosts may have upper and lower respiratory tract infections. An immunocompromised host can develop severe pneumonia, respiratory failure, shock, and death [3]. England et al. [3] described 163 immunocompromised patients who underwent BAL for atypical pneumonia, five of whom were positive for HMPV; four of these five died within 40 days due to severe pneumonia. There are no specific recommendations regarding treatment of HMPV. The virus is susceptible to ribavirin in vitro and in animal models [4]. Until now there have been few reports in the literature describing cases treated successfully with a combination of intravenousribavirinandimmunoglobulin[5],andnorandomizedcontrol trials are available. The evidence of severe outcome in these patients and scattered reports of successful treatment suggest the need for other studies. Ribavirin and IVIG may be a suitable treatment for severe cases.

Rotavirus diarrhea in Jewish and bedouin children in the Negev region of Israel : epidemiology, clinical aspects and possible role of malnutrition in severity of illness

We conducted a 1-year prospective study in the Negev region of southern Israel to determine the epidemiologic and clinical patterns of rotavirus diarrhea. A total of 605 patients were studied, 392 Bedouins and 213 Jews, 441 of whom had diarrhea (449 episodes) and 164 did not. Rotavirus was the most common organism detected in children with diarrhea (63 of 444; 14%) but was rarely found in controls (3 of 163; 2%) (P < 0.001). In 22% (12 of 54) of the rotavirus-positive patients, at least one other organism was also detected. The rate of rotavirus detection decreased as age increased, from 18% in the first year to 8% in the third year of life. Hospitalization with rotavirus diarrhea occurred more frequently in the summer. However, during winter, when diarrhea was less prevalent in the community, the proportion of cases associated with rotavirus was higher. Compared with controls, malnourished children were more likely to be hospitalized. However, rotavirus was detected in similar proportions among well-nourished and malnourished cases with diarrhea. The most prevalent rotavirus serotype was type 1 (in 69%), followed by types 4 and 2 (18 and 13%, respectively). We estimated that during the study period, approximately 2% of all Bedouin infants vs. only 0.2% of Jewish infants were hospitalized with rotavirus disease in their first year of life. Clinical signs and symptoms and stool appearance were

Hospitalization of Children With Influenza A(H1N1) Virus in Israel During the 2009 Outbreak in Israel: A Multicenter Survey

OBJECTIVESnTo describe the clinical characteristics of children hospitalized with 2009 influenza A(H1N1) infection in Israel and the risk factors associated with this infection.nnnDESIGNnProspective collection of data on children hospitalized with 2009 influenza A(H1N1) infection.nnnSETTINGnSeven medical centers around Israel. Patients From July 12, 2009, to December 24, 2009, all patients 18 years or younger hospitalized with acute respiratory or acute unspecified febrile illness were screened for 2009 influenza A(H1N1) virus by reverse transcription-polymerase chain reaction.nnnINTERVENTIONnProspective data collection for patients with confirmed infection.nnnMAIN OUTCOME MEASURESnClinical characteristics of patients and hospitalization rates.nnnRESULTSnThe mean age of 478 patients studied was 6.1 years. Forty-two patients (8.8%) were admitted to the pediatric intensive care unit; 3 patients (0.6%) died. The most frequent clinical presentations were pneumonia, influenza-like illness, wheezing exacerbation, and convulsions. Predisposing underlying illnesses were detected in 48.7% of patients. Patients with metabolic and neurologic disorders were at highest risk for severe complications (relative risk, 6.5 and 2.9, respectively). In addition, patients with cyanotic heart lesions and infants 3 months or younger who were born at 33 weeks gestation or earlier tended to require higher rates of mechanical ventilation. The hospitalization rate for 2009 influenza A(H1N1) was 0.7 per 1000 children. The mortality rate was 3.6 per 1 000 000 children.nnnCONCLUSIONSnThe severity variables for 2009 influenza A(H1N1) were similar to the figures reported for seasonal influenza. Patients with underlying metabolic and neurologic metabolic disorders and presumably patients with cyanotic heart lesions and infants born prematurely are at highest risk for severe complications following 2009 influenza A(H1N1) infection.