Eugene Leibovitz

Introduction and Proliferation of Multidrug-Resistant Streptococcus pneumoniae Serotype 19A Clones That Cause Acute Otitis Media in an Unvaccinated Population

BACKGROUNDnIntroduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in the United States in 2000 was temporally associated with an increase in the incidence of disease caused by Streptococcus pneumoniae serotype 19A (Sp19A) and with increasing drug resistance within this serotype. A causative role of PCV7 was speculated. We prospectively studied the dynamics of acute otitis media (AOM) caused by Sp19A in southern Israel before the introduction of PCV7.nnnMETHODSnAOM in children < 5 years old undergoing tympanocentesis during 1999-2006 was studied. Antibiotic prescriptions for approximately 20% of children < 5 years old were recorded. Sp19A isolates were studied for antibiotic-resistance and pulsed-field gel electrophoresis patterns; multilocus sequence typing of representative isolates was compared with that of international clones.nnnRESULTSnSp19A caused 438 (9.8%) of 4449 pneumococcal AOM episodes, increasing by 63.1% from 1999-2001 (mean +/- SD, 8.4% +/- 0.8%) to 2004-2006 (mean +/- SD, 13.7% +/- 0.9%) among Bedouin children, who were characterized by overcrowding and high antibiotic use. Penicillin, erythromycin, and multidrug resistance increased from < 10% to 78.6%, 50.0%, and 50.0%, respectively (P < .001), and was associated with the introduction and proliferation of 2 multidrug-resistant clones that were not previously associated with multidrug resistance. This was temporally associated with the introduction of and rapid increase in azithromycin use and the frequent use of oral cephalosporins.nnnCONCLUSIONSnThe introduction and proliferation of multidrug-resistant Sp19A occurred before the introduction of PCV7. The increasing proportion of antibiotic-resistant Sp19A suggests that antibiotic use plays an important role in the community.

Bacteriologic and clinical efficacy of amoxicillin/clavulanate vs. azithromycin in acute otitis media.

Objectives. To compare the bacteriologic and clinical efficacy of amoxicillin/clavulanate and azithromycin in patients with acute otitis media (AOM), particularly the ability to eradicate the predominant AOM pathogens from middle ear fluid as assessed by mandatory second tympanocentesis. Methods. In this single blind study 238 infants and children with AOM were randomized to receive amoxicillin/clavulanate (45/6.4 mg/kg/day in two divided doses for 10 days) or azithromycin (10 mg/kg on Day 1, then 5 mg/kg daily on Days 2 through 5). Tympanocentesis was performed before the first dose and repeated on Day 4, 5 or 6. Clinical response was assessed at end of therapy between Days 12 and 14 and at follow‐up between Days 22 and 28. Results. Amoxicillin/clavulanate was significantly more likely to eradicate all bacterial pathogens [83% (54 of 65) vs. 49% (35 of 71), P = 0.001] and Haemophilus influenzae [87% (26 of 30) vs. 39% (13 of 33), P = 0.0001] from middle ear fluid than was azithromycin. Amoxicillin/clavulanate was also more likely to eradicate Streptococcus pneumoniae, but the difference was not statistically significant [90% (18 of 20) vs. 68% (3 of 19), P = 0.095]. On Days 12 to 14, signs and symptoms were more likely to resolve completely or improve in all culture‐positive patients [86% (60 of 70) vs. 70% (51 of 73), P = 0.023] and in those with H. influenzae infections [91% (30 of 33) vs. 65% (22 of 34), P = 0.010] who received amoxicillin/clavulanate compared with those who received azithromycin. Otherwise there were no significant differences between groups in clinical outcomes on Days 12 to 14 or at follow‐up. Conclusions. Our findings indicate that amoxicillin/clavulanate has superior bacteriologic and clinical efficacy compared with azithromycin in children with AOM.

Bacteriologic Response to Oral Cephalosporins: Are Established Susceptibility Breakpoints Appropriate in the Case of Acute Otitis Media?

Bacteriologic response to cefuroxime axetil and cefaclor administered for 10 days was evaluated in acute otitis media (AOM) in patients aged 6-36 months. Middle ear fluid culture was obtained by tympanocentesis before treatment, on day 4 or 5 after initiation of treatment, and if clinical relapse occurred before day 17. Bacteriologic failure was observed in 32% of patients receiving cefaclor versus 15% of patients receiving cefuroxime axetil (P = .009). Failure rates increased with increasing MIC: For Streptococcus pneumoniae, 0.5 microg/mL (established as cutoff value for cefuroxime by the National Committee for Clinical Laboratory Standards [NCCLS]) discriminated between success and failure. For Haemophilus influenzae, high failure rates were observed for cefaclor, even with low MICs (< or = 1.0 microg/mL), and with both drugs they tended to increase with increasing MIC, even for values below the cutoff suggested by the NCCLS (8.0 and 4.0 microg/mL for cefaclor and cefuroxime, respectively). Thus, for AOM caused by H. influenzae, lower susceptibility cutoff levels for MICs should be established.

Near-Elimination of Otitis Media Caused by 13- Valent Pneumococcal Conjugate Vaccine (PCV) Serotypes in Southern Israel Shortly After Sequential Introduction of 7-Valent/13-Valent PCV

BACKGROUNDnOtitis media (OM) is common in early childhood. Streptococcus pneumoniae caused approximately 30%-60% of episodes before the pneumococcal conjugate vaccine (PCV) era. The 7-valent PCV (PCV7) was introduced to the Israeli National Immunization Plan in July 2009, and was gradually replaced by the 13-valent PCV (PCV13) starting in November 2010. We aimed at assessing the impact of PCV7/PCV13 sequential introduction on pneumococcal and overall OM necessitating middle ear fluid culture in children aged <2 years in southern Israel.nnnMETHODSnThis was a prospective, population-based, active surveillance. Our medical center is the only one in the region, enabling incidence calculation. All pneumococcal episodes submitted for culture between July 2004 and June 2013 were included. Three subperiods were defined: pre-PCV, PCV7, and PCV13.nnnRESULTSnOverall, 6122 OM episodes were recorded, and 1893 were pneumococcal. Compared with the pre-PCV period, OM caused by PCV7 plus serotype 6A and the 5 additional PCV13 serotypes (5VT : 1, 3, 5, 7F, 19A) decreased by 96% and 85%, respectively (incidence rate ratios [IRRs], 0.04 [95% confidence interval {CI}, .02-.08] and 0.15 [95% CI, .07-.30], respectively) in a 2-step pattern: In the PCV7 period, only OM caused by PCV7 + 6A serotypes was decreased; in the PCV13 period, 5VT OM rates decreased, along with an additional PCV7 + 6A OM reduction. A nonsignificant increase in non-PCV13 serotype OM was observed (IRR, 1.07 [95% CI, .72-1.58]). In total, 77% and 60% reductions of all-pneumococcal and all-cause OM incidences, respectively, were observed.nnnCONCLUSIONSnA substantial 2-step reduction of pneumococcal OM rates, with near-elimination of PCV13 disease, was observed shortly after PCV7/PCV13 introduction.

Acute Otitis Media Caused by Streptococcus pyogenes in Children

BACKGROUNDnStreptococcus pyogenes, or group A beta -hemolytic Streptococcus (GAS), is an important causative agent of bacterial pharyngotonsillititis and skin, soft-tissue, and invasive infections. Although it is also an important pathogen in acute otitis media (AOM), its exact role has not been determined.nnnMETHODSnPatients aged 0-18 years with AOM, from whom a specimen of middle-ear fluid was obtained and cultured during 1999-2003, were enrolled. Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and GAS were considered pathogens. Information collected included demographic characteristics, clinical history, and signs and symptoms.nnnRESULTSnGAS otitis was observed in 350 (3.1%) of 11,311 episodes (of which 117 were also culture-positive for other pathogens). The other 10,961 episodes involved H. influenzae only (n = 2507), S. pneumoniae only (n = 2131), dual infection with H. influenzae and S. pneumoniae (n = 1290), M. catarrhalis only (n = 129), and other combinations of pathogens (n = 271). Increased age and Jewish ethnicity were independent, significant, positive risk factors for GAS AOM, and fall season was a negative risk factor. Episodes of GAS infection were less frequently bilateral, febrile, and accompanied by other systemic findings than were other episodes of other types of infection. Most patients with GAS AOM presented with acute drainage from the ears. A lower proportion of cases of AOM were due to GAS in children with recurrent AOM and in patients recently treated with antibiotics, compared with patients with AOM who did not have these factors. The risk for mastoiditis was highest among patients with GAS AOM, compared with patients infected with other pathogens: 11.6 episodes per 1000 episodes of GAS AOM, compared with 2.2, 0.3, and 0 episodes of mastoiditis per 1000 episodes of AOM due to S. pneumoniae, H. influenzae, and M. catarrhalis, respectively.nnnCONCLUSIONnCompared with AOM caused by pathogens other than GAS, GAS AOM is characterized by older age and higher local aggressiveness manifested by lower rates of fever and respiratory symptoms and higher rates of tympanic perforation and mastoiditis.

Bacterial eradication in the treatment of otitis media

Drugs differ in their ability to eradicate various pathogens from the middle-ear cavity during acute otitis media (AOM), and these differences clearly affect clinical outcome. Outcome is derived from differences in the association between concentrations of the drugs at the site of infection and the antimicrobial effect (termed pharmacodynamics). These differences are even more marked in the present era of antimicrobial resistance. However, since AOM is a self-limiting disease in most cases, difference in clinical outcome is more difficult to ascertain than that of bacteriological outcome, which is measured within 3-5 days. A favourable clinical outcome regardless of the bacteriological effect of the drug can result in false optimism when less-effective antibiotic drugs are used. Inappropriate study design and manipulation of clinical results add to this confusion. In this review we attempt to highlight the evidence regarding bacteriological response to antibiotics in AOM and to draw attention to potential flaws that may mislead clinicians.

The bacteriology of the nasopharynx in childhood

Non-typeable Haemophilus influenzae and Streptococcus pneumoniae (Pnc) are frequently isolated from the nasopharynx (NP) of young healthy children. Colonization of the NP may be detected in early infancy with peaks toward the second year of life. NP carriage of Pnc and especially of antibiotic-resistant Pnc is common and plays an important role in its spread in children, its prevalence increases in those coming into close contact, such as children attending day-care facilities. Several studies show that the presence of older siblings, antibiotic treatment during the month preceding the culture and the attendance at a large day-care center are associated with carriage of drug-resistant Pnc. Significant changes may occur early during antibiotic treatment, and these changes may vary with the use of different antibiotics. Also new strains of Pnc not detected initially emerge, and newly detected organisms are most often resistant to the administered drug. Nasopharyngeal colonization with resistant bacteria was shown to be associated with an increased incidence of acute otitis media with resistant organisms and growing incidence of unresolved otitis media. Preliminary studies show that conjugate pneumococcal vaccine might reduce the nasopharyngeal pneumococcal carriage in general, and of resistant organisms in particular.

Salmonella diskitis in a 2-year old immunocompetent child.

Spine infections are uncommon in paediatrics and are generally caused by Staphylococcus aureus. Salmonella spp. are a rare cause of spine infections, usually affecting children with sickle-cell anaemia. We present a case of group C1 Salmonella diskitis in a previously healthy 2-y-old child, and review the relevant literature.

Acute Otitis Media Caused by Moraxella catarrhalis: Epidemiologic and Clinical Characteristics

BACKGROUNDnThis study describes the epidemiologic, microbiologic, and otologic features and selected signs and symptoms of acute otitis media (AOM) caused by Moraxella catarrhalis and compares them with AOM caused by other bacterial pathogens.nnnMETHODSnPatients aged <5 years with culture-positive AOM from whom a middle ear fluid specimen was obtained and cultured during 1999-2006 were enrolled in the study.nnnRESULTSnOf a total of 12,799 AOM episodes, 8198 (64%) were culture positive, with isolation of 10,382 pathogens: Haemophilus influenzae, 4982 (48.0%); Streptococcus pneumoniae, 4450 (42.9%); M. catarrhalis, 501 (4.8%); and group A streptococci, 449 (4.3%). The distribution of single versus mixed M. catarrhalis infection was significantly different compared with the 3 other pathogens (165 cases [32.9%] as a single pathogen of all M. catarrhalis AOM episodes vs 3108 [62.4%] in AOM caused by H. influenzae, 2592 [58.2%] in AOM caused by S. pneumoniae, and 304 [67.7%] in AOM caused by group A streptococci; P < .001 for all comparisons). In multivariate analysis, M. catarrhalis AOM was more frequent in patients experiencing their first AOM episode versus recurrent AOM and mixed infections. M. catarrhalis AOM was associated with lower proportions of spontaneous perforation of tympanic membrane compared with all other pathogens. None of the AOM episodes caused by M. catarrhalis was associated with mastoiditis.nnnCONCLUSIONSnCompared with AOM caused by other pathogens, AOM caused by M. catarrhalis is characterized by a higher proportion of mixed infections, younger age at diagnosis, a lower proportion of spontaneous perforation of the tympanic membrane, and no mastoiditis.

Complicated community acquired pneumonia in children prior to the introduction of the pneumococcal conjugated vaccine

Increasing prevalence of pleural empyema (PE) complicating community acquired pneumonia (CAP) is reported worldwide. We compared hospitalized children with PE or non-purulent pleural effusion (NP-PEF) prior to the inclusion of the pneumococcal conjugated vaccine (PCV7) in the Israeli immunization schedule. We conducted a retrospective analysis of medical files of all children <18 y of age hospitalized with either PE or NP-PEF and CAP during 1990–2002. 75 children with NP-PEF and 37 with PE were identified. PE annual incidence increased from 0.5 in 1990 to 4.2 per 100,000 children in 2002. Higher WBC and absolute neutrophils counts were found in sera and pleural fluid of PE. The leading pathogens included Streptococcus pneumoniae (42%, all penicillin-susceptible) and Staphylococcus aureus (23%, all methicillin-susceptible). Blood cultures were positive only in children with PE (12/37, 32.4%). Patients with PE presented with higher respiratory rate and required longer hospitalization, more PICU admission, and more patients needed mechanical ventilation. PE prevalence increased in southern Israel during the study period. Streptococcus pneumoniae (62.5% serotype 1) was the most common pathogen causing PE before the introduction of PCV7. Future introduction of PCV7 or equivalents in the immunization schedule may impact clinical presentation and epidemic trends and will require future consideration.