Pharmacokinetics of the Meropenem Component of Meropenem-Vaborbactam in the Treatment of KPC-Producing Klebsiella pneumoniae Bloodstream Infection in a Pediatric Patient.

Meropenem-vaborbactam is a new ß-lactam/ß-lactamase inhibitor combination designed to target Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae. Meropenem-vaborbactam was United States Food and Drug Administration-approved for complicated urinary tract infections in patients 18 years of age or older. An understanding of the pharmacokinetics of meropenem when given in combination with vaborbactam is important to understanding the dosing of meropenem-vaborbactam. In addition, the safety and efficacy of meropenem-vaborbactam in a pediatric patient have yet to be described in the literature. The authors conducted a retrospective single-patient chart review for a 4-year-old male patient with short bowel syndrome, colostomy and gastrojejunal tube, bronchopulmonary dysplasia, and a central line for chronic total parenteral nutrition and hydration management, complicated with multiple central line-associated bloodstream infections (BSIs). The patient was brought to our medical center with fever concerning for a BSI. On day 2, the patient was started on meropenem-vaborbactam at a dosage of 40 mg/kg every 6 hours infused over 3 hours for KPC-producing K. pneumoniae BSI. Meropenem serum concentrations obtained on day 5 of meropenem-vaborbactam therapy, immediately following the completion of the infusion and 1 hour after the infusion, were 51.3 and 13.6 µg/ml, respectively. Serum concentrations correlated to a volume of distribution of 0.59 L/kg and a clearance of 13.1 ml/min/kg. Repeat blood cultures remained negative, and meropenem-vaborbactam was continued for a total of 14 days. A meropenem-vaborbactam regimen of 40 mg/kg every 6 hours given over 3 hours was successful in providing a target attainment of 100% for meropenem serum concentrations above the minimum inhibitory concentration for at least 40% of the dosing interval and was associated with successful bacteremia clearance in a pediatric patient.

Sterility Duration of Preprimed Extracorporeal Membrane Oxygenation Circuits.

OBJECTIVES: There is a lack of standardization and supporting data regarding the duration preassembled and preprimed extracorporeal membrane oxygenation (ECMO) circuits are expected to be sterile. Therefore, the purpose of this study was to prospectively evaluate whether preassembled and preprimed ECMO circuits could maintain sterility for a period up to 65 days. DESIGN: Four ECMO circuits (2 neonatal/pediatric»" and 2 adolescent/adult ⅜ ") were assembled and primed under sterile conditions and maintained at room temperature. Culture samples were obtained from each circuit and plated within 1 hour. Culture samples were obtained on day 0 when assembled and primed then every 5 days up to day 65. Samples were plated on several different media including the following: blood agar plate: trypticase soy agar with 5% sheep blood, MacConkey agar, and thioglycollate broth then incubated at 35°C for 3 days. RESULTS: All cultures obtained from the priming solution from of the»" and ⅜ " ECMO circuits produced no microbial or fungal growth for the 65-day study period. CONCLUSION: These pilot data suggest preprimed ECMO circuits may maintain sterility for a period up to 65 days. Additional studies evaluating a larger number of ECMO circuits are needed to confirm these findings.

Antimicrobial Susceptibility and Molecular Detection of Pertactin-producing and Pertactin-Deficient Bordetella pertussis.

Resurgence of Bordetella pertussis in recent years in the United States has coincided with a dramatic rise in pertactin-deficient strains. Limited data exist on detectability by nucleic acid amplification testing and antimicrobial susceptibility of pertactin-deficient B. pertussis. This study compares 15 pertactin-producing and 15 pertactin-deficient B. pertussis isolates. Pertactin-producing and pertactin-deficient strains were equally detected by nucleic acid amplification testing and were susceptible to antibiotics.

Clinical Manifestations and Molecular Characterization of Pertactin-Deficient and Pertactin-Producing Bordetella pertussis in Children, Philadelphia 2007-2014.

BACKGROUND: Bordetella pertussis strains lacking expression of pertactin, a bacterial adhesin and vaccine target, are emerging. There are limited data on disease manifestations of mutant strains in children. We sought to compare clinical manifestations of pertactin-deficient and pertactin-producing B. pertussis infection in infants and describe corresponding molecular characteristics. METHODS: Molecular characterization of archived B. pertussis isolates (collected January 2007 to March 2014) included Western blot analysis, pulsed-field gel electrophoresis (PFGE), polymerase chain reaction, and pertactin gene sequencing. Medical record review compared epidemiologic and clinical courses of pertactin-producing and pertactin-deficient B. pertussis infections. RESULTS: Sixty of 72 B. pertussis isolates were viable for analysis. Within the cohort of infants, the median age was 95 days, 90% received ≤1 dose of vaccine, and 72% were hospitalized. Pertactin deficiency was first noted in 2008, and its prevalence increased over time (68% overall prevalence). There were no statistically significant differences in presenting symptoms or signs, hospitalization, intensive care, respiratory support, or laboratory results related to pertactin expression. Illness length was shorter in pertactin-deficient group (mean difference, 3.2 days; P = .04); no difference was noted in the subgroup of infants <4 months old. Molecular analyses identified 11 PFGE profiles (Centers for Disease Control and Prevention profile No. 002 predominant, 47%). In 41 pertactin-deficient strains, sequencing identified 2 stop codon and 3 IS481 locations disrupting the prn gene. Mutations and nucleotide positions were not unique to PFGE type, nor were they clustered in time. CONCLUSIONS: In this cohort of predominantly unimmunized infants, clinical disease did not differ between infection with pertactin-deficient and those with pertactin-producing B. pertussis. Molecular analyses demonstrated remarkable PFGE strain diversity, with multiple mechanisms and molecular sites of pertactin inactivation.

Tracking resistance among bacterial respiratory tract pathogens: summary of findings of the TRUST Surveillance Initiative, 2001-2005.

Antimicrobial resistance observed among common respiratory tract pathogens--Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis--may complicate empiric therapeutic selection to treat community-acquired respiratory tract infections. The Tracking Resistance in the United States Today (TRUST) study determined the in vitro activities of frequently prescribed antimicrobial agents against isolates collected from all 50 states from 2001 to 2005. For S pneumoniae (N = 27,781), susceptibility of selected agents in ascending order were penicillin (oral) (65.4%), trimethoprim-sulfamethoxazole (TMP-SMX) (69.5%), erythromycin (72.0%), cefuroxime (oral) (75.9%), tetracycline (85.3%), amoxicillinclavulanate (92.6%), ceftriaxone (nonmeningitis) (96.6%), and levofloxacin (99.0%). Susceptibility to levofloxacin, which was used as a representative of the respiratory fluoroquinolones, was near 99% from 2001 to 2005, and the minimum inhibitory concentration (90%) (MIC(90)) remained unchanged at 1 microg/mL. Levofloxacin and the other respiratory fluoroquinolones remained highly effective against penicillin-resistant S pneumoniae(PRSP) (98%-99% susceptible). However, susceptibility of PRSP to amoxicillin-clavulanate decreased from 62%S in 2003 to 48%S in 2005. Haemophilus influenzae susceptibility to ampicillin averaged near 70%, and near 75% to TMP-SMX. Susceptibility rates to levofloxacin and the other respiratory fluoroquinolones for H influenzae and M catarrhalis remained at or near 100%. Although resistance rates among S pneumoniae have stabilized for penicillin (oral) at elevated levels and increased for macrolides, susceptibility to the respiratory fluoroquinolones has consistently remained high, as they have for H influenzae and M catarrhalis.

Sporadic occurrences of fluoroquinolone-resistant Streptococcus pneumoniae in the United States: longitudinal analysis of institutions from the New England and West South Central regions during the TRUST 4-9 (2000-2005) Surveillance Studies.

Twenty-six institutions in New England and 24 institutions in West South Central regions participating in the Tracking Resistance in the United States Today (TRUST) 4-9 surveillance studies (2000-2005) were monitored for levofloxacin-resistant Streptococcus pneumoniae to determine if resistance was sporadic or persistent. Levofloxacin was used as a representative of the respiratory fluoroquinolones. Levofloxacin-resistant isolates were identified in 8 of the 26 New England institutions and in 11 of the 24 West South Central institutions during the surveillance period. Resistant isolates were recovered in consecutive years from 3 institutions: 1 each in Massachusetts, Oklahoma, and Texas. In total, 34 levofloxacin-resistant isolates (14 from New England, 20 from the West South Central region) were identified over the 6-year period. Two of these isolates from an institution in Connecticut and 2 from an institution in Oklahoma had the same serotype, pulsed-field gel electrophoresis pattern, and quinolone resistance-determining region (QRDR) mutations. States with elevated pneumococcal levofloxacin resistance rates, compared with the national average, did not maintain this status in consecutive years. Based on data from the same institutions over 6 years, levofloxacin resistance among US pneumococci has been sporadic, nonclonal, and rare.

Antimicrobial activity among multidrug-resistant Streptococcus pneumoniae isolated in the United States, 2001-2005.

Infections caused by multidrug-resistant (MDR) Streptococcus pneumoniae remain a major concern when selecting an appropriate antimicrobial agent. In this analysis, 27 781 isolates of S pneumoniae collected from 2001 to 2005 in the United States were tested for MDR phenotypes. About 25% of all isolates were MDR, defined as resistant to 2 or more of the following agents: cefuroxime, a macrolide, penicillin, tetracycline (if available), and trimethoprim-sulfamethoxazole (TMP-SMX). There was a slight decreasing trend over time in multidrug resistance prevalence with erythromycin. Among MDR strains, the most common coresistance pair was erythromycin and TMP-SMX (74% of isolates, irrespective of resistance to other agents), although penicillin-erythromycin and penicillin-TMP-SMX coresistance patterns were also found in more than 56% of MDR strains. Resistance to 4 antimicrobial agents tested was observed in 33% of all antimicrobial-resistant isolates. Levofloxacin, which was used as a representative of the fluoroquinolone class, was active against at least 98% of all MDR isolates, and the minimum inhibitory concentration (90%) (MIC(90)) for this population was 1 microg/mL (identical to the total S pneumoniae, population). Multidrug-resistant isolates from 2003 to 2005 were found to be equally susceptible (98%) to other respiratory fluoroquinolones (gatifloxacin and moxifloxacin; data not shown), although only 88% of MDR isolates (from 2001-2005) were susceptible to ciprofloxacin. Careful monitoring of multidrug resistance patterns will help guide appropriate therapeutic selection and may provide early detection of changes in resistance to more potent agents.

Decline in the prevalence of pandemic clones Spain23F-1 and Spain9V-3 among US fluoroquinolone-resistant Streptococcus pneumoniae TRUST Surveillance isolates since 2001.

Fluoroquinolone-resistant variants of pandemic clones Spain(23F)-1, Spain(6B)-2, Spain(9V)-3, and Spain(14)-5 have been seen in various regions of the United States and the world, leading to the speculation that fluoroquinolone resistance among US Streptococcus pneumoniae may increase because of clonal spread. Using levofloxacin as a representative of the fluoroquinolone class, all 196 levofloxacin-resistant pneumococci from a total of 22 794 isolates in the Tracking Resistance in the United States Today (TRUST) 5-8 studies (2001-2004) were subjected to pulsed-field gel electrophoresis (PFGE), serotyping, and sequencing of parC/E and gyrA/B quinolone resistance-determining regions (QRDR) to measure the extent of clonality. In addition, susceptibility testing of these isolates to ciprofloxacin, gatifloxacin, levofloxacin, and moxifloxacin was performed. ATCC type strains of Spain(23F)-1, Spain(6B)-2, Spain(9V)-3, and Spain(14)-5 clones were included as comparators. Levofloxacin-resistant isolates with Spain(23F)-1-related PFGE patterns decreased from 28% of the resistant isolates in 2001 to 6% in 2004. These isolates, with serotypes 23F (n = 17), 19F (n = 17), or 19A (n = 1), had 15 different QRDR profiles and were all ciprofloxacin- and gatifloxacin-resistant. Levofloxacin-resistant isolates with Spain(9V)-3-related PFGE patterns decreased from 13% of the resistant isolates in 2001 to 2% in 2004. The Spain(9V)-3-related isolates were serotype 9V (n = 9), 9A (n = 2), and 9N (n = 1) and exhibited 6 different QRDR profiles. All were resistant to all fluoroquinolones tested. None of the levofloxacin-resistant isolates had PFGE patterns related to Spain(6B)-2 or Spain(14)-5. Resistance to respiratory fluoroquinolones among pneumococci has remained constant at about 1% (0.8%-1.1%) since 2001, and there has been a decrease in the prevalence of levofloxacin-resistant isolates similar to Spain(23F)-1 or Spain(9V)-3. Considerable QRDR variability among these strains appears to be the result of sporadic independent mutational events as opposed to clonal expansion.

Stratified analysis of multidrug-resistant Escherichia coli in US health care institutions.

Surveillance studies typically fail to provide sufficient information on how susceptibility rates differ among institutions and within patient age groups. Furthermore, antimicrobial resistance in context with resistance to other antimicrobial classes may help to understand resistance trends and may be useful for implementing control initiatives. This study used The Surveillance Network-USA (TSN-USA) and the Tracking Resistance in the United States Today (TRUST) surveillance data (2003-2005) to analyze multidrug-resistant (MDR) Escherichia coli at 229 institutions across the United States. Institutions with a higher prevalence of E coli resistant to multiple nonfluoroquinolone agents were associated with lower fluoroquinolone susceptibility. The prevalence of fluoroquinolone and multidrug resistance was also associated with increased patient age and locations such as long-term care facilities. Institutions attempting to understand and control E coli resistance to fluoroquinolones should carefully examine the patient population and prevalence of resistance to other agents.

Antimicrobial resistance trends among sinus isolates of Streptococcus pneumoniae in the United States (2001-2005).

OBJECTIVE: To test the susceptibility of Streptococcus pneumoniae sinus isolates collected across the United States against commonly used antimicrobial agents. STUDY DESIGN AND SETTING: S. pneumoniae sinus isolates (N = 847) collected as part of the Tracking Resistance in the US Today Surveillance Program from 2001 to 2005 were tested against 8 antimicrobial agents. RESULTS: In ascending order, the relative activities (% susceptible) were penicillin (51.8%), trimethoprim/sulfamethoxazole (TMP/SMX) (57.6%), erythromycin (59.5%), cefuroxime (62.0%), amoxicillin/clavulanate (85.5%), clindamycin (86.1%), levofloxacin (99.4%), and linezolid (100%; for 2004 and 2005 respiratory seasons, only). Resistance rates over the 5 years remained generally stable, although resistance to amoxicillin/clavulanate nearly doubled (from 6.5% to 12.9%). Forty percent of isolates were resistant to >or=2 agents tested. CONCLUSIONS AND SIGNIFICANCE: Susceptibility trends among sinus S. pneumoniae isolates appear to have stabilized over the past 5 years. Resistance rates remain elevated for penicillin and macrolides, whereas the high prevalence of multidrug resistance remains a concern.

Stable antimicrobial susceptibility rates for clinical isolates of Pseudomonas aeruginosa from the 2001-2003 tracking resistance in the United States today surveillance studies.

From 2001 to 2003, rates of susceptibility to piperacillin-tazobactam (86%), ceftazidime (80%), ciprofloxacin (68%), and levofloxacin (67%) did not decrease or decreased by <1.5%, whereas the rate of susceptibility to gentamicin decreased by 3.2% (from 75.5% to 72.3%) and the rate of susceptibility to imipenem decreased by 5.6% (from 84.4% to 78.8%), for 2394 clinical isolates of Pseudomonas aeruginosa collected in the Tracking Resistance in the United States Today surveillance studies. Rates of multidrug resistance (i.e., resistance to > or =3 antimicrobial agents) increased from 7.2% in 2001 to 9.9% in 2003 and were significantly higher for isolates from the East North Central and Mid-Atlantic regions of the United States than for isolates from other regions. Analysis of minimum inhibitory concentrations (MICs) suggested that combining an antipseudomonal beta -lactam with ciprofloxacin or levofloxacin would yield a 3.4%-7.1% increase in the percentage of isolates susceptible to the combination, compared with the beta -lactam alone. Ratios of the area under the serum concentration-time curve values for free drug to modal MICs for ciprofloxacin and levofloxacin were similar and were >125 (target ratio), whereas those ratios for gatifloxacin and moxifloxacin were significantly lower. Ongoing surveillance of P. aeruginosa is essential.

Susceptibilities to levofloxacin in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis clinical isolates from children: results from 2000-2001 and 2001-2002 TRUST studies in the United States.

Among respiratory tract isolates of Streptococcus pneumoniae from children, resistance to penicillins, cephalosporins, macrolides, and trimethoprim-sulfamethoxazole (SXT) increases on an annual basis. Pediatric patients who do not respond to conventional therapy for respiratory tract infections someday may be treated with fluoroquinolones. In this study, MICs of beta-lactams, azithromycin, SXT, and levofloxacin were determined and interpreted by using NCCLS guidelines for isolates of S. pneumoniae (2,834 from children and 10,966 from adults), Haemophilus influenzae (629 from children and 2,281 from adults), and Moraxella catarrhalis (389 from children and 1,357 from adults) collected during the 2000-2001 and 2001-2002 respiratory illness seasons in the United States as part of the ongoing TRUST surveillance studies. Rates of resistance to penicillin, azithromycin, and SXT were > or = 7.5% higher among patients < or = 4 years old than among patients 5 to 10, 11 to 17, and > or = 18 years old in both the 2000-2001 and the 2001-2002 respiratory illness seasons. Levofloxacin resistance was detected in 2 of 2,834 isolates (0.07%) from patients <18 years old. Levofloxacin MICs of 0.25 to 1 micro g/ml accounted for 99.6, 99.5, 99.3, 99.7, 98.4, and 98.0% of isolates from patients < 2, 2 to 4, 5 to 10, 11 to 17, 18 to 64, and > 64 years old. Multidrug resistance was twice as common among patients < or = 4 years old (25.3%) as among patients 5 to 10 years old (13.7%), 11 to 17 years old (11.9%), 18 to 64 years old (12.1%), and > 64 years old (12.4%). The most common multidrug resistance phenotype in S. pneumoniae isolates for all age groups was resistance to penicillin, azithromycin, and SXT (70.3 to 76.6%). For H. influenzae and M. catarrhalis isolates from patients < 2, 2 to 4, 5 to 10, 11 to 17, 18 to 64, and > 64 years old, levofloxacin MICs at which 90% of the isolates were inhibited were 0.015 and 0.03 to 0.06 microg/ml, respectively, in the 2000-2001 and 2001-2002 respiratory illness seasons. In the 2000-2001 and 2001-2002 respiratory illness season surveillance studies in the United States, 99.9% of pediatric isolates of S. pneumoniae were susceptible to levofloxacin. If fluoroquinolones become a treatment option for pediatric patients, careful monitoring of fluoroquinolone susceptibilities will be increasingly important in future surveillance studies.

Factors associated with relative rates of antimicrobial resistance among Streptococcus pneumoniae in the United States: results from the TRUST Surveillance Program (1998-2002).

To identify factors associated with antimicrobial resistance, data were analyzed from 27,828 isolates of Streptococcus pneumoniae submitted to the Tracking Resistance in the United States Today (TRUST) surveillance program during 4 consecutive respiratory seasons. From the 1998-1999 season to the 2001-2002 season, the prevalence of azithromycin resistance increased by 4.8% to 27.5%, the prevalence of penicillin resistance increased by 3.7% to 18.4%, the prevalence of ceftriaxone resistance increased by 0.5% to 1.7%, and the prevalence of levofloxacin resistance increased by 0.3% to 0.9%. Isolates recovered from patients <18 years of age and lower respiratory tract specimens had elevated rates of penicillin, azithromycin, and trimethoprim-sulfamethoxazole resistance (P<.00001); penicillin resistance correlated with coresistance to trimethoprim-sulfamethoxazole (87.3%), azithromycin (76.3%), ceftriaxone (9.1%), and levofloxacin (1.3%) (P<.00001). Only 62 (0.2%) of 27,828 isolates were concurrently resistant to penicillin and levofloxacin. Minimum inhibitory concentrations (MICs) of penicillin correlated strongly with MICs of ceftriaxone (R2=0.90), trimethoprim-sulfamethoxazole (R2=0.53), and azithromycin (R2=0.41). Patient age, specimen source, and penicillin resistance were factors associated with antimicrobial resistance, particularly for nonfluoroquinolone antimicrobial agents.

Regional trends in antimicrobial resistance among clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States: results from the TRUST Surveillance Program, 1999-2000.

The ongoing TRUST (Tracking Resistance in the United States Today) study, which began monitoring antimicrobial resistance among respiratory pathogens in 1996, routinely tracks resistance at national and regional levels. The 1999-2000 TRUST study analyzed 9499 Streptococcus pneumoniae, 1934 Haemophilus influenzae, and 1108 Moraxella catarrhalis isolates that were prospectively collected from 239 laboratories across the 9 US Bureau of the Census regions. Penicillin-resistant S. pneumoniae varied significantly by region, from 8.3% to 24.8% (P<.001). In each region, penicillin resistance closely predicted resistance to other beta-lactams, macrolides, and trimethoprim-sulfamethoxazole. Levofloxacin resistance was 0.5% nationally (regional range, 0.1%-1.0%). Multidrug resistance also varied significantly (P<.001) by region. beta-Lactamase production among H. influenzae varied significantly (regional range, 24.0%-34.6%) and M. catarrhalis (86.2%-96.8%) also varied by region. Notable variation in regional antimicrobial resistance rates (S. pneumoniae) and beta-lactamase production (H. influenzae, M. catarrhalis) exists throughout the United States.

Susceptibility to fluoroquinolones among commonly isolated Gram-negative bacilli in 2000: TRUST and TSN data for the United States. Tracking Resistance in the United States Today. The Surveillance Network.

From January to May 2000, as part of the Tracking Resistance in the United States Today (TRUST) surveillance initiative, clinical isolates of Enterobacteriaceae (n=2519) and non-fermentative Gram-negatives (n=580) were prospectively collected from 26 hospital laboratories across the United States. Isolates were tested for susceptibility to three fluoroquinolones (ciprofloxacin, levofloxacin, gatifloxacin) and seven other agents. In addition, data for the same period were collected from The Surveillance Network (TSN) Database-USA, an electronic surveillance network that receives data from more than 200 laboratories in the US. Both surveillance methods produced similar results. Against isolates of Enterobacteriaceae, imipenem was the most active agent, followed by the fluoroquinolones; > or = 86.7% of isolates of all species of Enterobacteriaceae except Providencia spp. were susceptible to fluoroquinolones by TRUST and TSN surveillance. TRUST identified differences in susceptibility to the three fluoroquinolones of > or = 2% for Citrobacter spp., Enterobacter cloacae, Proteus mirabilis and Serratia marcescens. Isolates of P. mirabilis were considerably more susceptible to levofloxacin (94.0%) than to ciprofloxacin (87.7%) and gatifloxacin (87.7%). Other results from TRUST included Pseudomonas aeruginosa being slightly more susceptible to ciprofloxacin (73.5%) and levofloxacin (73.0%) than gatifloxacin (71.0%). Imipenem was the only compound with significant activity (95.1% susceptible, TRUST; 87.4% susceptible, TSN) against Acinetobacter baumannii, but it was inactive against Stenotrophomonas maltophilia. S. maltophilia isolates were more susceptible to levofloxacin and gatifloxacin (77.7-79.8%) than ciprofloxacin (29.7-33.0%). Against 513 urinary isolates of Escherichia coli in TRUST, levofloxacin, gatifloxacin and ciprofloxacin were equipotent. Age and gender had no clear effect on the activity of levofloxacin, ciprofloxacin or gatifloxacin. Similar results for all three fluoroquinolones were seen in outpatients and inpatients. TRUST and TSN data indicated that resistance rates had not changed appreciably for any compound studied since a similar study conducted in 1999. TRUST centralized in vitro and electronic (TSN) surveillance methods provided an effective strategy for monitoring trends in resistance.