Erythromycin Nonsusceptibility Research Articles

Continued Increase of Erythromycin Nonsusceptibility and Clindamycin Nonsusceptibility Among Invasive Group A Streptococci Driven by Genomic Clusters, United States, 2018-2019.

We analyzed 9630 invasive GAS surveillance isolates in the USA. From 2015-2017 to 2018-2019, significant increases in erythromycin-nonsusceptibility (18% vs 25%) and clindamycin-nonsusceptibility (17% vs 24%) occurred, driven by rapid expansions of genomic subclones. Prevention and control of clustered infections appear key to containing antimicrobial resistance.

Highly prevalent emmSTG840.0 and emmSTC839.0 types of erythromycin non-susceptible group G Streptococcus isolated from bacteremia in southern Taiwan.

Group G Streptococcus (GGS) infections in human have increased. Treatment relied on antibiotic therapy, including erythromycin. However, information regarding the dominant strains and erythromycin susceptibility in GGS bacteremia is limited. A total of 134 GGS were isolated from patients with bacteremia in a university hospital of southern Taiwan during 1993-2010. The erythromycin susceptibility was determined by disc diffusion and agar dilution assays. The bacterial species was determined by MALDI-TOF. The presence of erythromycin-resistant genes and emm types were determined by polymerase chain reaction and sequence. The clonal spreading was analyzed by pulsed-field gel electrophoresis with SmaI or SgrAI digestion. The annual erythromycin non-susceptible rate varied, with an average of 40.3%. All erythromycin non-susceptible strains belonged to the Streptococcus dysgalactiae. No erythromycin non-susceptible strains belong to the anginosus group. The most prevalent erythromycin-resistant gene was mefA (57.4%), followed by ermB (37%), and ermA (3.7%). The N terminal hyper variable region of emm was sequenced to determine the emm type, and only S. dysgalactiae had the emm gene. The most prevalent emm types were emmSTG840.0 (17.2%), emmSTG485.0 (10.4%), and emmSTC839.0 (9.0%). 73% and 47% of the strains with only mefA and ermB belonged to emmSTG840.0 and emmSTC839.0 types, respectively. Pulsed-field gel electrophoresis showed that different clones of emmSTG840.0 and emmSTC839.0 strains were spread in this region during the 18 years of surveillance. Our data indicate that there were dominant emm types with erythromycin non-susceptibility in S. dysgalactiae isolated from bacteremia in Taiwan, and thus constant surveillance is warranted.

Attributable healthcare utilization and cost of pneumonia due to drug-resistant streptococcus pneumonia: a cost analysis.

BackgroundThe burden of disease due to S. pneumoniae (pneumococcus), particularly pneumonia, remains high despite the widespread use of vaccines. Drug resistant strains complicate clinical treatment and may increase costs. We estimated the annual burden and incremental costs attributable to antibiotic resistance in pneumococcal pneumonia.MethodsWe derived estimates of healthcare utilization and cost (in 2012 dollars) attributable to penicillin, erythromycin and fluoroquinolone resistance by taking the estimate of disease burden from a previously described decision tree model of pneumococcal pneumonia in the U.S. We analyzed model outputs assuming only the existence of susceptible strains and calculating the resulting differences in cost and utilization. We modeled the cost of resistance from delayed resolution of illness and the resulting additional health services.ResultsOur model estimated that non-susceptibility to penicillin, erythromycin and fluoroquinolones directly caused 32,398 additional outpatient visits and 19,336 hospitalizations for pneumococcal pneumonia. The incremental cost of antibiotic resistance was estimated to account for 4% ($91 million) of direct medical costs and 5% ($233 million) of total costs including work and productivity loss. Most of the incremental medical cost ($82 million) was related to hospitalizations resulting from erythromycin non-susceptibility. Among patients under age 18 years, erythromycin non-susceptibility was estimated to cause 17% of hospitalizations for pneumonia and $38 million in costs, or 39% of pneumococcal pneumonia costs attributable to resistance.ConclusionsWe estimate that antibiotic resistance in pneumococcal pneumonia leads to substantial healthcare utilization and cost, with more than one-third driven by macrolide resistance in children. With 5% of total pneumococcal costs directly attributable to resistance, strategies to reduce antibiotic resistance or improve antibiotic selection could lead to substantial savings.

Antimicrobial Resistance in Relation to Sero- and Genotypes Among InvasiveStreptococcus pneumoniaein Finland, 2007–2011

We studied the serotypes and antimicrobial resistance of the invasive Streptococcus pneumoniae that had been isolated in Finland during 5 years. The 10-valent vaccine was introduced into the National Vaccination Programme in September 2010. We examined the antimicrobial resistance and serotype distribution of the invasive pneumococci (n=4,194) that had been isolated in Finland during 2007-2011. The penicillin-resistant (PEN R) (≥4 mg/L) isolates (n=12) were genotyped by MLST. Serotype 14 was consistently the most prominent serotype, covering 18.0-20.1% of all the isolates. The proportion of serotypes 3, 19A, and 22F increased significantly, while that of 6B and the PCV10 vaccine serotypes combined decreased. PEN nonsusceptibility (≥0.12 mg/L) increased, ranging from 14.4% to 23.2% by year, and was the highest (28.5%) among the 0-2 year olds. The PEN and/or erythromycin (ERY) nonsusceptibility of several vaccine serotypes (4, 6B, 14, and 19F) increased significantly over the study period. The ERY nonsusceptibility was 26.6%. There was limited diversity among the PEN R isolates; all were a part of serotype 19F, 19A, or 14, and two globally disseminated genetic lineages carrying one or both pilus-encoding islets. High and/or increasing nonsusceptibility rates underline the importance of monitoring the serotype distribution and antimicrobial susceptibility of pneumococci, especially after large-scale vaccination.

Invasive isolates of Streptococcus pneumoniae in Serbia: Antimicrobial susceptibility and serotypes

Streptococcus pneumoniae is one of the leading causes of bacterial meningitis and sepsis. Invasive pneumococcal disease is a significant medical problem worldwide, particularly in children, due to a huge increase of pneumococcal resistance to antibiotics. The aim of the study was to investigate the antimicrobial susceptibility pattern of invasive pneumococcal isolates, as well as to determine whether decreased S. pneumoniae susceptibility to antibiotics was related to a particular serotype. Antimicrobial susceptibility to 19 antibiotics was determined in 58 invasive pneumococcal strains that were collected from seven regional centers during the period July 2009 to February 2011 in the National Reference Laboratory for streptococci and pneumococci. The overall nonsusceptibility rate to penicillin was detected in 34% of pneumococcal isolates and to erythromycin in 36%. Higher resistance rates were observed among children than among adults. Penicillin resistance rate was 65% in children versus 22% in adults, while erythromycin nonsusceptibility rate was 47% in children versus 32% in adults. Co-resistance to penicillin and erythromycin was detected in 21% strains, mostly isolated from children. Multiresistance was found in one third of isolates. All strains were susceptible to vancomycin, linezolid, fluoroquinolones, telithromycin and rifampicin, while 23 (40%) isolates were susceptible to all tested antibiotics. The most common resistant serotypes were 19F and 14. The study has revealed that penicillin and macrolide resistance among invasive pneumococcal isolates is very high in Serbia. This emphasizes the need for continuous monitoring for invasive pneumococcal disease to document the serotype distribution and antimicrobial susceptibility pattern.

Macrolide-resistant phenotypes of invasive streptococcus pneumoniae isolates in Serbia

Macrolide resistance in Streptococcus pneumoniae has emerged as an important worldwide problem over the past decade. The aim of this study was to investigate macrolide-resistant phenotypes and the antimicrobial susceptibility patterns of invasive pneumococci in Serbia. A total of 68 invasive pneumococcal strains, collected from 2009 to 2011, were sent from regional laboratories to the National Reference Laboratory. Susceptibility testing was performed using the VITEK2 system and phenotypes were determined by triple-test. Overall penicillin and erythromycin nonsusceptibility rates were 26% and 43%, respectively. Resistance rates were higher in children than in adults. Co-resistance to penicillin and erythromycin was detected in 18% strains. Resistance rates to the third generation of cephalosporins, TMP-SXT and tetracycline were 16%, 37% and 29%, respectively. All isolates were fully susceptible to vancomycin, linezolid, fluoroquinolones, telithromycin and rifampicin. Twenty-two isolates (79%) an expressed macrolide-lincosamide-streptogramin B (MLSB) resistance phenotype and M phenotype was found in 21% of macrolide resistant strains.

Evolution of Clonal and Susceptibility Profiles of Serotype 19A Streptococcus pneumoniae among Invasive Isolates from Children in Spain, 1990 to 2008

The genetic structure and antibiotic nonsusceptibility of all serotype 19A Streptococcus pneumoniae pediatric pneumococcal isolates received at the Spanish Pneumococcal Reference Laboratory (1990 to 2008) were analyzed. Of them, 410 (79.8%) isolates belonged to 14 sequence types (STs) with >10 isolates each, and 104 to 73 STs (with 21 new STs, ST5141 to ST5161, with one isolate each). Time trends in 2000 to 2008 (n=471) were explored by lineal regression. Serotype 19A increased from 5.7% in 2000 to 16.8% in 2008 (R2=0.872; P=0.001). Decreasing trends (P<0.03) were found for ST202 (R2=0.774) and ST81 (R2=0.559), and increasing trends (P<0.03) for ST878 (R2=0.544) and ST320 (R2=0.530), both belonging to the clonal complex (CC) Denmark(14)-32 and first detected in 2003 and 2007, respectively, and ST2013 (R2=0.704) and ST4461 (R2=0.707), both appearing in 2004. Penicillin nonsusceptibility was clustered in ST81, ST276, ST320, ST878, ST2013, and ST4461 (>90% nonsusceptibility), and amoxicillin and cefotaxime nonsusceptibility in ST320: 87% amoxicillin (MIC50/MIC90=8/8 μg/ml) and 43.5% cefotaxime (MIC50/MIC90=1/2 μg/ml) nonsusceptibility. No trends were found for erythromycin nonsusceptibility (ranging from 38.5% to 66.7%) and cefotaxime nonsusceptibility (ranging from 0.0% to 7.8%), but increasing trends (P<0.02) were found for oral penicillin (from 16.7% in 2000 to 56.3% in 2008; R2=0.628) and amoxicillin (from 0.0% before 2007 to 13.8% in 2008; R2=0.628) nonsusceptibility. This study warns about the emergence of serotype 19A STs associated with high-level antibiotic nonsusceptibility, with a role for ST320 and ST878 occupying the niche left by some pneumococcal 7-valent conjugate vaccine (PCV7)-related resistant STs. The rapid expansion of serotype 19A and STs related to antibiotic resistance indicates that vaccines covering serotype 19A present advantages in countering invasive disease.

Temporal trends of antimicrobial resistance and clonality of invasive Streptococcus pneumoniae isolates in Finland, 2002 to 2006.

The antimicrobial resistance of Streptococcus pneumoniae, or pneumococcus, is a growing global problem. In our study, 3,571 invasive pneumococcal isolates, recovered from blood and cerebrospinal fluid samples from patients in Finland between the years 2002 and 2006, showed an increase in erythromycin nonsusceptibility from 16% to 28% (P < 0.0001) over the 5-year study period, as well as a doubling of penicillin nonsusceptibility from 8% to 16% (P < 0.0001). Erythromycin nonsusceptibility increased especially in isolates derived from 0- to 2-year-old children and was 46% for this age group in 2006. Although multiresistance, defined as nonsusceptibility to penicillin, erythromycin, and tetracycline, was fairly rare (5.1% in 2006), 38% of the erythromycin-nonsusceptible isolates were also penicillin nonsusceptible, while 74% of the penicillin-nonsusceptible isolates were nonsusceptible to erythromycin. In contrast to the situation in continental Europe, but mirroring that in North America, the most frequent macrolide resistance determinant carried by 56% of the tested macrolide-resistant pneumococci was the mef gene. Serotypes 14, 9V, 19A, 6B, and 19F were most frequently nonsusceptible to erythromycin or penicillin. The penicillin-resistant invasive isolates (n = 88) were genotyped by multilocus sequence typing, which revealed the presence of 25 sequence types, 9 of which were novel. The majority of the isolates were related to one of several globally disseminated penicillin- or multiresistant clones, most importantly the rlrA adhesion pilus carrying clones Spain(9V) ST156 and Taiwan(19F) ST236. The penicillin-resistant pneumococcal population in Finland is therefore a combination of internationally recognized genotypes as well as novel ones.

Temporal Trends of Invasive Streptococcus pneumoniae Serotypes and Antimicrobial Resistance Patterns in Spain from 1979 to 2007

Temporal trends of serotypes from invasive pneumococcal disease (IPD) in Spain from 1979 to September 2007 under antibiotic and vaccine pressure were analyzed. A significant trend in pneumococcal conjugate 7-valent vaccine (PCV7) serotypes (except serotype 4) was found, whereby the prevalence increased from the early 1980s and decreased in the 2000s for all but serotype 23F, which began decreasing in the late 1980s. Among the major non-PCV7 serotypes, a significant decrease was observed for serotypes 1, 5, and 7F in the 1980s. From the late 1990s, serotypes 1, 5, 6A, 7F, and 19A increased significantly, while serotypes 3 and 8 showed similar but nonsignificant trends over time. The incidence of IPD cases was 10.7/100,000 for the period 1996 to 2006, with reporting coverage ranging from 18% to 43%. A significant decrease in IPD incidence due to PCV7 serotypes was observed, while the incidence of non-PCV7 serotypes increased, with the consequence that there was no clear pattern in the overall incidence of IPD. Penicillin nonsusceptibility was correlated with the proportion of PCV7 serotypes. Erythromycin nonsusceptibility increased in association with long-half-life macrolide consumption and then decreased in 2004 to 2007. The increase in PCV7 serotypes and antibiotic nonsusceptibility related to antibiotic consumption in the 1980s and 1990s was reversed in the 2000s, probably as a result of PCV7 immunization. The decrease in IPD incidence due to PCV7 serotypes was mirrored by an increase in that of non-PCV7 serotypes. The impact of various preventive/therapeutic strategies on pneumococcal evolution is serotype dependent, and the dynamics remain unpredictable.

Has the licensing of respiratory quinolones for adults and the 7-valent pneumococcal conjugate vaccine (PCV-7) for children had herd effects with respect to antimicrobial non-susceptibility in invasive Streptococcus pneumoniae?

The aim of the study was to analyse the evolution of antibiotic non-susceptibility in Spanish invasive Streptococcus pneumoniae after licensure of respiratory-quinolones for adults and 7-valent pneumococcal conjugate vaccine (PCV-7) for immunization of children. All invasive pneumococci received in the Reference Laboratory (January 2000-August 2007; n = 12 957 isolates) were serotyped, and susceptibility to penicillin/erythromycin/levofloxacin was determined. Antibiotic consumption and PCV-7 doses/year were provided by IMS and the manufacturer, respectively. In 2000-07, PCV-7 distribution (doses/1000 inhabitants </=59 months age/year) increased from 0.0 to 411.90, and antibiotic consumption (DDD/1000 inhabitants/day) was maintained for beta-lactams ( approximately 16), decreased for macrolides (from 4.4 to 2.7) and increased for respiratory fluoroquinolones (from 0.3 to 2.7). The increase in PCV-7 distribution correlated with a decrease in PCV-7 serotypes prevalence among invasive isolates in children (r = -0.976; P < 0.001) and adults (r = -0.905; P = 0.002). This decrease in PCV-7 serotypes correlated with a decrease in penicillin non-susceptibility in children (r = 0.929; P < 0.001) and adults (r = 0.905; P = 0.002) and with erythromycin non-susceptibility in children (r = 0.833; P = 0.010). Penicillin/erythromycin non-susceptibility in 2000 was significantly higher in paediatric versus adult isolates (penicillin: 51.4% versus 29.2%; erythromycin: 39.5% versus 20.4%), but similar in 2006-07 (20% to 24%). The increase in respiratory quinolones consumption correlated with the increase in levofloxacin non-susceptibility in adults (r = 0.926; P = 0.008) but not in children, with different non-susceptibility rates in 2007 (1.6% versus 0.0%; P = 0.013). This ecological analysis suggests that PCV-7 vaccination in children had a herd effect in adults, but consumption of respiratory quinolones in adults had no effect on pneumococcal susceptibility to levofloxacin in children. Penicillin/erythromycin non-susceptibility decreased along the studied period among paediatric invasive S. pneumoniae isolates to a level similar to that seen in adults.

Antimicrobial susceptibility and serogroup/serotype distribution of nasopharyngeal isolates of Streptococcus pneumoniae in healthy Estonian children in 1999–2003

This study determined nasopharyngeal (NP) carriage rates of Streptococcus pneumoniae among healthy Estonian children, aged 1-7 years, and characterised the serotype/serogroup distribution and antibiotic susceptibility rates. NP swabs were collected from 685 previously healthy children attending 29 day care centres during the winters of 1999-2000 and 2003. The NP carriage rate of S. pneumoniae was 44%. Rates of penicillin and erythromycin non-susceptibility were low (both 6%), but high (67%) rates of co-trimoxazole resistance were found. Among the pneumococcal serotypes identified, 64% were included in or cross-reacted with the licensed heptavalent pneumococcal vaccine.

Evolution of resistance patterns and identification of risk factors for Streptococcus pneumoniae colonisation in daycare centre attendees in Athens, Greece

Two cross-sectional surveillance studies were conducted during the winters of 2000 and 2003 in Athens, Greece, to obtain nasopharyngeal swabs from healthy pre-school children attending kindergartens. A total of 460 strains were examined in 2000 and 485 strains in 2003, with carriage rates of 31.7% and 34.6%, respectively. Susceptibility patterns were evaluated for penicillin G, erythromycin, ceftriaxone, moxifloxacin, linezolid and telithromycin. Penicillin non-susceptibility increased from 20% to 34.9%, whereas erythromycin non-susceptibility increased from 23% to 30.5%. Resistance to both agents climbed from 7.5% to 22.3% ( P < 0.001). No isolates were found to be resistant to any of the other antimicrobial agents. Risk factors for carriage and/or antimicrobial resistance were also assessed.

Population antibiotic susceptibility for Streptococcus pneumoniae and treatment outcomes in common respiratory tract infections

Antibiotic-resistant Streptococcus pneumoniae potentially threatens the successful treatment of common respiratory tract infections (RTIs); however, the relationship between antibiotic resistance and treatment outcomes remains unclear. We aimed to test the hypothesis that higher in vitro penicillin and erythromycin nonsusceptibility levels among clinical isolates of S. pneumoniae are associated with higher risk of treatment failure in suppurative acute otitis media (AOM), acute sinusitis, and acute exacerbation of chronic bronchitis (AECB). We conducted a population-level analysis using treatment outcomes data from a national, managed-care claims database, and antibiotic susceptibility data from a national repository of antimicrobial susceptibility results between 1997 and 2000. Treatment outcomes in patients with suppurative AOM, acute sinusitis, or AECB receiving selected macrolides or beta-lactams were assessed. Associations between RTI-specific treatment outcomes and antibiotic nonsusceptibility were determined using Spearman correlation coefficients with condition-specific paired outcome and susceptibility data for each region and each year. There were 649 552 available RTI outcomes and 7252 susceptibility tests performed on S. pneumoniae isolates. There were no statistically significant trends across time for resolution proportions following treatment by either beta-lactams or macrolides among any of the RTIs. Correlation analyses found no statistically significant association between S. pneumoniae susceptibility and RTI treatment outcomes apart from a significant positive association between of erythromycin nonsusceptibility in ear isolates and macrolide treatment resolution for suppurative AOM. On the population level, in vitro S. pneumoniae nonsusceptibility to macrolide or beta-lactam antibiotics was not associated with treatment failure in conditions of probable S. pneumoniae etiology.

Trends of penicillin and erythromycin resistance among invasive Streptococcus pneumoniae in Europe

To forecast trends in resistance to penicillin and erythromycin among Streptococcus pneumoniae in Europe. Since 1999, the European Antimicrobial Resistance Surveillance System (EARSS) has collected routine antimicrobial susceptibility test results of S. pneumoniae. To observe and predict changes of reduced susceptibility over time, we used a multinomial logistic regression model. Large variations in penicillin and erythromycin non-susceptibility were observed between countries, and reduced susceptibility to erythromycin (17%) has become more frequent than reduced susceptibility to penicillin (10%) in Europe overall. An overall decrease in single penicillin non-susceptibility, but an increase in dual non-susceptibility was observed, indicating a shift of single penicillin to combined non-susceptibility with erythromycin. By 2006, the proportion of single erythromycin and dual non-susceptibility could increase to as much as 20.4% and 8.9%, respectively. Our results indicate that appropriately dosed beta-lactams for empirical therapy are still the treatment of choice, and that macrolides should be used with prudence.

Elimination of racial differences in invasive pneumococcal disease in young children after introduction of the conjugate pneumococcal vaccine.

Racial differences in the epidemiology of invasive pneumococcal disease (IPD) have been widely recognized, but the impact of conjugate pneumococcal vaccine (PCV) introduction in 2000 on these differences has not been extensively studied. IPD episodes in 5 Tennessee counties from January 1995 through December 2002 were collected prospectively using the Centers for Disease Control and Prevention's Active Bacterial Core Surveillance system (ABCs). Trained nurses collected clinical data, and antibiotic susceptibility testing was performed on available isolates. Before vaccine licensure, IPD rates were highest in children younger than 2 years and in blacks. The disparity in IPD rates between blacks and whites younger than 2 years of age substantially diminished after PCV introduction. In 1999, the IPD rate in black children younger than 2 years was 340.2 per 100,000, representing 176.5 more events per 100,000 than in white children (P < 0.001). In 2002, this rate had decreased 83% to 57.4 per 100,000, similar to the rate in white children (39.6 per 100,000; P = 0.31). Before vaccine licensure, a higher percentage of isolates from whites were antibiotic-nonsusceptible. In 2002, the proportion of antibiotic-nonsusceptible pneumococcal isolates was similar in whites and blacks of all ages for the first time during the study period (P > 0.05 for separate comparisons of penicillin, cephalosporin and erythromycin nonsusceptibility). These changes occurred despite a lower PCV vaccination coverage in Tennessee in blacks than in whites (31.2% versus 47.6%). With conjugate pneumococcal vaccine introduction in Tennessee, racial differences in the incidence rates of IPD have largely been eliminated, particularly in young children.

Detection of Macrolide Resistance in Streptococcus pneumoniae

We determined the susceptibilities of recent clinical isolates of Streptococcus pneumoniae to 19 antibiotics. The frequency of erythromycin nonsusceptibility was high, i.e. 8/13 (61.5%), 10/14 (71.4%) and 11/11 isolates (100%) from 13 penicillin-susceptible, 14 penicillin-intermediate and 11 penicillin-resistant S. pneumoniae, respectively. Macrolide resistance was detected by polymerase chain reaction (PCR) and disk diffusion methods. Of these erythromycin-nonsusceptible pneumococcal isolates, 13/29 (44.8%) isolates contained genomic copies of mefA and showed non-‘D’-shaped zones of inhibition observed around rokitamycin and/or clindamycin disks. Sixteen out of 29 isolates (55.2%) contained copies of ermB and showed typical ‘D’-shaped zones of inhibition, except one isolate. Although the macrolide resistance determinants, mefA and ermB, could be identified by PCR and disk diffusion methods, PCR methods were more reliable in elucidating these determinants. The susceptibility pattern to 14-, 15- and 16-membered macrolides and clindamycin differed between the mefA+ and ermB+ isolates. All isolates were susceptible to levofloxacin, sparfloxacin and vancomycin. The MICs of sitafloxacin were lowest among the fluoroquinolones examined for 38 isolates.