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Biomedical subjects

Thomas R Fritsche

Publications and source records attributed to Thomas R Fritsche.

At least 73 records · Page 4Linked to original sources

Doripenem (S-4661), a novel carbapenem: comparative activity against contemporary pathogens including bactericidal action and preliminary in vitro methods evaluations.

OBJECTIVES: To investigate the potency of doripenem, a broad-spectrum carbapenem characterized by a wider spectrum of activity combining antimicrobial and bactericidal features of imipenem and meropenem. METHODS: This parenteral compound was studied against recent clinical isolates (2001-2002) from a worldwide organism collection. A total of 902 strains were susceptibility tested by reference methods against doripenem and six to 28 comparators including ertapenem, imipenem and meropenem. The organisms tested included: Enterobacteriaceae (281 strains), Acinetobacter spp. (33), Pseudomonas aeruginosa (35), Stenotrophomonas maltophilia (36), other non-fermenters (22), Haemophilus influenzae (61), Moraxella catarrhalis (33), oxacillin-susceptible staphylococci (39), enterococci (84), streptococci (163), various anaerobes (98), and other Gram-positive species such as Corynebacterium and Bacillus spp. (17). RESULTS: Against Enterobacteriaceae, the average doripenem MIC90 was 0.03 mg/L (range, < or =0.015-0.25 mg/L). Doripenem was two- to 16-fold more potent than imipenem and comparable to ertapenem and meropenem; all doripenem MIC values with enteric bacilli were < or =4 mg/L. Doripenem was active against Aeromonas (MIC50, 0.03 mg/L), Bacillus spp. (MIC50, 0.03 mg/L) and all tested anaerobic species (MIC range, < or =0.015-4 mg/L), but was less active against S. maltophilia (MIC90, >32 mg/L) and Enterococcus faecium (MIC90, >32 mg/L) among the enterococcal species. Time-dependent bactericidal action was observed for doripenem and broth MIC results were slightly greater when compared to agar MIC results. In pilot testing, the optimal doripenem disc concentration was 10 microg, identical to standardized reagents for other clinically available carbapenems. CONCLUSIONS: Doripenem appears to be a potent carbapenem with a spectrum resembling currently marketed antipseudomonal carbapenems, but with greater activity when tested against some non-fermentative bacillary strains. Continued evaluation of doripenem against isolates resistant to other beta-lactams appears to be warranted.

Anti-Bacterial Agents↗

Topical polyene antifungals in hematopoietic cell transplant patients: tolerability and efficacy.

PURPOSE: The effectiveness of amphotericin B oral suspension versus nystatin oral suspension for the prevention of oral colonization by Candida in hematopoietic cell transplant (HCT) patients was examined. METHODS: Prior to hematopoietic cell infusion, 40 patients receiving systemic fluconazole for prophylaxis were randomized to receive either amphotericin B oral suspension or nystatin oral suspension, q.i.d. The study continued to day 21 or until the patient was discharge from the hospital or withdrawn from the study. Oral examinations were conducted twice weekly, and adverse events and compliance were recorded. Cultures were taken for quantitative counts and species identification. Candida isolates were assessed for resistance to the oral antifungal agents. Blood was collected for assessment of amphotericin B levels. RESULTS AND DISCUSSION: Ulcerative mucositis occurred in 84.6% of patients undergoing HCT, and no correlation was observed between the severity of mucositis and the presence of oral Candida and the severity of mucositis. Systemic and topical antifungal treatment resulted in a decrease in the number of colonized patients (54.8% before treatment; 23.1% during treatment); however, oral colonization was not eliminated. Tolerability of the oral rinse products was limited, with greater noncompliance in the amphotericin B than the nystatin group. Reports of altered taste appeared to be greater in the amphotericin B group. Minimal absorption of amphotericin B was seen following oral rinsing (serum levels 0.12-0.50 microg/ml), and no consistent changes in organism susceptibility to polyenes were seen. The results suggest that topical antifungal rinses may further control oropharyngeal colonization by Candida in patients on systemic antifungals receiving HCT, but the effect is limited by tolerability and reformulation and should be considered in order to increase compliance.

Administration, Oral↗

Potential utility of a peptide deformylase inhibitor (NVP PDF-713) against oxazolidinone-resistant or streptogramin-resistant Gram-positive organism isolates.

OBJECTIVES: To evaluate the potency of a novel peptide deformylase inhibitor, NVP PDF-713, against Gram-positive organisms having resistances to linezolid or quinupristin/dalfopristin. MATERIALS AND METHODS: A total of 45 strains from three genera (six species groups) were tested by reference broth microdilution methods. The mechanism of resistance to the oxazolidinone was determined by sequencing of the gene encoding the ribosomal target. RESULTS: NVP PDF-713 retained activity against linezolid-resistant staphylococci (MIC range 0.25-2 mg/L), Streptococcus oralis (MIC 0.5 mg/L), Enterococcus faecalis (MIC range 2-4 mg/L) and Enterococcus faecium (MIC range 0.5-4 mg/L). Quinupristin/dalfopristin-resistant E. faecium (MIC range 1-2 mg/L) and staphylococci (MIC range 0.12-2 mg/L) were also inhibited by NVP PDF-713. Many (10 of 13 strains) of the linezolid-resistant enterococci were resistant to vancomycin and these clinical strains had a G2576U ribosomal target mutation. CONCLUSIONS: NVP PDF-713 appears to be a promising clinical candidate among the peptide deformylase inhibitors for the treatment of infections caused by Gram-positive organisms that possess resistances to oxazolidinones or streptogramin combinations.

Amidohydrolases↗

Worldwide assessment of dalbavancin activity and spectrum against over 6,000 clinical isolates.

Continuing emergence of new antimicrobial resistance mechanisms and the increased frequency of existing resistances, requires the development of alternative antimicrobial agents. Dalbavancin is an amide glycopeptide derivative with a markedly extended serum elimination half-life. Dalbavancin and selected comparators were tested against 6,339 recent clinical isolates (2002) from the Americas and Europe using reference susceptibility testing methods. The general characteristics of this Gram-positive organism collection were: oxacillin (OXA)-resistant Staphylococcus aureus (ORSA) at 39% of strains; vancomycin-resistant enterococci (VRE) at 10%; and penicillin-nonsusceptible pneumococci at 28%. The overall distribution of dalbavancin minimum inhibitory concentration (MIC) values ranged from < or = 0.015 to > 32 microg/ml, but > 99% of MIC results were at < or =1 microg/ml. S. aureus and coagulase-negative staphylococci were extremely susceptible to dalbavancin (MIC90, 0.06 microg/ml) despite resistance patterns to other agents. Dalbavancin was the most potent compound (by weight) against vancomycin-susceptible Enterococcus faecalis and E. faecium (MIC90, 0.06 and 0.12 microg/ml, respectively); however, VRE strains showed decreased dalbavancin susceptibility (MIC50, 4 or 8 microg/ml). All streptococcal isolates were inhibited at < or =0.25 microg/ml of dalbavancin. This reported dalbavancin activity indicates that the new glycopeptide has significant activity, superior to available agents in the class, and a potency that was uniform across geographically sampled organisms. Some VRE were inhibited by very low dalbavancin concentrations (< or = 1 microg/ml; Van B phenotypes). Further clinical development seems warranted for this once-weekly administered agent.

Anti-Bacterial Agents↗

Antimicrobial spectrum and activity of NVP PDF-713, a novel peptide deformylase inhibitor, tested against 1,837 recent Gram-positive clinical isolates.

Continued emergence of antimicrobial resistances among gram-positive pathogens requires further development of compounds with novel modes of action. The peptide deformylase inhibitor NVP PDF-713 was tested against 1,837 recent strains of Gram-positive organisms. All NVP PDF-713 MICs were at < or = 4microg/mL except for 6 enterococci (0.3% of strains overall). NVP PDF-713 MIC(90) results were: Staphylococcus aureus, beta-haemolytic and viridans group streptococci and Streptococcus bovis at 1 microg/ml; coagulase-negative staphylococci, Streptococcus pneumoniae, and Listeria spp. at 2 microg/mL; and the enterococci at 4 microg/mL. NVP PDF-713 appears to be a promising new agent worthy of continued in vivo development.

Amidohydrolases↗

Antimicrobial resistance rates and clonality results from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) programme: report of year five (2003).

The U.S. Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Programme in the fifth year continues to monitor the spectrum of activity and potency of meropenem within medical centers where carbapenems are used for the treatment of serious infections. The antimicrobial activity of 11 broad-spectrum agents (including initial comparisons for levofloxacin) was assessed against 2,848 isolates in 2003. The minimum inhibitory concentration (MIC) results demonstrate the continued high potency of meropenem against all monitored pathogens. Against all Gram-negative bacilli tested, the overall rank order of susceptibility was meropenem (96.3%) > imipenem (95.6%) > cefepime (93.7%) > tobramycin (91.9%) > piperacillin/tazobactam (90.2%) > ceftazidime (90.1%) > gentamicin (89.6%) > levofloxacin (82.8%) > ciprofloxacin (82.5%) > aztreonam (81.8%) > ceftriaxone (72.3%). Clonal-based resistances were observed that adversely influenced carbapenem resistance rates, particularly among Klebsiella spp. and Acinetobacter baumannii isolates. Continued surveillance of the carbapenem class and other broad-spectrum agents is warranted to monitor activity against pathogens causing serious infections in hospitalized patients.

Academic Medical Centers↗

Doxycycline use for community-acquired pneumonia: contemporary in vitro spectrum of activity against Streptococcus pneumoniae (1999-2002).

Because of the limited clinical testing of doxycycline, it has received guarded acceptance as an inexpensive, fluoroquinolone-sparing agent for treatment of community-acquired pneumonia. Examination of in vitro data from 3,902 recent Streptococcus pneumoniae isolates (SENTRY Program, USA) suggests that doxycycline has wider clinical application compared to macrolides, oral cephalosporins (directed by penicillin susceptibility), and trimethoprim-sulfamethoxazole.

Anti-Bacterial Agents↗

In vitro activity of tigecycline (GAR-936) tested against 11,859 recent clinical isolates associated with community-acquired respiratory tract and gram-positive cutaneous infections.

Tigecycline is a novel 9-t-butylglycylamido derivative of minocycline that has demonstrated activity against a variety of bacterial pathogens, including resistant isolates, during preclinical studies. In vitro activities of tigecycline and comparators were tested against 11,859 recent (2000 and 2002) bacterial strains recovered from patients in 29 countries with community-acquired respiratory tract disease (3,317 gram-positive and -negative strains) and skin and soft tissue infections (8,542 gram-positive strains). All oxacillin-susceptible and -resistant Staphylococcus aureus (5,077 strains; tigecycline MIC(90), 0.5 microg/mL) and coagulase-negative staphylococci (1,432 strains; MIC(90), 0.5 microg/mL), penicillin-susceptible and -resistant Streptococcus pneumoniae (1,585 strains; MIC(90), < or =0.25 microg/mL), viridans group streptococci (212 strains; MIC(90), < or =0.25-0.5 microg/mL), vancomycin-susceptible and -resistant enterococci (1,416 strains; MIC(90), 0.25-0.5 microg/mL), beta-haemolytic streptococci (405 strains; MIC(90), < or =0.25 microg/mL), beta-lactamase positive and negative Haemophilus influenzae (1,220 strains; MIC(90), 1 microg/mL), Moraxella catarrhalis (495 strains; MIC(90), 0.25 microg/mL), and Neisseria meningitidis (17 strains; MIC(90), < or =0.12 microg/mL) were inhibited by 2 microg/mL or less of tigecycline. Whereas potency of tetracycline and doxycycline markedly dropped in various resistant organism subsets, tigecycline was unaffected with an overall MIC(90) of 0.5 microg/mL. These findings confirm that tigecycline maintains a truly broad spectrum like the tetracycline class while enhancing potency. It also incorporates stability to the commonly occurring tetracycline resistance mechanisms, making it an attractive candidate for continued clinical development against pathogens causing serious community-acquired respiratory tract infections, as well as cutaneous infections.

Anti-Bacterial Agents↗

Molecular epidemiology of selected multidrug-resistant bacteria: a global report from the SENTRY Antimicrobial Surveillance Program.

The SENTRY Antimicrobial Surveillance Program was initiated in 1997 as a global network for the longitudinal tracking of antimicrobial resistance and has incorporated a molecular typing protocol to detect and monitor emerging resistances in participant medical centers. Isolates with similar resistance profiles and patient demographics that were temporally related or those exhibiting emerging resistance phenotypes were routinely compared. Isolates were initially analyzed using the automated Riboprinter Microbial Characterization System (Qualicon, Inc., Wilmington, DE). Isolates with identical ribotype patterns were further characterized by pulsed field gel electrophoresis. During 2001, a total of 647 bacterial isolates were processed using this typing protocol; 36% were Staphylococcus aureus with multidrug-resistant, mupirocin- or quinupristin/dalfopristin-resistant phenotypes. Five ribotypes were predominant in this species with some occurring on more than one continent (184.5), whereas others were restricted to a single geographic region (893.2). Among S. aureus, 51 clusters demonstrating dissemination among patients were identified (31 medical centers). Twenty-three outbreaks/clusters were found among Enterobacteriaceae producing either extended-spectrum beta-lactamases or demonstrating resistance to fluoroquinolones. Carbapenem-resistant Pseudomonas aeruginosa and Acinetobacter spp. strains were also analyzed, some of which produced metallo-beta-lactamase enzymes. Clusters of carbapenem-resistant Acinetobacter were identified in Argentina and Israel, whereas metallo-beta-lactamase-producing P. aeruginosa epidemic strains were observed in Italy (three sites) and Brazil. The coupling of molecular epidemiologic investigations with global surveillance such as the SENTRY program adds significant value to participating medical centers and has proven to be effective in tracking changing trends and distribution of resistance genotypes both locally and globally.

Anti-Bacterial Agents↗

Determination of epidemic clonality among multidrug-resistant strains of Acinetobacter spp. and Pseudomonas aeruginosa in the MYSTIC Programme (USA, 1999-2003).

The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Programme was initiated in 1997 (1999 for the United States). This program monitors resistance in participant medical centers where carbapenems are prescribed and drug use data can be obtained. An earlier report found antimicrobial use was not a clear cause of local or aggregate changes in resistance rates. This study addresses the role of dissemination of resistant clones on susceptibility rates for nonfermentors, Acinetobacter spp. (ACB) and Pseudomonas aeruginosa (PSA). Carbapenem (CARB)-multidrug-resistant strains (MDR) from among 236 ACB and 1,111 PSA were tested by reference broth microdilution methods, automated ribotyping, and pulsed field gel electrophoresis to determine possible clonal dissemination. Each strain was also tested for metallo-beta-lactamases (MbetaL) (phenotypic and polymerase chain reaction); and then analyzed by CARB-R rate and defined daily dose (DDD)/100 days use groupings (high, moderate, and low). For the aggregate 15 sites in the MYSTIC Programme each year, the CARB-resistant rate decreased over 5 years; but other drug-resistance rates generally escalated. Changes were not related to antimicrobial use calculations. The discovered clonally spread MDR-PSA strains were more frequent in high- (1.8 clones/site) and moderate-resistance (0.6 clones/site) rate centers (21.7% to 29.5% were clonal), compared with unique strains in low-resistance hospitals. ACB clonality was extreme in one geographic area, with dissemination of 5 different clones (931.7/B, C, or D; 1090.2/A; 167.5/A) in 4 centers (02, 04, 06, and 18). Resistance rates in ACB and PSA were clearly related to clonal occurrence and spread, and one MbetaL (VIM-7) was detected. Decreased CARB resistance rates from 1999 through 2002 were directly attributed to the disappearance of resistance clones in some locations. In conclusion, ACB and PSA CARB and MDR resistance rates in MYSTIC Programme institutions have been greatly influenced by clonal dissemination and less by antimicrobial use patterns. The most serious examples of resistance were the clonality observed among ACB in New York City and the documented endemic nature of VIM-7-producing PSA (0.09% of all PSA isolates). Meropenem remained the most active antimicrobial agent tested in the program, and surveillance networks must implement epidemiologic typing to accurately assess the role of clonal spread on the study results.

Acinetobacter↗

Bactericidal activity of BAL9141, a novel parenteral cephalosporin against contemporary Gram-positive and Gram-negative isolates.

BAL9141, the active principle of prodrug BAL5788, is a parenteral cephalosporin active against oxacillin-resistant Staphylococcus aureus. Previous studies have reported the cidal action of BAL9141 towards limited numbers of isolates by time-kill methods. We tested >100 staphylococci, streptococci, and Gram-negative isolates by broth microdilution methods to determine the antibacterial activity of BAL9141 and to compare minimum inhibitory concentrations (MICs) with minimum bactericidal concentrations (MBCs). Among the 53 staphylococcal isolates, all but one (98%) had a, MBC:MIC ratio < or =2. Forty-five percent (five strains) of the penicillin-nonsusceptible Streptococcus pneumoniae isolates had an MBC:MIC ratio >4. Among 22 Enterobacteriaceae, 73% of isolates had MBC:MIC ratios of 2 or less; three strains with ratios greater than 4 were Serratia marcescens. BAL9141 displayed a predominant bactericidal activity against the majority of Gram-positive and -negative species, including resistant subsets, making it an attractive candidate for further development.

Cephalosporins↗

Potency and spectrum reevaluation of cefdinir tested against pathogens causing skin and soft tissue infections: a sample of North American isolates.

Cefdinir is a widely used orally administered cephalosporin for community-acquired respiratory tract infections and skin and soft tissue infections (SSTI). A total of 415 nonduplicate isolates of community-acquired SSTI (CA-SSTI) were collected from medical centers in North America and susceptibility tested against cefdinir and various compounds indicated for the treatment of CA-SSTI. The cefdinir MIC(50/90) in microg/mL/% susceptible for strains of the 7 principal CA-SSTI pathogens were: oxacillin-susceptible Staphylococcus aureus (0.5/0.5/100%), oxacillin-susceptible coagulase-negative staphylococci (0.06/0.12/100%), group A streptococci (< or =0.03/< or =0.03/100%), group B streptococci (< or =0.03/0.06/100%), viridans group streptococci (0.25/2/88%), Klebsiella spp. (0.12/1/95%), and Escherichia coli (0.25/0.5/95%). Cefdinir was the most potent oral cephalosporin tested against staphylococci and the Enterobacteriaceae species, and 8-fold to 64-fold more potent than cephalexin against these pathogens. Beta-Hemolytic streptococci was highly susceptible to cefdinir (MIC(90), < or =0.03-0.06 microg/mL), while viridans group streptococci showed slightly elevated MIC results. Cephalexin MIC values for streptococcal strains (MIC(90), 1-32 microg/mL) were 32-fold to 64-fold higher than those of cefdinir or other oral cephalosporins evaluated. Only 0.5% of all 415 recent CA-SSTI pathogens were resistant to cefdinir (MIC, > or = 4 mg/L). Cefdinir showed a spectrum and potency comparable or superior to other orally administered beta-lactams (cephalexin).

Anti-Infective Agents↗

Antimicrobial activity of daptomycin against multidrug-resistant Gram-positive strains collected worldwide.

Daptomycin is a cyclic lipopeptide recently released for clinical use in the treatment of serious Gram-positive infections in hospitalized patients. We evaluated the in vitro activity of daptomycin tested against recently isolated multidrug-resistant Gram-positive clinical strains. A total of 386 isolates were selected from a large collection of strains from more than 70 centers located in Europe, North America, and South America. The strains were tested by reference broth microdilution methods in Mueller-Hinton broth with 50 mg/L Ca++ against daptomycin. Daptomycin was the most potent compound tested against penicillin-resistant Streptococcus pneumoniae with MIC50/90 values at < or =0.12 and 0.25 microg/mL, respectively. Daptomycin was also highly active against vancomycin-resistant enterococci and staphylococcal strains with various resistance patterns. Enterococcus faecium showed higher daptomycin MIC values (MIC90, 4 microg/mL) when compared to E. faecalis (MIC90, 1 microg/mL). In summary, resistance to vancomycin, teicoplanin, quinupristin/dalfopristin, or penicillin among the Gram-positive isolates did not adversely influence daptomycin activity. Daptomycin showed a significant potency and spectrum against Gram-positive species, including multidrug-resistant strains, and may represent a reasonable therapeutic option for infections caused by these important pathogens.

Anti-Bacterial Agents↗

Validation of commercial dry-form broth microdilution panels and test reproducibility for susceptibility testing of dalbavancin, a new very long-acting glycopeptide.

Results from dalbavancin dry-form commercial broth microdilution MIC panels (Sensititre, TREK Diagnostics) were compared with reference frozen-form MIC values to assure the validity and reproducibility of the extended shelf-life product. A collection of 402 organisms from four major organism groups were used in the validation trial and 10 strains for reproducibility replicate tests. A total of 98.6% commercial dalbavancin MIC results were within +/-1 log(2) dilution of reference values (76.2% were identical) and reproducibility trials produced identical MIC results in 88.9-92.2% of dalbavancin MIC comparisons. These dalbavancin MIC results demonstrated the acceptable accuracy of commercially-prepared broth microdilution products for use in subsequent clinical trials.

Bacterial Infections↗

Assessment of pathogen occurrences and resistance profiles among infected patients in the intensive care unit: report from the SENTRY Antimicrobial Surveillance Program (North America, 2001).

Originating from 25 selected intensive care units (ICUs) in North America, a total of 1,321 bacterial strains from blood, respiratory tract, urine and wound sites were processed at a central laboratory as part of the SENTRY Antimicrobial Surveillance Program (2001) to assess their occurrence rates and antimicrobial susceptibility profiles. The rank order of pathogens recovered was Staphylococcus aureus (24.1%), Pseudomonas aeruginosa (12.2%), Escherichia coli (10.1%), Klebsiella spp. (8.9%), Enterococcus spp. (7.2%), coagulase-negative staphylococci (7.0%) and Enterobacter spp. (7.0%). Although oxacillin resistance among S. aureus was 51.4%, no resistance was detected to vancomycin, linezolid and quinupristin/dalfopristin. The most active agents tested against P. aeruginosa were amikacin, cefepime, tobramycin, meropenem and piperacillin/tazobactam (3.1-13.0% resistance). Among agents tested against the Enterobacteriaceae, amikacin, cefepime, imipenem and meropenem showed greatest in vitro activity (0.0-3.4% resistance). Extended-spectrum beta-lactamase-producing phenotype rates were 11.2 and 16.2% in E. coli and Klebsiella spp., respectively. Linezolid was most active against enterococci (1.1% resistance; G2576U ribosomal mutation) whereas 28.4% of isolates were resistant to vancomycin. Cefepime and the carbapenems (imipenem or meropenem) for Gram-negative isolates and linezolid for Gram-positive isolates, provided the broadest spectrum of in vitro activity against contemporary ICU pathogens in North America.

Anti-Bacterial Agents↗

Antimicrobial activity of tigecycline (GAR-936) tested against 3498 recent isolates of Staphylococcus aureus recovered from nosocomial and community-acquired infections.

Tigecycline is a novel 9-t-butylglycylamido derivative of minocycline that has demonstrated activity against a variety of Gram-positive and -negative bacterial pathogens. In vitro activity of tigecycline and comparator agents was determined for 3498 recent (2000-2003) strains of Staphylococcus aureus recovered from patients with either nosocomial or community-acquired infections. Oxacillin-susceptible and -resistant S. aureus from both patient populations displayed identical results for tigecycline (MIC(50) and MIC(90) results at 0.25 and 0.5 mg/L, respectively) and all strains were inhibited by 1 mg/L or less. While co-resistances to other antimicrobial classes were present in oxacillin-resistant strains, susceptibility to tigecycline remained unaffected, making the compound an attractive candidate for treatment of serious hospital as well as community-acquired staphylococcal infections.

Community-Acquired Infections↗

Babesia divergens-like infection, Washington State.

Most reported U.S. zoonotic cases of babesiosis have occurred in the Northeast and been caused by Babesia microti. In Washington State, three cases of babesiosis have been reported previously, which were caused by WA1 (for "Washington 1")-type parasites. We investigated a case of babesiosis in Washington in an 82-year-old man whose spleen had been removed and whose parasitemia level was 41.4%. The complete 18S ribosomal RNA gene of the parasite was amplified from specimens of his whole blood by polymerase chain reaction. Phylogenetic analysis showed the parasite is most closely related, but not identical, to B. divergens (similarity score, 99.5%), a bovine parasite in Europe. By indirect fluorescent-antibody testing, his serum reacted to B. divergens but not to B. microti or WA1 antigens. This case demonstrates that babesiosis can be caused by novel parasites detectable by manual examination of blood smears but not by serologic or molecular testing for B. microti or WA1-type parasites.

Aged↗