To The Editors:
Viridans streptococci are a heterogeneous group of different species of Gram-positive cocci that form part of the normal bacterial flora of the upper respiratory tract, the female genital tract and the gastrointestinal tract, particularly the area of the oral cavity. Although in general they are considered to be low virulence bacteria, they are an important cause of subacute bacterial endocarditis complicating valvular disease1 and may also to be the causative agents in various infections affecting neutropenic patients.2 There have also been reports of cases of meningitis, pneumonia, pericarditis, upper respiratory tract infections, orodental infections, peritonitis and endophthalmitis.1
Traditionally viridans streptococci have been considered to be susceptible to beta-lactam antimicrobial agents, tetracyclines and macrolides, but in recent years the prevalence of antibiotic resistance has increased.3, 4 This tendency began with the isolation of a few penicillin-resistant strains in patients under prolonged prophylactic treatment with this antibiotic. By the end of the 1980s the large majority of these streptococci were inhibited with quantities ≤0.12 μg/ml of penicillin, and no strain was found with MIC ≥4 μg/ml.4 In a recent study in the US3 the percentage of high level resistance to penicillin (MIC ≥4 μg/ml) in strains isolated in blood in 1993 and 1994 reached 13%.
Streptococcus mitis, one of the species included in the viridans group, is the most resistant to beta-lactams of the group. We present a case of urinary tract infection by a strain of S. mitis with high level resistance to penicillin (MIC = 32 μg/ml) in a patient receiving prophylaxis with cephalexin for urinary infection.
The patient was a 4-year-old girl with right Grade II and left Grade III vesicoureteral reflux and two previous well-documented episodes of urinary tract infection by Escherichia coli. The first, at the age of 7 months, was treated with cephalexin (125 mg/6 h) for 1 week, after which prophylaxis with trimethoprim-sulfamethoxazole (32/160 mg/day) was commenced. The second, at the age of 3 years, required hospital admission and was treated with cephalexin (250 mg/6 h). After this episode prophylaxis was changed to cephalexin (250 mg/day). At 4 years of age she presented with fever of up to 39°C, vomiting and general malaise, for which she was referred to our hospital where urine culture was performed and empiric treatment with amoxicillin-clavulanic acid (125/31.25 mg/8 h) was commenced. At 48 h after initiation of treatment, temperature returned to normal and symptoms disappeared.
In the urine culture the blood agar plate showed growth of nearly 105 colony-forming units/ml of an alpha-hemolytic bacterium, which failed to grow in MacConkey agar. The Gram-stained smear showed Gram-positive cocci grouped in short chains. The catalase test was negative. The microorganism was identified with the API 20 Strep® and Rapid ID 32 Strep® galleries (BioMerieux, France) as S. mitis. An antibiogram performed by the agar diffusion method failed to show an inhibition zone around the disks of penicillin G and ampicillin. The MICs determined by the agar dilution method were 32 μg/ml for penicillin G, 64 μg/ml for ampicillin, 32 μg/ml for amoxicillin and cefuroxime, 8 μg/ml for cefotaxime and 0.75 μg/ml for imipenem. No relapse was reported during the next 2 months. A control culture performed 1 month later was negative.
S. mitis has been implicated as the etiologic agent in urinary infections. A study of 242 strains of streptococci causing urinary tract infection showed that 1.2% belonged to this species.5
Very few strains with such a high MIC for penicillin have been described. Venditti et al.4 found no strain of S. mitis with MIC >4 μg/ml. McWhinney et al.2 found that 90% of the viridans streptococci strains studied were inhibited with 4 μg/ml of penicillin. In a very recent study only 3 of 352 streptococci of the viridans group isolated from blood presented MICs ≥32 μg/ml for penicillin.3
Resistance to beta-lactams in streptococci of the viridans group is associated with diminished affinity for penicillin-binding proteins because of structural changes in the latter.6 Sustained prophylaxis with cephalexin, an antibiotic with little affinity for the penicillin-binding proteins of these microorganisms, could have brought about a continuous selection of strains with resistance to penicillins and cephalosporins.
The high level of resistance of the strain isolated was not, in this case, clinically significant. The high concentrations of amoxicillin habitually reached in urine (300 to 1300 μg/ml) made this antibiotic therapeutically useful in spite of the high MIC. The implication of strains with this resistance phenotype in infections in other sites could lead to serious therapeutic problems.
Emergence of viridans streptococci highly resistant to penicillin is a cause for concern. The growing use of cephalosporins with little affinity for the penicillin-binding proteins of these bacteria will lead to an increase in the number of strains with resistance to penicillins and cephalosporins, some of which will presumably be involved in clinically significant infections.
Jesús Oteo, M.D.
José Avilla, M.D.
Juan-Ignacio Alós, Ph.D.
José-Luis Gómez-Garcés, M.D., Ph.D.
Departments of Microbiology (JO, JIA, JLGG); and Pediatrics (JA); Hospital de Móstoles; Madrid, Spain
1. Johnson CC, Tunkel AR. Viridans streptococci and groups C and G streptococci. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. New York: Churchill Livingstone, 1995:1845-57.
2. McWhinney PHM, Patel S, Whiley RA, Hardie JM, Gillespie SH, Kibbler CC. Activities of potential therapeutic and prophylactic antibiotics against blood culture isolates of viridans group streptococci from neutropenic patients receiving ciprofloxacin. Antimicrob Agents Chemother 1993;37:2493-5.
3. Doern GV, Ferraro MJ, Brueggemann AB, Ruoff KL. Emergence of high rates of antimicrobial resistance among viridans group streptococci in the United States. Antimicrob Agents Chemother 1996;40:891-4.
4. Venditti M, Baiocchi P, Santini C, et al. Antimicrobial susceptibilities of Streptococcus
species that cause septicemia in neutropenic patients. Antimicrob Agents Chemother 1989;33:580-2.
5. Collins LE, Clarke RW, Markell R. Streptococci as urinary pathogens. Lancet 1986;2:479-81.
6. Quinn JP, Divincenzo CA, Lucks DA, Luskin RL, Shatzer KL, Lerner SA. Serious infections due to penicillin resistant strains of viridans streptococci with altered penicillin-binding proteins. J Infect Dis 1988;157:764-9.