Identifying transmission routes of Streptococcus pneumoniae and sources of acquisitions in high transmission communities.

Identifying the transmission sources and reservoirs of Streptococcus pneumoniae (SP) is a long-standing question for pneumococcal epidemiology, transmission dynamics, and vaccine policy. Here we use serotype to identify SP transmission and examine acquisitions (in the same household, local community, and county, or of unidentified origin) in a longitudinal cohort of children and adults from the Navajo Nation and the White Mountain Apache American Indian Tribes. We found that adults acquire SP relatively more in the household than other age groups, and children 2-8 years old typically acquire in their own or surrounding communities. Age-specific transmission probability matrices show that transmissions within household were mostly seen from older to younger siblings. Outside the household, children most often transmit to other children in the same age group, showing age-assortative mixing behavior. We find toddlers and older children to be most involved in SP transmission and acquisition, indicating their role as key drivers of SP epidemiology. Although infants have high carriage prevalence, they do not play a central role in transmission of SP compared with toddlers and older children. Our results are relevant to inform alternative pneumococcal conjugate vaccine dosing strategies and analytic efforts to inform optimization of vaccine programs, as well as assessing the transmission dynamics of pathogens transmitted by close contact in general.

Mutations within the rplD Gene of Linezolid-Nonsusceptible Streptococcus pneumoniae Strains Isolated in the United States.

Three invasive Streptococcus pneumoniae strains nonsusceptible to linezolid were isolated in the United States between 2001 and 2012 from the CDC's Active Bacterial Core surveillance. Linezolid binds ribosomal proteins where structural changes within its target site may confer resistance. Our study identified mutations and deletions near the linezolid binding pocket of two of these strains within the rplD gene, which encodes ribosomal protein L4. Mutations in the 23S rRNA alleles or the rplV gene were not detected.

Estimating the prevalence of coinfection with influenza virus and the atypical bacteria Bordetella pertussis, Chlamydophila pneumoniae, and Mycoplasma pneumoniae.

Coinfections with common bacterial respiratory pathogens and influenza viruses are well-known causes of disease, often via synergistic interactions between the influenza virus, the bacteria, and the human host. However, relatively little is known about interactions between atypical bacteria and influenza viruses. A recent report by Reinton et al. explored this issue by analyzing data from 3,661 patients seeking medical assistance for the presence of Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Bordetella pertussis, as well as influenza A or B virus in nasal swab specimens. The report, however, did not accurately assess the epidemiologic interactions of these pathogens. We aimed to describe the interactions between these bacterial species and influenza infections. Strong and highly statistically significant antagonistic interspecies interactions were detected between C. pneumoniae and influenza virus [odds ratio (OR): 0.09; p < 0.0001) and M. pneumoniae and influenza virus infections (OR: 0.29; p = 0.003). No association was detected between B. pertussis and influenza infection (p = 0.34), contrary to the initial report, and coinfection was not detected at a higher-than-by-chance frequency within the population. Further support of these results is supplied by the analysis of two earlier investigations reporting data on influenza virus and these atypical bacteria. Our results supplement the large body of literature regarding interactions between influenza virus and typical respiratory pathogens, providing a fuller picture of the spectrum of interactions between influenza viruses and respiratory bacteria. Further, we demonstrate the importance of choosing the most appropriate reference populations for the analysis being performed and describe the pitfalls that may occur when care is not taken in this regard.

Use of a rapid test of pneumococcal colonization density to diagnose pneumococcal pneumonia.

BACKGROUND: There is major need for a more sensitive assay for the diagnosis of pneumococcal community-acquired pneumonia (CAP). We hypothesized that pneumococcal nasopharyngeal (NP) proliferation may lead to microaspiration followed by pneumonia. We therefore tested a quantitative lytA real-time polymerase chain reaction (rtPCR) on NP swab samples from patients with pneumonia and controls. METHODS: In the absence of a sensitive reference standard, a composite diagnostic standard for pneumococcal pneumonia was considered positive in South African human immunodeficiency virus (HIV)-infected adults hospitalized with radiographically confirmed CAP, if blood culture, induced good-quality sputum culture, Gram stain, or urinary Binax demonstrated pneumococci. Results of quantitative lytA rtPCR in NP swab samples were compared with quantitative colony counts in patients with CAP and 300 HIV-infected asymptomatic controls. RESULTS: Pneumococci were the leading pathogen identified in 76 of 280 patients with CAP (27.1%) using the composite diagnostic standard. NP colonization density measured by lytA rtPCR correlated with quantitative cultures (r = 0.67; P < .001). The mean lytA rtPCR copy number in patients with pneumococcal pneumonia was 6.0 log(10) copies/mL, compared with patients with CAP outside the composite standard (2.7 log(10) copies/mL; P < .001) and asymptomatic controls (0.8 log(10) copies/mL; P < .001). A lytA rtPCR density ≥8000 copies/mL had a sensitivity of 82.2% and a specificity of 92.0% for distinguishing pneumococcal CAP from asymptomatic colonization. The proportion of CAP cases attributable to pneumococcus increased from 27.1% to 52.5% using that cutoff. CONCLUSIONS: A rapid molecular assay of NP pneumococcal density performed on an easily available specimen may significantly increase pneumococcal pneumonia diagnoses in adults.

Colony morphology of piliated Neisseria meningitidis.

An association between piliation and colony morphology has not been observed for the meningococcus. We have found that growth of meningococci overnight at 30 degrees C in a candle extinction jar allows observation of distinct colonial phenotypes correlated to the presence or absence of piliation and the expression of opacity-associated proteins. These phenotypes are similar to those observed in gonococci grown overnight at 37 degrees C.

Association of serotypes of Streptococcus pneumoniae with disease severity and outcome in adults: an international study.

BACKGROUND: The introduction of conjugate pneumococcal vaccination for children has reduced the burden of invasive disease due to pneumococcal conjugate vaccine (PCV) types (i.e., serotypes 9V, 14, 6B, 18C, 23F, 19F, and 4) in adults. As nonvaccine serotypes become predominant causes of invasive disease among adults, it is necessary to evaluate the disease severity and mortality associated with infection due to nonvaccine serotypes, compared with PCV serotypes, in adults. METHODS: The association of pneumococcal serotype and host-related variables with disease severity and mortality was statistically examined (with multivariable analysis) in 796 prospectively enrolled, hospitalized adult patients with bacteremia due to Streptococcus pneumoniae. RESULTS: In multivariate analyses of risk in patients with invasive pneumococcal disease, older age (age, > or = 65 years; P = .004), underlying chronic disease (P = .025), immunosuppression (P = .035), and severity of disease (P < .001) were significantly associated with mortality; no association was found between nosocomial infection with invasive serotypes 1, 5, and 7 and mortality. The risk factors meningitis (P = .001), suppurative lung complications (P < or = .001), and preexisting lung disease (P = .051) were significantly associated with disease severity, independent of infecting serotype. No differences were seen in disease severity or associated mortality among patients infected with PCV serotypes, compared with patients infected with nonvaccine serotypes. CONCLUSIONS: Our data support the notion that host factors are more important than isolate serotype in determining the severity and outcome of invasive pneumococcal disease and that these outcomes are unlikely to change in association with nonvaccine serotype infection in the post-conjugate vaccine era.

Management of community-acquired pneumonia in the era of pneumococcal resistance: a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group.

OBJECTIVE: To provide recommendations for the management of community-acquired pneumonia and the surveillance of drug-resistant Streptococcus pneumoniae (DRSP). METHODS: We addressed the following questions: (1) Should pneumococcal resistance to beta-lactam antimicrobial agents influence pneumonia treatment? (2) What are suitable empirical antimicrobial regimens for outpatient treatment of community-acquired pneumonia in the DRSP era? (3) What are suitable empirical antimicrobial regimens for treatment of hospitalized patients with community-acquired pneumonia in the DRSP era? and (4) How should clinical laboratories report antibiotic susceptibility patterns for S pneumoniae, and what drugs should be included in surveillance if community-acquired pneumonia is the syndrome of interest? Experts in the management of pneumonia and the DRSP Therapeutic Working Group, which includes clinicians, academicians, and public health practitioners, met at the Centers for Disease Control and Prevention in March 1998 to discuss the management of pneumonia in the era of DRSP. Published and unpublished data were summarized from the scientific literature and experience of participants. After group presentations and review of background materials, subgroup chairs prepared draft responses, which were discussed as a group. CONCLUSIONS: When implicated in cases of pneumonia, S pneumoniae should be considered susceptible if penicillin minimum inhibitory concentration (MIC) is no greater than 1 microg/mL, of intermediate susceptibility if MIC is 2 microg/ mL, and resistant if MIC is no less than 4 microg/mL. For outpatient treatment of community-acquired pneumonia, suitable empirical oral antimicrobial agents include a macrolide (eg, erythromycin, clarithromycin, azithromycin), doxycycline (or tetracycline) for children aged 8 years or older, or an oral beta-lactam with good activity against pneumococci (eg, cefuroxime axetil, amoxicillin, or a combination of amoxicillin and clavulanate potassium). Suitable empirical antimicrobial regimens for inpatient pneumonia include an intravenous beta-lactam, such as cefuroxime, ceftriaxone sodium, cefotaxime sodium, or a combination of ampicillin sodium and sulbactam sodium plus a macrolide. New fluoroquinolones with improved activity against S pneumoniae can also be used to treat adults with community-acquired pneumonia. To limit the emergence of fluoroquinolone-resistant strains, the new fluoroquinolones should be limited to adults (1) for whom one of the above regimens has already failed, (2) who are allergic to alternative agents, or (3) who have a documented infection with highly drug-resistant pneumococci (eg, penicillin MIC > or =4 microg/mL). Vancomycin hydrochloride is not routinely indicated for the treatment of community-acquired pneumonia or pneumonia caused by DRSP.

Impact of the Hajj on pneumococcal transmission.

Over two million Muslim pilgrims assemble annually in Mecca and Medina, Saudi Arabia, to complete the Hajj. The large number of people in a crowded environment increases the potential for pneumococcal carriage amplification. We evaluated pneumococcal carriage prevalence with four cross-sectional studies conducted at beginning-Hajj (Mecca) and end-Hajj (Mina) during 2011 and 2012. A questionnaire was administered and a nasopharyngeal swab was collected. The swab was tested for pneumococcus, serotype and antibiotic resistance. A total of 3203 subjects (1590 at beginning-Hajj and 1613 at end-Hajj) originating from 18 countries in Africa or Asia were enrolled. The overall pneumococcal carriage prevalence was 6.0%. There was an increase in carriage between beginning-Hajj and end-Hajj cohorts for: overall carriage (4.4% versus 7.5%, prevalence ratio (PR) 1.7, 95% CI 1.3-2.3), and carriage of 23-valent pneumococcal polysaccharide vaccine serotypes (2.3% versus 4.1%, PR 1.8, 95% CI 1.2-2.7), 13-valent pneumococcal conjugate vaccine (PCV) serotypes (1.1% versus 3.6%, PR 3.2, 95% CI 1.9-5.6), 10-valent PCV serotypes (0.6% versus 1.6%, PR 2.6, 95% CI 1.2-5.3), antibiotic non-susceptible isolates (2.5% versus 6.1%, PR 2.5, 95% CI 1.7-3.6) and multiple non-susceptible isolates (0.6% versus 2.2%, PR 3.8, 95% CI 1.8-7.9). Fifty-two different serotypes were identified, most commonly serotypes 3 (17%), 19F (5%) and 34 (5%). These results suggest that the Hajj may increase pneumococcal carriage-particularly conjugate vaccine serotypes and antibiotic non-susceptible strains, although the exact mechanism remains unknown. The Hajj may therefore provide a mechanism for the global distribution of pneumococci.

Efficacy of pneumococcal conjugate vaccines and their effect on carriage and antimicrobial resistance.

Pneumococcal conjugate vaccines have shown a high degree of success in preventing pneumococcal bacteraemia in children. They also reduce the acquisition of carriage of vaccine serotypes in the nasopharynx, and reduce otitis media caused by those serotypes. Non-vaccine serotypes, which can colonise vaccinated infants, are associated with otitis media in these children and lower the overall effectiveness of the vaccine to this disorder. Longer term studies, however, could show that immunised children develop immunity to a broad range of pneumococcal serotypes at a younger age than non-immunised children. Preliminary data suggest that these vaccines could reduce the burden of radiologically confirmed pneumonia. Pneumococcal conjugate vaccines interrupt the transmission of antibiotic-resistant pneumococci and thus decrease the burden of antibiotic resistance in immunised children and in their contacts. Studies are underway to assess conjugate vaccine efficacy against invasive disease, pneumonia, and all-cause mortality in developing countries, and to assess the potential use of these vaccines in adults.

Substance P increases hypothalamic blood flow via an indirect adrenergic-cholinergic interaction.

1 Hypothalamic blood flow (HBF) was measured in conscious rabbits by the 133xenon washout technique. 2 Substance P in a dose of 50 or 500 ng increases HBF while 5 ng is without effect. 3 Cholinoceptor blockade, with either atropine or mecamylamine abolishes the vasodilator effect of substance P. 4 Chemical sympathectomy of the hypothalamus with 6-hydroxydopamine, or adrenoceptor blockade with either propranolol or phenoxybenzamine abolishes the effect of substance P on HBF. 5 Destruction of the intracerebral noradrenergic pathway (INP), or blockade of its vasodilator action, with barbiturate or bicarbonate, likewise prevent the vasodilator action of substance P. 6 These results suggest that substance P may cause an increase in HBF via the release of endogenous acetylcholine, which in turn stimulates the INP.

Penicillin- and cephalosporin-resistant Streptococcus pneumoniae. Emerging treatment for an emerging problem.

The global emergence of pneumococci resistant to antimicrobial therapy has led to dilemmas in the management of pneumococcal infections. The principles of pharmacodynamics predict that penicillin and cephalosporin therapy of pneumonia will be successful against pneumococci with minimum inhibitory concentrations of penicillin up to 4 micrograms/ml. These predictions are supported by the observations of a number of recent clinical studies. Otitis media therapy is influenced by penicillin-resistance and current recommendations are that amoxicillin is the drug of choice for this infection, given at a double dose of 80 to 90 mg/kg/day. For the therapy of meningitis, cefotaxime or ceftriaxone in maximal doses is recommended and vancomycin may be added if cephalosporin-resistant strains are encountered with reasonable frequency in the population. The new fluoroquinolones with excellent antipneumococcal activity may be considered for use in the setting of pneumonia caused by highly resistant pneumococci and are under evaluation for the management of meningitis.

Bacteremic pneumococcal pneumonia in HIV-seropositive and HIV-seronegative adults.

STUDY OBJECTIVES: To compare the demographic, clinical, laboratory, and microbiological data, and the hospital course and outcome of HIV-seropositive and HIV-seronegative adults with bacteremic pneumococcal pneumonia. DESIGN: Retrospective observation study conducted over a 2-year period. SETTING: Academic teaching hospital attached to the University of the Witwatersrand, Johannesburg, South Africa. PATIENTS: Consecutive patients with bacteremic pneumococcal pneumonia were identified on the basis of positive blood culture results. INTERVENTIONS: All available demographic, clinical, routine laboratory, radiographic, and microbiological data were recorded retrospectively for each of the patients, and the combined data for the HIV-seropositive patients were compared with those of the HIV-seronegative patients. MEASUREMENT AND RESULTS: A total of 112 patients (31 HIV-seropositive and 81 HIV-seronegative patients) were entered into the study. The HIV-seropositive patients were significantly younger than the HIV-seronegative patients (32.8 vs 39.6 years old) and had lower admission hemoglobin (11.8 vs 13.4 g/dL), WBC count (10.3 vs 14.3 x 10(9)/L), serum albumin (31 vs 36 g/L), sodium (129 vs 132 mmol/L), and potassium (3.0 vs 3.5 mmol/L), respectively. Although the HIV-seropositive patients appeared to have more multilobar pulmonary consolidation on the chest radiograph than the HIV-seronegative patients (60% vs 34%), this did not quite reach statistical significance. In addition, the HIV-seropositive patients had significantly more infections (48.4% vs 20.8%) with pneumococcal serogroups/serotypes (serogroups 6, 19, 23, and serotype 14) that are found more commonly in children, and they also had more penicillin-resistant isolates (13% vs 2.5%) than the HIV-seronegative patients, respectively. Similarly, it was noted that when these data were analyzed according to gender (irrespective of HIV status), women had significantly more infections than men (47% vs 21%) with serogroups/serotypes that are usually found in children, more penicillin-resistant isolates (15% vs 1%), and more co-trimoxazole-resistant isolates (21% vs 5%), respectively. There were no differences noted in any of the other parameters, including initial APACHE (acute physiology and chronic health evaluation) II score, PaO2/fraction of inspired oxygen ratio, duration of temperature, duration of IV therapy, duration of hospitalization, complications, and outcome, when comparing HIV-seropositive and HIV-seronegative patients. Two patients in each group died. CONCLUSIONS: The clinical features of bacteremic pneumococcal pneumonia are similar in HIV-seropositive and HIV-seronegative patients. Although differences are noted in various laboratory and microbiological parameters, they do not appear to have an impact on outcome.

Neonatal typhoid fever.

Typhoid fever occurs in children less than 2 years of age but is thought to be a mild, often unrecognized illness. Neonatal typhoid fever is a rare but often life-threatening illness, uniformly fatal in the preantibiotic era. Vertical intrauterine transmission from a typhoid-infected mother is implicated in neonatal typhoid fever. Ten cases at a rural African hospital are presented. Three patients died with two deaths associated with empiric management inappropriate for Salmonella typhi. A second clinical presentation in the neonate is asymptomatic persistent excretion. Infants < or = 3 weeks old may also be infected from an exogenous source and have severe disease. Where typhoid is endemic S. typhi should be considered as a cause of sepsis neonatorum and appropriate antibiotics included in empiric therapy.

Impact of human immunodeficiency virus type 1 on the disease spectrum of Streptococcus pneumoniae in South African children.

BACKGROUND: HIV-infected children are at increased risk of developing invasive Streptococcus pneumoniae disease. OBJECTIVE: To determine the impact of the HIV epidemic on the epidemiology of invasive pneumococcal disease in hospitalized African children. METHODS: Children <12 years of age with invasive pneumococcal disease were enrolled between March, 1997, and February, 1999. RESULTS: The seroprevalence of HIV was 64.9% (146 of 225). In children with pneumococcal isolates from serogroups 6, 9, 14, 19 or 23 (pediatric serogroups), pneumonia and pneumonia with concurrent meningitis was more common in HIV-infected children (P = 0.03 and P = 0.003, respectively), whereas septic shock occurred more often in HIV-uninfected children (P = 0.0003). The overall burden of severe invasive pneumococcal disease was 41.7 (95% confidence interval, 26.5 to 65.6) fold increased in HIV-infected compared with HIV-uninfected children. Reduced susceptibility to penicillin (45.91% vs. 27.9%, P = 0.009), trimethoprim-sulfamethoxazole (44.5% vs. 19.0%, P = 0.0002) and multiple drug resistance was more common in HIV-infected than in HIV-uninfected children (24.0% vs. 6.4%, P = 0.01), respectively. The increased burden of disease and reduced antibiotic susceptibility of pneumococcal isolates in HIV-infected children was because of a heightened susceptibility to disease caused by pediatric serogroups in these children than in HIV-uninfected children (P = 0.01). Although the case fatality rates did not differ between HIV-infected and -uninfected children, mortality in HIV-infected children with advanced AIDS (Stage C, 22 of 61; 36.1%) was greater than that in children with moderate AIDS (Stage B, 12 of 85; 14.1%, P = 0.002). CONCLUSIONS: In children with invasive pneumococcal disease caused by the pediatric serogroups, HIV-infected children have more antibiotic-resistant isolates and have a different clinical presentation than do HIV-uninfected children.

Differing manifestations of respiratory syncytial virus-associated severe lower respiratory tract infections in human immunodeficiency virus type 1-infected and uninfected children.

BACKGROUND: Respiratory syncytial virus (RSV) causes increased morbidity and mortality in immunocompromised children. The outcome of RSV-associated lower respiratory tract infections (LRTI) in HIV-infected children, is less well described. METHODS: Children from a prospective study evaluating the etiology of

Antimicrobial resistance of nasopharyngeal isolates of Streptococcus pneumoniae and Haemophilus influenzae from children in the Central African Republic.

BACKGROUND: To assist the Central African Republic (CAR) develop national guidelines for treating children with pneumonia, a survey was conducted to determine antimicrobial resistance rates of nasopharyngeal isolates of Streptococcus pneumoniae (SP) and Haemophilus influenzae (HI). Secondary purposes of the survey were to identify risk factors associated with carriage of a resistant isolate and to compare the survey methods of including only children with pneumonia vs. including all ill children. METHODS: A cross-sectional survey of 371 ill children was conducted at 2 outpatient clinics in Bangui, CAR. RESULTS: In all 272 SP isolates and 73 HI isolates were cultured. SP resistance rates to penicillin, trimethoprim-sulfamethoxazole (TMP-SMX), tetracycline and chloramphenicol were 8.8, 6.3, 42.3 and 9.2%, respectively. All penicillin-resistant SP isolates were intermediately resistant. HI resistance rates to ampicillin, TMP-SMX and chloramphenicol were 1.4, 12.3 and 0%, respectively. The most common SP serotypes/groups were 19, 14, 6 and 1; 49% of HI isolates were type b. History of antimicrobial use in the previous 7 days was the only factor associated with carriage of a resistant isolate. Resistance rates were similar among ill children regardless of whether they had pneumonia. CONCLUSIONS: Resistance rates were low for antimicrobials recommended by the World Health Organization for children with pneumonia. We recommended TMP-SMX as the first line treatment for pneumonia in CAR because of its low cost, ease of dosing and activity against malaria.

Antibiotic-resistant pneumococci in pediatric disease.

The surveillance of pneumococcal resistance in nasopharyngeal isolates is a practical way to determine the prevalence of resistant strains and is a reasonable predictor of resistance in systemic isolates. The increasing prevalence of resistance is shifting the distribution of invasive pneumococcal serotypes toward those included in conjugate vaccines. If these vaccines reduce carriage, they may eliminate or greatly reduce the prevalence of resistant strains. Meningitis is the most important infection caused by PRP for which penicillin or ampicillin therapy is inappropriate. Although the extended spectrum cephalosporins will be effective for most cases of PRP meningitis, it is clear that such therapy is not foolproof. It is important for the laboratory to test CSF isolates not only for penicillin resistance but also for resistance to the cephalosporins. beta-Lactam antibiotics can still be considered appropriate empiric therapy for otitis media, pneumonia, or sepsis. However, occasional treatment failures with these agents may necessitate use of alternative therapeutic strategies.

Non-Penicillin-Binding protein mediated high-level penicillin and cephalosporin resistance in a Hungarian clone of Streptococcus pneumoniae.

A clone of Hungarian pneumococcal strains has recently been isolated with notably high levels of beta-lactam resistance (penicillin MIC, 16 microg/mL; cefotaxime MIC, 4 microg/mL). The role that each penicillin-binding protein (PBP) plays in the development of resistance in these strains was investigated via transformation of susceptible strain R6 with pbp DNA from resistant strain 3191. Transformation of strain R6 with pbp2X DNA resulted in transformants with penicillin and cefotaxime MICs of 0.06 and 0.25 microg/mL, respectively. Further introduction of pbp2B and 1A DNA increased penicillin MICs to 0.25 and 4 microg/mL, respectively. Transformation of strain R6 with a combination of pbp2X and pbp1A DNA produced R63191/2X/1A strains with an unexpected low cefotaxime MIC of 0.5 microg/mL. This low-level of cefotaxime resistance was surprisingly increased from 0.5 to 2 microg/mL in R63191/2X/2B/1A strains. This suggests the involvement of altered PBP 2B in cefotaxime resistance. Therefore, within this particular setting of resistance, the environmental presence of selectors for altered PBP 2B (penicillin or piperacillin) are required for the development of high-level cefotaxime resistance. The MICs of R63191/X/2B/1A strains never reached the MICs of the donor strain. Full MICs of the donor were eventually reached by transforming R63191/2X/2B with chromosomal3191 DNA. Resultant transformants revealed the introduction of altered PBP 1A, while unaltered PBPs 1B, 2A, and 3 proved that these PBPs were not involved in resistance. A non-PBP resistance determinant has therefore made up the difference in resistance between R63191/2X/2B/1A and donor strain 3191. Beta-lactamase activity and efflux systems have so far been eliminated as causes of resistance. This resistance determinant represents a novel mechanism for beta-lactam resistance in clinical isolates of pneumococci, operates at the highest level of resistance, and remains to be identified.

The molecular mechanisms of tetracycline resistance in the pneumococcus.

Tetracycline resistance in the pneumococcus is a result of the acquisition of one of two resistance determinants, tet(M) or tet(O). These genes encode ribosomal protection proteins that have homology to the elongation factors G and Tu. Tet(M) and Tet(O) both have GTPase activity that appears to be important in the displacement of tetracycline from the ribosome. Modification of tRNA may also be important for tetracycline resistance. Transcription of tet(M) is thought to be regulated by transcriptional attenuation. Transcription of tet(O) is constitutive, however, upstream of the gene are sequences that also appear to be involved in transcriptional attenuation. tet(M) is transferred on the conjugative transposons, Tn1545 and Tn5151. It is not yet known whether tet(O) is transported on transposons or plasmids, or whether it is chromosomally integrated, in pneumococci.