John R. Lonks

Failure of Macrolide Antibiotic Treatment in Patients with Bacteremia Due to Erythromycin-Resistant Streptococcus pneumoniae

The rate of macrolide resistance among Streptococcus pneumoniae is increasing, but some investigators have questioned its clinical relevance. We conducted a matched case-control study of patients with bacteremic pneumococcal infection at 4 hospitals to determine whether development of breakthrough bacteremia during macrolide treatment was related to macrolide susceptibility of the pneumococcal isolate. Case patients (n=86) were patients who had pneumococcal bacteremia and an isolate that was either resistant or intermediately resistant to erythromycin. Controls (n=141) were patients matched for age, sex, location, and year that bacteremia developed who had an erythromycin-susceptible pneumococcus isolated. Excluding patients with meningitis, 18 (24%) of 76 case patients and none of 136 matched controls were taking a macrolide when blood was obtained for culture (P=.00000012). Moreover, 5 (24%) of 21 case patients with the low-level-resistant M phenotype and none of 40 controls were taking a macrolide (P=.00157). These data show that development of breakthrough bacteremia during macrolide or azalide therapy is more likely to occur among patients infected with an erythromycin-resistant pneumococcus, and they also indicate that in vitro macrolide resistance resulting from both the efflux and methylase mechanisms is clinically relevant.

Hidden epidemic of macrolide-resistant pneumococci.

Community-acquired respiratory tract infections (RTIs) account for a substantial proportion of outpatient antimicrobial drug prescriptions worldwide. Concern over the emergence of multidrug resistance in pneumococci has largely been focused on penicillin-resistant Streptococcus pneumoniae. Macrolide antimicrobial drugs have been widely used to empirically treat community-acquired RTIs because of their efficacy in treating both common and atypical respiratory pathogens, including S. pneumoniae. However, increased macrolide use has been associated with a global increase in pneumococcal resistance, which is leading to concern over the continued clinical efficacy of the macrolides to treat community-acquired RTIs. We provide an overview of macrolide-resistant S. pneumoniae and assess the impact of this resistance on the empiric treatment of community-acquired RTIs.

Telithromycin: A Ketolide Antibiotic for Treatment of Respiratory Tract Infections

Telithromycin, a recently approved ketolide antibiotic derived from 14-membered macrolides, is active against erythromycin-resistant pneumococci. Telithromycin has enhanced activity in vitro because it binds not only to domain V of ribosomal RNA (like macrolides do) but also to domain II. However, it is not active against streptococci and staphylococci with constitutive macrolide, lincosamide, and streptogramin B resistance. Telithromycin, available in an oral formulation, is approved by the US Food and Drug Administration for use in adults for treatment of (1) community-acquired pneumonia due to Streptococcus pneumoniae (including multidrug-resistant isolates), Haemophilus influenzae, Moraxella catarrhalis, Chlamydia pneumoniae, or Mycoplasma pneumoniae; (2) acute exacerbation of chronic bronchitis due to S. pneumoniae, H. influenzae, or M. catarrhalis; or (3) acute bacterial sinusitis due to S. pneumoniae, H. influenzae, M. catarrhalis, or methicillin- and erythromycin-susceptible Streptococcus aureus. It is not approved for treatment of tonsillitis, pharyngitis, or severe pneumococcal pneumonia. Unique visual adverse effects occurred in 0.27%-2.1% of patients receiving telithromycin therapy. Its enhanced activity against some common respiratory pathogens makes it a valuable addition to the available macrolides.

High rate of erythromycin and clarithromycin resistance among Streptococcus pneumoniae isolates from blood cultures from Providence, R.I.

Four (5%) of 81 recent isolates of Streptococcus pneumoniae from the blood of adult patients but no isolates from pediatric patients (n = 51) were resistant (MIC, > or = 1 microgram/ml) to erythromycin. The MICs of clarithromycin were slightly lower than those of erythromycin, but there was complete cross-resistance. Routine testing and surveillance are needed to determine whether erythromycin resistance among S. pneumoniae isolates is increasing throughout the United States.

The growing threat of antibiotic-resistant streptococcus pneumoniae

Resistance to penicillin has spread worldwide during the past 25 years. Strains resistant to alternative antibiotics have also emerged. Strains resistant to multiple antibiotics increasingly are isolated worldwide. Recently, isolates of penicillin-resistant S. pneumoniae resistant to cefotaxime and ceftriaxone have caused meningitis. As a result, recommendations for the empiric therapy of pneumococcal infections, especially meningitis, are changing.

Extragenital Infections Caused by Chlamydia trachomatis and Neisseria gonorrhoeae: A Review of the Literature

In the United States, sexually transmitted diseases due to Chlamydia trachomatis and Neisseria gonorrhoeae continue to be a major public health burden. Screening of extragenital sites including the oropharynx and rectum is an emerging practice based on recent studies highlighting the prevalence of infection at these sites. We reviewed studies reporting the prevalence of extragenital infections in women, men who have sex with men (MSM), and men who have sex only with women (MSW), including distribution by anatomical site. Among women, prevalence was found to be 0.6–35.8% for rectal gonorrhea (median reported prevalence 1.9%), 0–29.6% for pharyngeal gonorrhea (median 2.1%), 2.0–77.3% for rectal chlamydia (median 8.7%), and 0.2–3.2% for pharyngeal chlamydia (median 1.7%). Among MSM, prevalence was found to be 0.2–24.0% for rectal gonorrhea (median 5.9%), 0.5–16.5% for pharyngeal gonorrhea (median 4.6%), 2.1–23.0% for rectal chlamydia (median 8.9%), and 0–3.6% for pharyngeal chlamydia (median 1.7%). Among MSW, the prevalence was found to be 0–5.7% for rectal gonorrhea (median 3.4%), 0.4–15.5% for pharyngeal gonorrhea (median 2.2%), 0–11.8% for rectal chlamydia (median 7.7%), and 0–22.0% for pharyngeal chlamydia (median 1.6%). Extragenital infections are often asymptomatic and found in the absence of reported risk behaviors, such as receptive anal and oral intercourse. We discuss current clinical recommendations and future directions for research.

Candida and cardiovascular implantable electronic devices: A case of lead and native aortic valve endocarditis and literature review

Use of cardiovascular implantable electronic devices (CIED), including permanent pacemakers (PPM) and implantable cardioverter defibrillators (ICD), has increased dramatically over the past two decades. Most CIED infections are caused by staphylococci. Fungal causes are rare and their prognosis is poor. To our knowledge, there has not been a previously reported case of multifocal Candida endocarditis involving both a native left‐sided heart valve and a CIED lead. Here, we report the case of a 70‐year‐old patient who presented with nausea, vomiting, and generalised fatigue, and was found to have Candida glabrata endocarditis involving both a native aortic valve and right atrial ICD lead. We review the literature and summarise four additional cases of CIED‐associated Candida endocarditis published from 2009 to 2014, updating a previously published review of cases prior to 2009. We additionally review treatment guidelines and discuss management of CIED‐associated Candida endocarditis.

Structural and Regulatory Changes in PBP4 Trigger Decreased β-Lactam Susceptibility in Enterococcus faecalis

ABSTRACT Enterococcus faecalis strains resistant to penicillin and ampicillin are rare and have been associated with increases in quantities of low-affinity penicillin-binding protein 4 (PBP4) or with amino acid substitutions in PBP4. We report an E. faecalis strain (LS4828) isolated from a prosthetic knee joint that was subjected to long-term exposure to aminopenicillins. Subsequent cultures yielded E. faecalis with MICs of penicillins and carbapenems higher than those for wild-type strain E. faecalis JH2-2. Sequence analysis of the pbp4 gene of LS4828 compared to that of JH2-2 revealed two point mutations with amino acid substitutions (V223I, A617T) and deletion of an adenine from the region upstream of the predicted pbp4 −35 promoter sequence (UP region). Purified PBP4 from LS4828 exhibited less affinity for Bocillin FL than did PBP4 from JH2-2, which was recapitulated by purified PBP4 containing only the A617T mutation. Differential scanning fluorimetry studies showed that the LS4828 and A617T variants are destabilized compared to wild-type PBP4. Further, reverse transcription-PCR indicated increased transcription of pbp4 in LS4828 and Western blot analysis with polyclonal PBP4 antibody revealed greater quantities of PBP4 in LS4828 than in JH2-2 lysates and membrane preparations. Placing the promoter regions from LS4828 or JH2-2 upstream of a green fluorescent protein reporter gene confirmed that the adenine deletion was associated with increased transcription. Together, these data suggest that the reduced susceptibility to β-lactam antibiotics observed in E. faecalis LS4828 results from a combination of both increased expression and remodeling of the active site, resulting in reduced affinity for penicillins and carbapenems. IMPORTANCE Enterococcus faecalis is an important cause of community-acquired and nosocomial infections and creates therapeutic dilemmas because of its frequent resistance to several classes of antibiotics. We report an E. faecalis strain with decreased ampicillin and imipenem susceptibility isolated after prolonged courses of aminopenicillin therapy for a prosthetic joint infection. Its reduced susceptibility is attributable to a combination of increased quantities of low-affinity PBP4 and an amino acid substitution in proximity to the active site that destabilizes the protein. Our findings provide a cautionary tale for clinicians who elect to “suppress” infections in prosthetic joints and offer novel insights into the interaction of β-lactam antibiotics with low-affinity PBP4. These insights will help inform future efforts to develop therapeutics capable of inhibiting clinical enterococcal strains. Enterococcus faecalis is an important cause of community-acquired and nosocomial infections and creates therapeutic dilemmas because of its frequent resistance to several classes of antibiotics. We report an E. faecalis strain with decreased ampicillin and imipenem susceptibility isolated after prolonged courses of aminopenicillin therapy for a prosthetic joint infection. Its reduced susceptibility is attributable to a combination of increased quantities of low-affinity PBP4 and an amino acid substitution in proximity to the active site that destabilizes the protein. Our findings provide a cautionary tale for clinicians who elect to “suppress” infections in prosthetic joints and offer novel insights into the interaction of β-lactam antibiotics with low-affinity PBP4. These insights will help inform future efforts to develop therapeutics capable of inhibiting clinical enterococcal strains.

Rare but not forgotten: A case of meningitis due to ceftriaxone-resistant Streptococcus pneumoniae

Despite the dramatic decrease in invasive pneumococcal disease since the widespread use of the first pneumococcal vaccine, invasive and resistant disease still occurs. We present a case of ceftriaxone-resistant pneumococcal meningitis suggesting that continued vigilance is warranted for empiric treatment of meningitis when Streptococcus pneumoniae is a concern.