VRE, MRSA, PRP, and DRGNB in LTCF: Lessons To Be Learned from This Alphabet

In this issue of JAGS, Brennen and colleagues provide one of the first published series of cases of vancomycin-resistant enterococcus/enterococci (VRE) isolated from residents in a long-term care facility (LTCF).1, 2 However, VRE has been a well-described clinical problem in the setting of nosocomial infections.3, 4 Bacteremia caused by VRE is associated with a high mortality rate.5 Moreover, patients who have VRE bacteremia appear to have a poorer prognosis than patients with blood stream infections with vancomycin-sensitive enterococci.6 In large part, this poor clinical outcome with VRE infections is a result of the unavailability of effective antibiotics against the organism and the severe clinical condition of the patient. Risk factors for VRE infection include severe underlying illness, immunosuppression, advanced age, requirement of intensive care unit treatment, prolonged hospitalization, surgical interventions, and previous exposure to antibiotics, especially vancomycin, third-generation cephalosporins, and antianaerobic agents.7-9 Interestingly, in a recent report of 89 nonhospitalized patients infected with human immunodeficiency virus (HIV) who were receiving long-term antibiotic therapy – but only one patient each receiving a cephalosporin or antianaerobic agent – there were no cases of rectal colonization with VRE.10 Enterococci were previously classified as streptococci of the Lancefield group D. There are two major pathogenic species in humans, Enterococcus faecalis and E. faecium, with occasional infections caused by E. durans. Rarely, infections are caused by E. avium; E. gallinarum is generally nonpathogenic to humans. E. faecalis is the most commonly isolated Enterococcus spp. from infections, including the vast majority of cases of enterococcal endocarditis, a disease of older people.11, 12 However, E. faecium seems to infect more severely ill patients, compared with E. faecalis, and is associated with a higher mortality rate.13 Not surprisingly, VRE strains are found more frequently in E. faecium than in other species of enterococci. Until recently, enterococci were typically susceptible to glycopeptides, i.e., vancomycin and teicoplanin, the latter drug not being commercially available in the United States. Glycopeptide-resistant enterococci are phenotypically grouped or classified as VanA, VanB, and VanC; for practical purposes VanC is not clinically relevant because it involves E. gallinarum. VanA enterococci are resistant to both vancomycin and teicoplanin and VanB strains are resistant to vancomycin but susceptible to teicoplanin.7 Resistance to glycopeptides occurs through a genetic abnormality that affects synthesis of the cell wall. Glycopeptides bind to cell wall precursors ending in alanine-alanine, which is produced by the enzyme alanine-alanine-ligase.14 VRE strains have an enzyme that is slightly different from alanine-alanine-ligase, called VanA ligase (or simply VanA), which synthesizes alanine-lactate. Vancomycin and teicoplanin cannot bind to cell wall precursors with alanine-lactate. Unfortunately, the glycopeptide resistance genes are often carried on DNA, such as transposons and plasmids, which can be spread easily from one organism to another. See also p 157 Most persons with VRE who live in LTCF are simply colonized and do not have a true infection; this is similar to LTCF residents harboring methicillin-resistant Staphylococcus aureus (MRSA). These colonized individuals do not require antibiotic therapy. However, residents infected with VRE should receive antimicrobial therapy, preferably in an acute care facility. Unfortunately, the therapeutic options for VRE infections are extremely limited. Consequently, in vitro laboratory susceptibility testing of VRE, as well as in vitro synergy tests of antibiotics, should be used to determine appropriate antibiotic therapy. Some VRE may be susceptible to doxycycline, chloramphenicol, or novobiocin. Joshi et al. have suggested the following treatment options for serious VRE infections10: Combination of penicillin, vancomycin, and gentamicin if the organism has susceptibility to gentamicin at a minimum inhibitory concentration (MIC) of <32 μg/mL. Ciprofloxacin in combination with ampicillin, novobiocin, or rifampin if the VRE has a MIC to ciprofloxacin of <8 μg/mL. Ampicillin or teicoplanin if the organisms are susceptible and in combination with an aminoglycoside (provided MIC indicates susceptibility to the aminoglycoside). Streptogramin RP 59500 (quinupristin/dalfopristin). Although VRE has been the most recent concern of the problem of drug-resistant organisms, other pathogens with diminished or absent susceptibility to antimicrobial agents have plagued hospitals and other health care institutions, including LTCFs. Methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant pneumococci (PRP; penicillin-resistant Streptococcus pneumoniae: PRSP), and drug-resistant Gram-negative bacilli (DRGNB) have been isolated repeatedly from residents residing in LTCF.15 MRSA was first reported in nursing home residents in 1970,16 but reports of major outbreaks of MRSA colonization and infection in LTCFs appeared in the literature on numerous occasions in the late 1980s. Moreover, MRSA appeared in a variety of LTCF settings (community, Veterans Affairs (VA), large, small, adult, pediatric, urban, rural) throughout the US. In one survey of 81 LTCFs in western New York, 81% of the 75 responding facilities indicated that one or more cases of MRSA had been identified in their facility.17 Unfortunately, the majority of strains of MRSA are also resistant to all antistaphylococcal penicillins, cephalosporins, and quinolones; vancomycin remains the drug of choice for treating MRSA infections.18 MRSA colonization requires no antimicrobial therapy. In the 1990s, PRP became recognized as a prevalent and serious problem throughout the US.19, 20 Strains of pneumococci (Streptococcus pneumoniae) that have an MIC of >1.0 μg/mL are considered resistant.21 In nine CDC Active Surveillance sites during 1995–1996, 30% (range among sites: 17–39%) of all penicillin-resistant invasive pneumococcal infections occurred in persons aged 65 years and older.22 Moreover, multi-drug resistant S. pneumoniae23 have now been isolated from older residents with serious pneumococcal infections, including bacteremia, residing in an LTCF in Oklahoma.24 Three of the four residents with S. pneumoniae bacteremia died. The same resistant strains were isolated from 23% of 74 asymptomatic residents. The organism was resistant to penicillin, cefotaxime, cefaclor, erythromycin, trimethoprim-sulfamethoxazole, clindamycin, tetracycline, and chloramphenicol.24 Urinary tract infections (UTI) are the most common causes of bacteremic infections in residents of LTCF.25 The majority of UTIs in these LTCF residents are caused by Gram-negative bacilli.26, 27 However, resistance to a variety of antibiotics used commonly to treat Gram-negative bacillary infections is occurring at an alarming rate in LTCFs. Drug-resistant Gram-negative bacilli (DRGNB) in residents of LTCF have been reported for Escherichia coli against ampicillin, Klebsiella spp. against cephalosporins, and Providencia spp. against aminoglycosides; other DRGNB, including Pseudomonas aeruginosa, that are not inhibited by trimethoprim-sulfamethoxazole, aminoglycosides, and fluoroquinolones are also being isolated in increasing frequency in LTCF residents.28-31 What lessons do we learn from the knowledge that antibiotic-resistant bacteria, including multidrug-resistant organisms, are a growing phenomenon in LTCFs as well as in other health care settings? Do we stop treating infections in the LTCF setting? Should we restrict our antimicrobial armamentarium to more narrow-spectrum drugs? Do we insist on culture and antibiotic susceptibility data on every infection we treat in residents of LTCF? These and other questions will arise under these circumstances and will require thoughtful consideration and evaluation on how clinicians manage infectious diseases in LTCFs. However, clinical studies and a wealth of clinical experience have provided the following information in regard to infections in residents of LTCF31: Clinical diagnosis of infections is difficult because of atypical and nonspecific clinical features; thus, the diagnosis may be delayed and/or identification of a specific site of infection is often difficult. In frail older residents, clinical specimens for culture and sensitivity are often difficult or impossible to obtain. Moreover, many LTCFs are not equipped to collect or process such diagnostic samples. Hence, the majority of infections in LTCF settings are treated empirically. Common infections in a LTCF setting, i.e., pneumonia, UTI, and skin/soft tissue infections are caused by staphylococci, streptococci, Gram-negative bacilli, anaerobic bacteria, or mixed organisms. The mortality rates of infections in LTCF residents are especially high. Thus, it is not surprising that residents of LTCFs who are suspected of having a serious infection are often treated empirically – and most appropriately in the majority of cases – with a broad-spectrum antibiotic, either in the LTCF or in the acute care facility. Once microbiological data become available, assuming they are obtainable, antimicrobial therapy is then adjusted as deemed appropriate. If this approach is accepted “standard of practice,” and yet this clinical paradigm to infections in LTCFs is a harbinger for developing drug-resistant organisms, how do we resolve this dilemma? The following principles should be considered: Not all clinical or functional changes in LTCF residents should be attributed to infections. Antibiotics should be administered only when there is evidence to indicate potential clinical benefit. For example, studies have clearly shown men and women residing in LTCFs derive no benefit from treatment of asymptomatic bacteriuria.26, 32, 33 Chronic suppressive therapy with antibiotics or antimicrobial chemoprophylaxis should be restricted unless there is documented evidence of clinical efficacy and therapeutic benefit. Continuation of antibiotic therapy beyond standard recommended periods should be discouraged. For example, catheter-related urosepsis should be treated until clinical sepsis is improved (generally about 5 to 7 days) but should not continue in an attempt to maintain the urine sterile. In circumstances in which a specific pathogen is isolated and antibiotic sensitivity studies are available, the initial broad-spectrum antibiotic should be changed to a more narrow-spectrum agent if the organism is susceptible to such an agent. Greater education about and stricter practices of infection control in the LTCF setting must be mandated. The details of the components of infection control and their importance in a LTCF are beyond the scope of this paper but have been recently reviewed.34 Nevertheless, it should be emphasized that only through rigorous and effective infection control measures and programs can we detect (early), isolate, and control potential outbreaks of serious infections, including those caused by drug-resistant organisms in a LTCF. Although physicians are committed to “relieve suffering and pain” in their patients, they are also have taken an oath to a higher calling, which is to “do no harm.” In our efforts to relieve the suffering from infectious diseases in our LTCF residents, we must also be aware of how to avoid creating more harm than good for our patients. Herein are the lessons to be learned from “VRE, MRSA, PRP, and DRGNB in LTCF.”