#54214: Multidrug-Resistant Microbial Infections

While MRSA has been found in hospitals of all sizes, the highest rates have been found in larger hospitals and in federally supported institutions. Although first seen primarily in large, metropolitan teaching hospitals, MRSA has been documented in increasing numbers in long-term care facilities. A 2012 study showed that large hospitals in urban centers act as proliferation and transmission hubs, where patients acquire disease and carry resistant novel strains into the community and especially to regional clinics through referrals [169]. It is theorized that willingness to travel long distances for medical treatment and centralized specialist treatment centers have contributed to the widespread distribution of MRSA.

MRSA frequently colonizes in older, debilitated patients and presents the great risk of being transferred between long-term care and acute-care facilities [170]. Antibiotic use may encourage colonization, and once colonized or infected, a patient may harbor MRSA for months. Then, because of close living conditions, the spread can be rapid. When these patients are then transferred to an acute-care setting, they bring the resistant organisms with them [13,170].

As noted, MRSA is thought to be transmitted within institutions from patient to patient primarily via hand carriage of healthcare workers who have been contaminated by contact with colonized or infected patients or with devices, items, or environmental surfaces that have been contaminated with body fluids containing MRSA. Colonized or infected healthcare workers may also be reservoirs [43]. The role of the environment seems to be less important, except in burn units, ICUs, and other special facilities where prevention and control measures should be tailored to the area's unique needs and population [11]. Other risk factors for acquiring MRSA during hospitalization vary and depend on the population studied and specific circumstances. Important risk factors include prolonged hospitalization, the length of the period preceding antimicrobial therapy, stay in an ICU or burn unit, or exposure to a colonized or infected patient [13,43].

One study conducted in Australia identified risk factors for the development of MRSA, including being male, admission due to trauma, immunosuppression, presence of a central line or indwelling urinary catheter, and a past history of MRSA infection. The study also found that MRSA bacteria are more likely to be associated with adverse outcomes and death [55]. Subsequent studies have confirmed the association [56,57].

In regards to community-acquired MRSA, the CDC has investigated clusters among athletes, military recruits, children, Pacific Islanders, Alaska Natives, Native Americans, men who have sex with men, and prisoners [58,59,60,61,62,63,64,65]. Factors that increase the risk of spreading MRSA skin infections include close skin-to-skin contact, openings in the skin such as cuts or abrasions, contaminated items and surfaces, crowded living conditions, and poor hygiene [38]. Recent studies have also documented the emergence of community-acquired MRSA strains in healthcare settings [66,67].

Prevention of MRSA infection has been listed among the safe healthcare practices established by the Agency for Healthcare Research and Quality (AHRQ) and the National Quality Forum. In 2004, the Institute for Healthcare Improvement (IHI) established the100,000Lives Campaignas a challenge to save 100,000 patient lives through healthcare interventions, such as infection prevention. Building on the success of that campaign, the IHI established the5 Million Lives Campaignin December 2006 and added reducing MRSA infection to its list of interventions[68]. The U.S. Department of Health and Human Services called for a 25% reduction of MRSA bacteremia in hospitals and a 50% reduction of MRSA invasive infections in the general population by 2013[69]. By 2014, MRSA bacteremia in hospitals had reduced 13% and MRSA invasive infections in the general population dropped 36%[69]. In the 2019 report, MRSA had reduced an additional 21% compared with 2015 data[14,69].

According to the 2019 national data analysis, the rate of MRSA bloodstream infections has decreased substantially in the past decade. From 2005 to 2016, the incidence of hospital-onset and community-onset MRSA bloodstream infection declined 74% and 40%, respectively[140]. For the most part, the decline in hospital-onset MRSA infection occurred in the early period (2005–2012); since 2013, the annual rate of hospital-onset MRSA bloodstream infection has not changed significantly. Adjusted community-onset MRSA bloodstream infection rates have continued to decline by 6.9% per year. This decrease in the incidence of severe MRSA infection is likely attributable to the surge in efforts to reduce the number of MRSA infections in the hospital and other healthcare settings, thereby reducing also the numbers of hospital-associated MRSA infections occurring in the community.

Although much progress has been made in reducing the incidence of serious MRSA infection in healthcare settings, S. aureus infection remains a significant cause of morbidity and mortality in the United States. A 2019 trend analysis estimates that nearly 120,000 S. aureus bloodstream infections and 20,000 associated deaths occurred in the United States in 2017[140]. This estimate includes healthcare- and community-onset infections caused by methicillin-sensitive and -resistant strains. Suggested strategies for further prevention of S. aureus infections include better adherence to CDC recommendations for preventing device- and procedure-associated infections and for interrupting transmission, combined with tailored interventions such as patient decolonization.

Evidence-based guidelines are at the heart of strategies to prevent and control drug-resistant infections. These guidelines have been developed primarily by the CDC and the World Health Organization, infection-related organizations, and other professional societies. The strongest recommendations for preventing and controlling MRSA outbreaks in the hospital or long-term care setting include the use of Contact Precautions (e.g., cohorting patients with MRSA, limiting patient transport) and Standard Precautions (e.g., strict hand washing, gloving, gowning) by all healthcare workers [43]. Outbreaks of MRSA infection have occurred commonly among surgical patients in burn units and in ICUs, and many outbreaks have been traced directly to carriage on the hands of healthcare workers [72]. Patient-to-patient transmission in healthcare settings, usually via the hands of healthcare workers, is a major factor in the incidence of MRSA in acute-care facilities. Hand hygiene is the most basic and single most important preventive measure, yet compliance rates among healthcare workers have averaged only 30% to 50% [70,73,78]. One large-scale study found that hand hygiene compliance is further diminished when gloves are worn [162].

Guidelines for the management of MRSA and other drug-resistant micro-organisms published by the CDC and the Society for Healthcare Epidemiology of America (SHEA) focus on the prevention of drug-resistant infections and the judicious use of antibiotics (i.e., antimicrobial stewardship) (Table 1) [11,80,163,164]. As noted, the CDC's National Action Plan for Combating Antimicrobial Resistance, which is based on the CDC's National Action Pan, summarized recommendations according to five overall strategies [11]:

Universal surveillance of MRSA at hospital admission has been suggested as a measure to help prevent the transmission of this infection in the healthcare setting; however, the CDC guideline states that the evidence on universal surveillance is limited and recommends surveillance only in specific subpopulations, defined in the context of the infection characteristics of the facility [80]. Since the publication of the guideline, conflicting data have been reported.

In 2008, the FDA approved the first rapid blood test for the detection of MRSA, which allows clinicians to more effectively identify and treat patients with the organism [81]. The BD GeneOhm StaphSR Assay is able to distinguish between MRSA and methicillin-susceptible strains of S. aureus and provides results within two hours. The FDA recommends that the test be used in conjunction with other diagnostic techniques and only in patients suspected of having an infection with S. aureus; it should not be used to either monitor treatment or rule out complications [81]. Since 2008, several rapid tests have been FDA approved, including the KeyPath MRSA/MSSA Blood Culture Test, the BD MAX MRSA Assay, Xpert MRSA/SA BC Assay [130].

Vancomycin has been the preferred treatment for both community-acquired and healthcare-associated MRSA. However, concerns have been raised about its efficacy, particularly over its slow bactericidal activity, emergence of resistant strains, and possible "MIC creep" among susceptible strains [82]. Strains of MRSA with reduced susceptibility to vancomycin were first discovered in Japan in 1996. Resistant strains are called VISA and VRSA. Several documented cases of VRSA infection have occurred worldwide, with most occurring in the United States, but as of 2014, these instances are exceedingly rare and are able to be treated with other FDA-approved antimicrobials [83,124]. In January 2011, the American Society of Health-System Pharmacists, the Infectious Diseases Society of America (IDSA), and the Society of Infectious Diseases Pharmacists published consensus-based recommendations for vancomycin dosing and monitoring [82].

Other oral agents that are usually active against MRSA include clindamycin, fluoroquinolones, tetracyclines, and trimethoprim-sulfamethoxazole (TMP-SMX). Although not specifically FDA-approved for the treatment of MRSA infection, clindamycin is approved for the treatment of serious infections due to S. aureus. Fluoroquinolones are not routinely recommended because resistance can emerge with monotherapy [82]. Among the tetracyclines, minocycline is the most active, followed by doxycycline and tetracycline [82]. As a group, they are about 90% effective. TMP-SMX is not FDA-approved for the treatment of any staphylococcal infection; however, it has become an important option for outpatient treatment of community-acquired MRSA [82].

Several parenteral medications are also useful for both community-acquired and healthcare-associated MRSA infections. These include daptomycin, linezolid, and tigecycline. Daptomycin is a cyclic lipopeptide with bactericidal activity against susceptible gram-positive bacteria, including most isolates of MRSA. At present, daptomycin is usually the preferred alternative therapeutic agent for invasive MRSA infections for which sensitivity to vancomycin is marginal and/or the clinical response is unsatisfactory. Linezolid is FDA-approved for the treatment of skin and soft-tissue infections and nosocomial pneumonia due to MRSA. Although resistance to linezolid has been a rare occurrence, a clinical outbreak of linezolid-resistant S. aureus was reported in 2010 [82,84]. Tigecycline is a derivative of the tetracyclines. Caution should be used when treating patients with bacteremia with tigecycline due to its demonstrated bacteriostatic activity against MRSA. An increase in all-cause mortality noted in phase III and IV clinical trials prompted the FDA to issue a warning regarding the use of tigecycline in patients with serious infections [82]. Daptomycin is FDA-approved for adults with S. aureus bacteremia. A possible cross-resistance between daptomycin and vancomycin has been reported [82].

The combination drug quinupristin/dalfopristin has also been advocated for severe infections; however, it has side effects that have led to a significant number of patients requiring discontinuation of therapy [82].

MRSA is far from being the only difficult resistant organism in healthcare, but it was one of the first to draw major attention to the growing problem of resistant organisms. MRSA has the potential to affect almost all hospital populations; however, if proper hand washing procedures are followed and antibiotic prescription patterns are monitored and controlled, it may be possible to reduce the number of infections. Research is ongoing for a vaccine against MRSA.

Several risk factors have been identified for VRE, including age older than 60 years, prior hospitalization, placement in the ICU, major underlying disease, surgery, immunosuppression, exposure to invasive devices, and long-term antibiotic therapy [125]. The reservoirs most often identified in outbreaks of VRE include infected or colonized patients, healthcare workers' hands, and contaminated inanimate objects. Risk of transmission is greatly increased in patients receiving care at multiple facilities and in patients who are transported between acute care, ambulatory and/or chronic care, and long-term care environments [9,11,72].

During the 1990s virtually no antimicrobial agents were available to treat VRE infections. Although this has changed, resistance to each new agent has emerged in clinical isolates [11]. The antibiotics with known effectiveness in vitro against VRE include linezolid, daptomycin, and tigecycline. Most experience has been with linezolid; unfortunately, a linezolid-resistant strain has been found in 10% to 20% of the isolates in some institutions. Tigecycline may be considered a drug of choice because it has good activity against gram-negative bacilli and anaerobes. Most VRE infections arise from an intra-abdominal source and may be present with other organisms, making tigecycline an effective choice [88].

Quinupristin/dalfopristin has emerged as an approved option for treatment of VRE. It is a streptogramin with bacteriostatic activity against vancomycin-resistant E. faecium but not against E. faecalis [89,90]. Myalgia/arthralgia is the most frequently reported treatment-limiting adverse effect. In vitro studies of quinupristin/dalfopristin combined with ampicillin or doxycycline have shown enhanced activity against VRE; however, the clinical use of combined therapy has not been established [89]. Studies comparing the efficacy and safety of quinupristin/dalfopristin to linezolid found that the two drugs had comparable clinical responses [91].

There has been a considerable amount of interest in and discussion about MRSA. However, other forms of resistant S. aureus also exist, such as erythromycin-resistant S. aureus (ERSA). Fortunately, the choice of antibiotics is not as severely limited in the case of ERSA as with MRSA. Therefore, ERSA has not received the same amount of attention, but it and other resistant organism outbreaks have encouraged researchers to develop a molecular analysis of bacterial isolates that may allow the identification of endemic strains of bacteria during an outbreak. This would facilitate a greater probability of identifying the source of the outbreak and help with the choice of a proper antibiotic [92]. Pulsed-field gel electrophoresis (PFGE) remains the gold standard for ERSA typing due to its high discriminatory power [93,94]. Penicillin (and alternately, amoxicillin) is the treatment of choice [54]. In patients who cannot tolerate penicillin, clindamycin is a good choice as a substitute for erythromycin, but reports have shown that some strains have developed resistance to both antibiotics [54,95,96,97,98].

Crowded conditions, such as those found in day care centers, and prior beta-lactam antibiotic therapy are the principal predisposing factors to colonization and disease. Populations at greatest risk include the elderly, children younger than 2 years of age, African Americans, American Indians, Alaska Natives, and persons with underlying medical conditions, including human immunodeficiency virus (HIV) infection and sickle-cell disease [99]. Acute otitis media and meningitis are the two conditions caused by resistant pneumococci that are the most difficult to treat [102]. Treating meningitis is especially challenging when caused by a strain of S. pneumoniae that is highly resistant to penicillin and third-generation cephalosporins [101]. The concentration of beta-lactams in cerebrospinal fluid and middle ear fluid are frequently inadequate to allow prompt elimination of some intermediate and highly resistant pneumococcal strains.

Pneumococci are easily spread from person to person by respiratory droplets or through direct inoculation of secretions [99]. The organism may spread from patients to hospital staff; the carrier rates among nurses caring for patients with pneumococcal pneumonia can be high. This increases the probability of nosocomial dissemination of resistant pneumococci, especially if the infection is not detected when the patient is admitted. Penicillin resistance has its most dramatic effects in patients with pneumococcal meningitis.

For community-acquired pneumonia, the consensus opinion is to use azithromycin in otherwise healthy patients who can be treated as outpatients. Older patients or those with comorbidities usually respond well to a beta-lactam agent, such as ceftriaxone or high-dose amoxicillin/clavulanate plus a macrolide [110]. The organism is uniformly susceptible to vancomycin and imipenem [106]. As penicillin-resistant S. pneumoniae continues to increase in the United States, there are signs of emerging fluoroquinolones-resistant strains as well.

Some experts believe that the use of therapeutic agents, such as ceftriaxone or clindamycin for acute otitis media and vancomycin or rifampin for meningitis, may be necessary. Although drugs with high levels of activity against penicillin-resistant pneumococci may solve this problem, antimicrobial drugs alone probably will not provide the final answer.

Pneumococcal vaccines have been improved over time by broadening the coverage of serotypes in the vaccine to include those that are causing the most common invasive infections. In the past, a single agent, the 23-valent polysaccharide vaccine (PPSV23) (Pneumovax), had been recommended for use in selected adults with conditions of impaired immunity, and for all adults older than 65 years of age [74]. This vaccine provided some protection against 85% to 90% of the pneumococcal serotypes that cause invasive disease in these populations [77]. In 2021, PCV15 (replacing PCV13) and PCV20 were introduced for adults [111].

The use of pneumococcal conjugate vaccines in the pediatric age group has been followed by a reduction in the incidence of pneumococcal disease among children, and, indirectly, among adults as well. By 2013, the incidence of invasive pneumococcal disease caused by serotypes represented in the PCV13 vaccine had declined in the adult population older than 65 years of age by approximately 50% compared with 2010 [171]. In 2012, upon approval by the FDA, the ACIP recommended the use of PCV13 for adults with immune deficits and other conditions that impose a heightened risk for invasive pneumococcal infection. After reviewing additional data in 2014, the ACIP extended its recommendation for PCV13 use to all adults older than 65 years age [171].

In 2021, the ACIP again amended its recommendation for PCV use in older adults, based on sharp declines in pneumococcal disease among adults since the advent of PCV13 use in children [171]. The ACIP now recommends a routine single dose of PCV20 for adults older than 65 years of age. Alternatively, one dose of PCV15 may be administered followed by PPSV23 given at least one year after the PCV15 dose. A minimum interval of eight weeks between PCV15 and PPSV23 can be considered for adults with an immunocompromising condition, cochlear implant, or cerebrospinal fluid (CSF) leak to minimize the risk of invasive pneumococcal disease caused by serotypes unique to PPSV23 in these vulnerable groups [74,171]. Current information, schedules, and guidance for adult immunizations is maintained at the CDC/ACIP website at https://www.cdc.gov/vaccines/schedules.

Limited functional status and complete dependence upon healthcare personnel for activities of daily living have been identified as independent risk factors for infection and colonization with CRKP [80]. Infections have been associated with high rates of morbidity and mortality among persons with prolonged hospital stays, the critically ill, and those exposed to invasive devices, such as ventilators or central venous catheters [30].

KPC-producing bacteria often are misidentified by routine susceptibility testing and incorrectly reported as sensitive to all carbapenems. Resistance to ertapenem is common and may be a better indicator of the presence of KPCs. Proficiency testing studies have shown both false resistance and false susceptibility with imipenem and meropenem [141,142,143,144]. Guidelines published in 2009 by the Clinical and Laboratory Standards Institute (CLSI) recommend that CRE with elevated MICs be tested for the presence of carbapenemases using the modified Hodge test (MHT). The MHT has demonstrated sensitivity and specificity exceeding 90% [30].

Infection control measures do not always detect all resistance problems, but they may help to limit the spread of KPCs. Surveillance, cohorting patients colonized and infected with KPC bacteria, and intensifying hygiene and cleaning practices are effective strategies to control the spread of KPCs [30,141,142,143,144]. The CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC) have developed guidelines for CRE infection prevention and control [30].

The optimal treatment of infections caused by KPC-producing bacteria has not been well established; however, most KPC-producing organisms are susceptible to tigecycline. Polymyxins used as monotherapy have demonstrated low success rates; their use in combination therapy has demonstrated higher success rates [138,143]. Polymyxins may be less nephrotoxic than previously believed, but caution with their use has been recommended. Furthermore, polymyxin resistance in KPC-producing organisms increasingly has been reported [143].

The main characteristics of A. baumannii are its tolerance to desiccation and ability to survive for prolonged periods in the environment. Isolates have been detected on hospital bed rails as many as nine days following discharge of an infected patient. Digestive tract colonization is common in hospitalized patients. Patients in ICUs and those with prolonged hospital stays may be particularly vulnerable to infection with A. baumannii. Clinical outcomes are worse and mortality rates as high as 54% have been reported in ICUs. A. baumannii wound infections associated with a healthcare setting have also been reported in military personnel in Iraq and Afghanistan [145,150,151]. Most of the reported outbreaks have been attributed to multidrug-resistant isolates, with limited available treatment options [152,153,154,155]. Use of Contact Precautions, hand hygiene, thorough environmental cleaning, and cohorting patients has been emphasized to control the spread of infection [145,147].

The pathologic changes associated with A. baumannii infection are not normally distinguishable from those caused by other aerobic gram-negative bacilli, such as Enterobacter species or P. aeruginosa, making diagnosis difficult. The primary task is to differentiate colonization from infection [156].

A. baumannii has become resistant to almost all available antimicrobials. Carbapenems remain the treatment of choice, even though increasing carbapenem-resistant Acinetobacter isolates have been reported worldwide. Most isolates remain sensitive to colistimethate, which is clinically effective. Other treatment options include high-dose ampicillin/sulbactam and tigecycline. It remains unclear whether combination therapy is more effective than monotherapy [145].

The populations reported to be at greatest risk of infection from P. aeruginosa include patients who are immunocompromised, those with prolonged hospital stays and prolonged use of antimicrobials, and those being mechanically ventilated. In patients hospitalized with cancer, cystic fibrosis, and burns, the case fatality rate from P. aeruginosa infection is nearly 50%. According to CDC estimates, the number of hospital-associated MDR P. aeruginosa infections has declined in recent years, from 46,000 cases in 2012 to 32,600 cases in 2017. This trend is attributed to ongoing infection control measures and appropriate antibiotic use [168]. Small retrospective case-control studies have identified advanced age, intravenous drug abuse, and the use of specific antimicrobials as potential risk factors for infection with multidrug-resistant P. aeruginosa; however, larger studies are needed to confirm these findings [158].

Diagnosis of P. aeruginosa infection depends upon isolation and laboratory identification of the bacterium. A culture should be obtained from the site of infection (i.e., blood, skin lesions, drainage fluid, urine, cerebrospinal fluid, or eye). P. aeruginosa can be identified based upon its gram morphology, inability to ferment lactose, a positive oxidase reaction, and its ability to grow at 42°C. Localized infection may produce a fruity smell, and pus may be greenish. Fluorescence under ultraviolet light may help with the early identification of P. aeruginosa colonies. Fluorescence is also used to suggest the presence of P. aeruginosa in wounds [33,157].

Patients with severe multidrug-resistant P. aeruginosa infections should be treated with combination therapy that consists of an antipseudomonal beta-lactam and an aminoglycoside or fluoroquinolone (rather than aminoglycoside and fluoroquinolone combinations), to provide adequate therapy and improve patient outcomes. Colistin with adjunctive therapy, such as a beta-lactam or rifampin, may be a useful agent when antimicrobial options are limited; however, patients should be monitored closely for toxicities associated with this agent [158,168].

Factors that may increase the risk of gonorrhea infection include younger age, new or multiple sex partners, and previous diagnosis of gonorrhea. Women and men younger than 25 years of age, including sexually active adolescents, are at highest risk, accounting for 50% of all reported infections. Other risk factors include inconsistent condom use, sex work, and drug use. The risk factors for pregnant women are the same as for nonpregnant women [127,134].

Specific diagnosis of N. gonorrhoeae infection may be performed by testing endocervical, vaginal, urethral (men only), pharyngeal, rectal (persons who have receptive anal intercourse), or urine specimens, using culture or nucleic acid testing [128]. Clinicians who diagnose N. gonorrhoeae infection in a patient with suspected treatment failure following the updated treatment regimen should culture relevant clinical specimens and perform antimicrobial susceptibility testing of N. gonorrhoeae isolates (i.e., disk diffusion, Etest, or agar dilution) [29]. Clinicians may also consult a specialist for guidance in clinical management and report the case to the CDC through state and local public health authorities. All persons diagnosed with gonorrhea also should be tested for other STIs, including chlamydia and syphilis. As gonococcal infection can facilitate HIV transmission, HIV testing is strongly encouraged [29,128].

On the basis of experience with other bacteria that have developed antimicrobial resistance rapidly, the CDC previously favored combination therapy using two antimicrobials with different mechanisms of action (e.g., a cephalosporin plus azithromycin) to improve treatment efficacy and potentially slow the emergence and spread of resistance to cephalosporins. In 2020, the CDC updated its guidelines with consideration to antimicrobial stewardship and now recommend a single dose of ceftriaxone 500 mg IM for treatment of uncomplicated urogenital, anorectal, and pharyngeal N. gonorrhoeae infection [29]. Use of azithromycin is no longer recommended, and doxycycline is only recommended for coadministration when the patient is coinfected with Chlamydia trachomatis (100 mg twice daily for seven days) [29,75].

C. auris, like other Candida species, readily colonizes the skin and mucous membranes of patients confined to hospital and other facilities where antibiotic usage is common. Under conditions of poor host defense, such colonization can lead to serious illness, including bloodstream infection and death. Risk factors include prolonged confinement in a healthcare facility, indwelling central venous or urinary catheters, and previous antibiotic or antifungal medications. Prolonged patient colonization and persistence of viable yeasts on environmental surfaces facilitate spread of C. auris between patients in healthcare facilities.

C. auris should be suspected whenever a clinical isolate is identified as an unusual Candida species or the yeast isolate cannot be identified to species level. C. auris infection is a nationally notifiable condition. Healthcare facilities and laboratories that suspect they have a patient with C. auris infection are urged to contact state or local public health authorities and the CDC immediately for guidance [161].

According to the Infectious Diseases Society of America, lipid formulation amphotericin B (AmB) (3–5 mg/kg daily) is a reasonable treatment alternative for infection with Candida spp. resistant to other antifungal agents.

(https://www.idsociety.org/practice-guideline/candidiasis Last Accessed: February 28, 2023)

Strength of Recommendation/Level of Evidence: Strong recommendation; high-quality evidence

The response to antifungal therapy is variable and unpredictable; mortality rates of 30% to 60% have been reported in association with outbreaks in some parts of the world [149]. Options for the treatment of C. auris infection are limited because of resistance to one or more of the available classes of antifungal drugs. In a study of isolates from 54 cases in five countries outside the United States, 93% of isolates were resistant to fluconazole, 35% were resistant to amphotericin-B, and 7% were resistant to echinocandins; 41% were resistant to two antifungal classes and 4% were resistant to all three classes [53].

For simple colonization (including asymptomatic, catheter-associated candiduria), management should center on infection control measures to include hand hygiene, Contact Precautions, environmental disinfection, and in the setting of urinary colonization, removal of any indwelling catheter. The recommended initial choice of therapy for patients with clinical signs of infection is an echinocandin (e.g., caspofungin, micofungin) at standard dosing [161,149].

The CDC provides specific guidance for infection prevention and control of C. auris transmission. The primary control measures for prevention of transmission in healthcare settings include adherence to hand hygiene, Standard and Contact Precautions, cleaning and disinfecting the patient care environment and reusable equipment, screening contacts of newly identified cases and carriers, and laboratory surveillance of clinical specimens any new transmission events [161].

As noted, the spread of TB in the United States has often correlated with immigration into the country by individuals from areas where the disease is endemic. Mexico, Laos, Vietnam, Africa, Eastern Europe, Russia, and South Korea are common countries of origin of MDR-TB cases introduced into the United States [118]. The incidence of TB among foreign-born individuals is 15.8 times higher than in U.S.-born individuals [104]. The incidence of MDR-TB cases among foreign-born individuals is 17.5 times higher than in U.S.-born individuals [121]. The increase in these cases has primarily been seen in urban areas, where close contact with large numbers of people compounds the risk [115].

Other factors that increase the risk of M. tuberculosis infection include poor nutrition, intravenous drug use, close contact with large groups of people (e.g., in schools, nursing homes, dormitories, long-term care facilities, homeless shelters, prisons), and HIV or other immunologic deficiencies. Close contact with an individual who has active TB is a major risk factor, especially if there is contact with aerosols or sputum. The organism is contained in droplet nuclei, which can be inhaled and deposited into the alveoli when someone is exposed to a cough or sneeze [117,118,122,123].

Intensive educational efforts at a level appropriate for the culture, language, age, and reading level of the patient, should be initiated as soon as TB is suspected. These efforts should include information about the disease, treatment regimen and expected outcomes, and potential drug side effects, and should also include a thorough discussion of infection control measures. A list of drugs used for the treatment of TB in the United States is included in Table 2 [23,126].

The CDC, the American Thoracic Society, and the IDSA provide updated guidance for the treatment of TB, most recently in 2016 [23]. Additionally, the National Institutes of Health (NIH) has joined in developing guidelines for those with special needs, such as patients who have HIV. These guidelines also discuss the appropriate treatment of pregnant women and children [23,129]. The CDC and the NIH additionally advise that practitioners consult an expert before attempting to treat a patient diagnosed with TB. Advice is usually available from local public health authorities.

For the treatment of multidrug-resistant TB, the American Thoracic Society, the Centers for Disease Control and Prevention, the European Respiratory Society, and the Infectious Diseases Society of America suggest using at least five drugs in the intensive phase of treatment and four drugs in the continuation phase of treatment.

(https://www.atsjournals.org/doi/10.1164/rccm.201909-1874ST Last Accessed: February 28, 2023)

Strength of Recommendation/Level of Evidence: Conditional recommendation, very low certainty in the evidence

Therapy should be initiated on the basis of strong clinical (or laboratory) suspicion, without waiting for culture confirmation of the diagnosis or sensitivity testing results. The recommended strategy is to use a multi-drug regimen administered in a two-step process: an initial four-drug intensive phase protocol for eight weeks, followed by a maintenance phase regimen to complete a total six- to nine-month course of therapy [21,23,126]. The recommended intensive phase regimen consists of isoniazid, rifampin, pyrazinamide, and ethambutol. This approach covers the possibility that infection is caused by a resistant strain and provides a quick "knockdown effect" designed to maximize the rate of clinical improvement, eliminate the risk of transmission, and prevent the emergence of resistant strains. After eight weeks, when culture and sensitivity results are known, pyrazinamide and ethambutol are discontinued in cases of presumed drug-sensitive infection, and isoniazid and rifampin are continued for an additional 18 to 24 weeks [23].

For patients with known isoniazid- and rifampin-susceptible M. tuberculosis, ethambutol may be omitted from the initial phase regimen; moreover, directly observed therapy (DOT) administered five days of each week is an acceptable alternative to daily treatment [23]. The continuation phase of this regimen, isoniazid and rifampin for 18 weeks, is then continued either by daily dosage or DOT five days per week. There are somewhat similar regimens have the same initial phase, with the continuation phase utilizing twice weekly doses of isoniazid and rifampin or once weekly doses of isoniazid with the addition of pyrazinamide or ethambutol. In each case, the choice is influenced by severity of disease, clinical response, ease of follow-up, and issues of compliance [21,23].

Clinical practice guidelines for the treatment of drug-resistant tuberculosis were published in 2019, prepared jointly by the CDC, the American Thoracic Society, the IDSA, and the European Respiratory Society [117]. These guidelines suggest using at least five drugs in the intensive phase of treatment and four drugs in the continuation phase, and expanding the duration of intensive-phase treatment to about 7 months and the total duration of antituberculous therapy to between 15 and 21 months. The specific regimen will vary in relation to the known or suspected susceptibility pattern of a given case. In order of strength of recommendation, selection of an oral drug(s) to add to the standard regimen includes the following choices: a fluoroquinolone (levofloxacin or moxifloxacin), bedaquiline, linezolid, clofazimine, and cycloserine [117]. Because patients with AIDS are usually taking antiretroviral and other medications, it is necessary to be especially diligent in recognizing possible drug interactions when these patients are also being treated for TB [23].

Assuring patient adherence to the treatment regimen is a critical goal of the overall management plan, not only for speedy control of infection and resolution of illness, but also to prevent emergence of resistance and limit transmission to others. It is strongly recommended that all patients be observed while taking their medication to be certain that they are conforming to the regimen. This is referred to as DOT and has been shown to markedly improve therapeutic results and enable early identification of nonadherence, adverse drug reactions, and clinical worsening of TB [23]. In most communities, a patient is assigned a public health case manager who assesses needs and barriers that may interfere with treatment adherence. With active input from the patient, family, and healthcare providers, the case manager, together with the patient, develops an individualized "case management plan" designed to address identified needs and barriers.

ESBL-producing Enterobacterales are most commonly encountered in healthcare settings, including hospitals and nursing homes [148]. As with many other resistant organisms, previous antibiotic use, previous hospitalization, catheterization (for urinary tract infections), and immunosuppression are potential risk factors.

Routine EBSL testing is typically available [165]. As such, diagnosis of ESBL-producing Enterobacterales is made in patients with Enterobacterales infection that does not respond to ceftriaxone.

For cystitis caused by ESBL-producing Enterobacterales, the recommended first-line agents are nitrofurantoin or trimethoprim-sulfamethoxazole; alternative options include amoxicillin-clavulanate, single-dose aminoglycosides, fosfomycin (for E. coli only), ciprofloxacin, levofloxacin, ertapenem, meropenem, or imipenem-cilastatin. The preferred options for pyelonephritis or complicated urinary tract infections are ertapenem, meropenem, imipenem-cilastatin, ciprofloxacin, levofloxacin, or trimethoprim-sulfamethoxazole. Available options for infections outside the urinary tract include meropenem, imipenem-cilastatin, and ertapenem [165].