Multi Drug Resistance : Another Fatal ICU Concern

AJITH KUMAR A.K; MD, DNB, EDIC
Consultant in Pulmonology and Critical Care, Sagar- Apollo Hospital, Bangalore - 41 (India)

The emergence of several bacterial pathogens thatare resistant to multiple conventional antibiotics is a toughchallenge to the treating physicians and intensivists as inmany such cases no viable options for treatment areavailable. The aim of this article is to briefly discuss thefactors contributing to resistance, the mechanisms of development of resistance, some notoriously resistant pathogens and their available treatment options and finally the prevention of transmission of resistant pathogens.

 Intrinsic resistance and acquired resistance are the major subdivisions of resistance, in which in the latter the once susceptible bacteria later on becomes resistant to the given drug in vivo. Indiscriminate use of antibiotics and increased at risk population are the major clinical factors contributing to the emergence of resistance. The former includes the antibiotic use in veterinary medicine and agriculture, public pressure on physicians to use antibiotics for viral illness, and inappropriate use of antibiotics resulting in selection of antibiotic resistant genes in the given bacterial population. The increase in at risk population also contributes to resistance eg by prompting the usage of repeated cycles of antibiotics in the immunosuppressed patients( eg AIDS, transplantation, chemotherapy etc) and also in the aged population with chronic debilitating illness. The health care centers are technically reservoirs of multi drug resistant pathogens.

Mechanisms of resistance could be discussed under four broad categories. They are decreased intracellular concentration of the drugs, drug inactivation, target modification and target bypass. Intracellular drug concentration can be reduced by the efflux systems of bacteria (eg E. coli’s tetracycline efflux system and Staphylococcus’s fluoroquinolone efflux system). Alteration of the porin protein of the outer membrane of Pseudomonas aerugenosa results in decreased permeability of the drug with decreased intracellular concentration. Some of the aminoglycoside resistant Staphylococcus shows decreased uptake of the antibiotic by the bacterial cytoplasmic membrane. Beta lactamase production is a classical example of drug inactivation. Target modification may range from a single mutation, to a multisequence event, to major alterations achieved by the incorporation of foreign DNA. Modification of penicillin-binding proteins is the mechanism of resistance used by penicillin-resistant pneumococcus, Neisseria meningitidis, and Enterococcus fecium, and by methicillin-resistant S. aureus. Modification of the genes for DNA gyrase confers fluoroquinolone resistance, and various ribosomal alterations contribute to macrolide, tetracycline, rifampin, and mupirocin resistance. Target bypass is by means of development of alternate metabolic pathways. Examples of this mechanism include enterococcal and staphylococcal vancomycin resistance and various bacterial pathogens’ resistance to the folate antagonists.

Drug resistant Streptococcus pneumoniae

Reports of highly resistant pneumococci came in the late 1970 from South Africa(1,2). In the USA, highly penicillin-resistant strains are estimated to occur in approximately 30% of pneumococcal isolates. Factors associated with colonization and infection with highly resistant pneumococci include age <2 and>60 years, participation in day care, contact with a child carrier, previous antibiotic treatment, immunosuppression, presence of debilitating disease, and also certain pneumococcal serotypes(3,4).

Most are sensitive to imipenam and many isolates are also susceptible to the third- and fourth-generation cephalosporins. Many are also resistant to erythromycin, the other macrolides, tetracyclines, and trimethoprimsulfamethoxazole. Resistance to chloramphenicol, rifampin, and clindamycin has been described. The penicillin-resistant pneumococci remain universally sensitive to vancomycin. Although S. pneumoniae has intrinsic resistance to many of the older fluoroquinolones, some of the newer agents, including levofloxacin, moxifloxacin and gemifloxacin have excellent activity against penicillin-resistant strains. Telithromycin is a ketolide related to macrolides, which has an excellent activity against drug resistant pneumococci(5,6). However it is recommended only as a second line agent in view of it’s potential for hepatic and ocular side effects. Linezolid and tigecycline also have good in vitro activity against drug resistant pneumococci. In addition, appropriate use of the pneumococcal vaccine may prevent many cases of invasive pneumococcal disease.

Vancomycin-resistant enterococci (VRE)

The most common species causing human infections are E. faecalis and E. faecium and together they account for more than 90 percent of clinical isolates. These organisms are part of the normal bowel flora, and can also be cultured from skin sites such as the groin and axilla. The most common sites of infection are the urinary tract and bloodstream. In addition, enterococci may cause endocarditis due to their ability to adhere to heart valves. They rarely cause respiratory tract infections.

Enterococci are intrinsically resistant to many antibiotics (including the cephalosporins), and acquired resistance has become an additional major problem. Traditional therapy for enterococcal infections has included penicillin or ampicillin with or without an aminoglycoside added for synergy. Vancomycin is an alternative agent for patients with penicillin allergy. Resistance to all of these agents has been described and some strains are now multidrug-resistant.

Analyses of clusters and case-control studies have identified risk factors for nosocomial acquisition of VRE. The most consistently observed risk factor is previous treatment with antimicrobials, especially vancomycin and cephalosporins. As an example, a prospective study of 126 adult intensive care units (ICU) in 60 hospitals found that vancomycin and cephalosporin use were significantly higher in patients with VRE, after controlling for the type of ICU and rates of VRE elsewhere in the institution(8). Use of multiple agents with a broad-spectrum of activity may predispose patients to colonization with resistant enterococci, probably via alteration of the normal bowel flora(9). In addition, among patients with VRE in stool, the administration of antibiotics active against anaerobic organisms can increase the density of stool colonization with VRE, which decreases after discontinuation of these agents(7).Contaminated surfaces in patient rooms, even after routine discharge cleaning with phenolics, may be associated with VRE acquisition(10). After a four hour cleaning protocol was adopted, there were no further positive environmental Colonization pressure, defined as the daily point prevalence of VRE colonized patients in an ICU, may be another important risk factor for acquisition of VRE(11). Once 50 percent or more of patients within the unit are colonized with VRE, colonization pressure may outweigh other risk factors including antibiotic use. Residents of long-term care facilities (LTCF) appear to be a reservoir for VRE. In a prospective cohort study, 45 percent of patients admitted to an acute care hospital from a LTCF had rectal colonization with VRE; risk factors included prior use of antibiotics and presence of a decubitus ulcer(12)

Occasionally, multidrug-resistant enterococci may be bacteriostatically susceptible to tetracycline, chloramphenicol, fluoroquinolones, novobiocin, and rifampin. Two antibiotics, dalfopristin-quinupristin and linezolid, are available currently to treat the resistant infectons effectively. Daptomycin and tigecycline are other drugs which may also be considered. Unlike MRSA, there is no evidence that the carrier state can be eliminated. Strict infection control measures, including contact isolation as well as restriction of vancomycin use, are crucial in containing the spread of VRE.

Methicillin-resistant staphylococci

The use of the semisynthetic penicillins against staphylococci in the 1960s was rapidly followed by the first outbreaks of MRSA. Current estimates of MRSA in large teaching hospitals approach 40% of S. aureus isolates. The majority of staphylococci are also resistant to erythromycin, tetracycline, and clindamycin. Resistance to the fluoroquinolones and mupirocin is becoming increasingly common. Methicillin resistance is controlled by a single genetic mutation (mecA gene) that is shared by both coagulase-positive and coagulase-negative staphylococci, resulting in the overproduction of a single, low-affinity, penicillin-binding protein. Methicillin-resistant staphylococci infections generally are treated with intravenous vancomycin. Alternatives may include fluoroquinolones plus rifampin, trimethoprimsulfamethoxazole, or minocycline. Although vancomycin resistance among staphylococci has been described in vitro for several years, the recent isolation of vancomycinresistant S. aureus from a hospitalized patient is alarming.

The other drugs that can be used for MRSA include quinupristin-dalfopristine, linezolid, daptomycin, tigecycline and teicoplanin. Some of the investigational drugs are evernimicin, lysostaphyn,dalbavancin, telavancin, oritavancin and staphylococcal antibody.

VISA and VRSA

In May 1996, a strain of MRSA with reduced susceptibility to Vancomycin was recovered in Japan from a patient who appeared to respond poorly to vancomycin therapy . Subsequently, similar strains with Vancomycin intermediate sensitivity were recovered from a number of patients in the United States. All of the isolates were also resistant to methicillin .Such strains are called glycopeptide (Vancomycin) intermediate S. aureus (GISA or VISA). Some of these patients received long courses of vancomycin prior to recovery of VISA isolates, suggesting that prolonged vancomycin therapy is a major risk factor for VISA. Two of the patients were treated with repeated courses of vancomycin for catheter-related MRSA infections. This observation highlights the need to promptly remove infected foreign bodies whenever possible. Patients infected with vancomycin-resistant S. aureus (VRSA) also have been reported in the United States since 2002. VISA and VRSA infections are currently rare. Treatment includes drugs like linezolid,daptomycin and quinupristinedalfopristine.

Mutidrug resistant gram negative bacilli

Enteric gram-negative rods (GNRs) began to emerge as major pathogens in the 1950s and 1960s. Subsequently, new classes of beta lactams were introduced to contain these organisms. However, the GNRs have developed increasingly more sophisticated mechanisms of resistance to overcome newer agents and the predominant mechanism of resistance being production of beta lactamases.

Multi drug resistant Pseudomonas could be treated with intravenous colistin though the drug is notorious for it’s nephro and ototoxicity(13). Another option could be polymyxin.

 The inhaled route could be a safer option for usage of drugs such as colistin which could be used for pneumonia caused by multidrug resistant gram negative bacilli. One report described three patients with nosocomial pneumonia or tracheobronchitis due to multidrug resistant strains of P. aeruginosa for whom aerosolized colistin proved beneficial as supplemental therapy(14).The difficulty in treating P.aeruginosa infections caused by strains that are resistant to all or all but one antibiotic has led investigators to use novel combinations of drugs that separately have no activity against the isolate.In vitro studies identified the following regimens of drugs as having enhanced activity in combination:

• Ticarcillin,tobramycin plus rifampin

• PolymyxinB plus rifampin

• Ceftazidime or Cefipime plus a fluoroquinolone

• Ceftazidime plus Colistin

• Clarithromycin plus tobramycin

• Azithromycin plus one of the following: tobramycin,doxycycline, trimethoprim or rifampin.

• Colistin plus rifampin.

The mechanisms for the enhanced activity are unknown for most of the above combinations.

Multi drug resistant acinetobacter is another major cause for resistant ICU infections. Carbapenems (imipenem and meropenem) are the mainstay of treatment for antimicrobial-resistant gram-negative infections, though carbapenem-resistant Acinetobacter is increasingly reported. Colistin and polymyxin B have been used to treat highly resistant Acinetobacter infections. Studies have also demonstrated in-vitro susceptibility of multidrug-resistant Acinetobacter to various synergistic combinations of antimicrobials including carbapenems, colistin, rifampin, and ampicillin-sulbactam.

Extended Spectrum Beta Lactamase (ESBL) producing Klebsiella and E.coli are another major concern, and restriction of oxyimino cephalosporins (eg cefotaxim,ceftriaxone,ceftazidime and cefipime) is important in their control. Treatment is by imipenems, carbapenem and ertapenem. Ciprofloxacin is also active to some extent.

Both the microbiology laboratory and the infection control committee play a crucial role in the control of drug resistant infections in the institution. A well equipped laboratory for accurate detection of the resistant organisms is essential. Infection control measures are critical in controlling the spread of antibiotic resistance among microorganisms. Goals of infection control include optimal use of antibiotic therapy, including appropriate perioperative prophylaxis, minimal effective duration of treatment, and limiting the use of vancomycin and broad-spectrum antimicrobials to appropriate clinical scenarios. In addition, development of an epidemiological plan to detect and report organisms is of primary importance. Perhaps the most important goal is to increase adherence to basic infection control policies and procedures. These include isolating colonized or infected patients, grouping patients and staff,using gloves and gowns appropriately, providing singlepatient- use non critical equipment, disinfecting the environment properly, and fully incorporating the most current laboratory techniques to detect antibiotic-resistant organisms. Obviously, the single most important and effective infection control technique is hand washing.

In 1996, the Hospital Infection Control Practices Advisory Committee (HICPAC) recommended a number of isolation and barrier precaution practices for use when caring for patients with MRSA(15). The Centers for Disease Control and Prevention (CDC) published a guideline in 2002, recommending a number of new strategies for improving hand hygiene among HCW (health care worker’s(16). The Society for Healthcare Epidemiology of America (SHEA) published a guideline in 2003 to prevent transmission of multidrug resistant strains of S.aureus and enterococci(17). The guidelines provide useful strategies for reducing the transmission of MRSA in healthcare facilities. The guideline recommendations are grouped by the strength of the recommendation based on available study data.

The following measures are strongly recommended and supported by well-designed experimental, clinical, or epidemiologic studies:

• Implement a program of active surveillance culturesto identify patients colonized or infected with MRSA. Early detection of colonized patients facilitates more timely institution of appropriate contact precautions (eg, use of gloves and gowns), which have been shown to control the spread of MRSA more effectively than standard precautions. Surveillance cultures of the anterior nares and open wounds are recommended for patients at high risk of MRSA colonization or infection.

• Wear clean, non-sterile gloves when entering the patient’s room; remove the gloves when leaving the patient’s room.

• Wear a gown when entering the room if substantial contact with the patient or environmental surfaces in the room is anticipated, or if the patient has wound drainage not contained by a dressing. Remove the gown before leaving the patient’s room.

• Upon removing gloves and gown, clean hands with an alcohol-based hand rub. However, if hands are visibly contaminated with blood or other proteinaceous materials, wash hands with an antimicrobial soap and water.

The following measures are strongly recommended and supported by some experimental, clinical, or epidemiologic studies and a strong theoretical rationale:

• Place the patient in a private room whenever possible. If a private room is not available, then place two or more patients with MRSA in the same room.

• Limit transport of the patient from the room to essential purposes only.

• When possible, dedicate the use of non-critical equipment to a single patient or cohort of patients. If use for another patient is unavoidable, adequately clean and disinfect the item before use.

The following measure is suggested and supported by suggestive clinical or epidemiologic studies or a theoretical rationale:

• Wearing a mask when caring for MRSA patients may reduce nasal acquisition of MRSA by HCWs.

In conclusion multi drug resistance is an alarming concern all over the world. Good clinical practices are vital in preventing the emergence of resistance whereas infection control measures stressing on hand hygiene stop the spread of the menace to a considerable extent.

References

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