One way to mitigate the problem of antimicrobial resistance is to prevent it from occurring. CDC has developed a campaign to promote strategies to decrease the incidence of the development of MDROs. The cornerstone of the 12-step program includes infection prevention, effective treatment and diagnosis of infection, wise use of antimicrobials, and prevention of transmission of infections. The recommendations are proactive and straightforward. To prevent infection, CDC advises appropriate vaccination and care of catheters. Infections should be treated using antimicrobials targeted to the suspected or known pathogen. Antimicrobials should be selected based on local antibiogram data and on cultures that were obtained properly. The treatment of colonization, particularly that of indwelling devices, should be avoided. The transmission of infections should be prevented by appropriate precautions during patient care as well as appropriate precautions for healthcare workers such as staying home in case of illness and performing proper hand hygiene. Additional tools and resources for various patient populations are available at the CDC’s website. Information about the 12 steps for maintaining proper hygiene is also available.

The appearance of a growing number of multidrug-resistant organisms (MDROs) is of considerable concern. Gram-positive cocci have reemerged as important pathogens in both nosocomial and community-acquired infections. The recent emergence of strains of drug-resistant Streptococcus pneumoniae is a serious clinical and public health problem.¹ The most common bacterial cause of community-acquired pneumonia is still Streptococcus pneumoniae, and these infections are associated with significant morbidity and mortality worldwide.² Serious skin and soft tissue infections (SSTIs) caused by multidrug resistant pathogens have become more common.³ While the majority of SSTIs are caused by Staphylococcus aureus or beta-hemolytic streptococci that are methicillin/oxacillin-susceptible, the emergence of methicillin-resistant and vancomycin-resistant community-acquired and nosocomial Gram-positive pathogens has been documented.³

The introduction and widespread use of systemic antifungal agents has produced major shifts in the occurrence of resistant candidal infections, both geographically and in prevalence. Study results from the Antifungal Surveillance Program (ARTEMIS) indicate that internationally, strains shown to be resistant to fluconazole exhibited variable cross-resistance to posaconazole, ravuconazole, and voriconazole, but were susceptible to caspofungin and flucytosine.⁴

In an effort to characterize and quantify baseline prevalence of resistant strains of enterococci in the environment, data from studies of enterococcal presence on fresh produce have been obtained. In one major study, 34% of the isolates studied had multiple-drug-resistance patterns, excluding intrinsic resistance.⁵

Regarding nosocomial infections, intensive care unit practices foster the development, dissemination, and amplification of antibiotic resistance for many reasons:

• Resistant microorganisms imported at admission
• Extensive use of broad-spectrum antibiotics precipitates the selection of resistant strains
• Cross-transmission of resistant strains via the hands or the environment⁶

Infections with MDROs are difficult to treat and pose great risk to patients. Treating resistant infections is also costly. Because nurses play such a vital role in the prevention and treatment of these infections, they need up-to-date information about the mechanisms of these infections and the circumstances that lead to the development of nosocomial infections, as well as information or guidelines based on the principles for controlling infections. Successful control has been demonstrated in many settings in which rates of MDROs have significantly decreased.⁶

Essential microbiology

Microorganisms require certain environmental factors, such as oxygen and nutrients, for survival. The host human body provides these elements and supports the growth of billions of normally residential microorganisms. This is a symbiotic relationship, that is, beneficial to both the human and the bacteria. For example, some intestinal flora help their human host by participating in the synthesis of vitamin K, aiding in nutrient absorption, and converting bile pigments and acids in the intestine. The population of microorganisms that inhabit the internal and external surfaces of humans is referred to as normal flora — microorganisms that prevent invasion and infection by competing against pathogens.⁷

A pathogen is a microorganism that has the potential to multiply in a host and inflict damage, sometimes producing disease. Normal flora can become pathogenic under certain circumstances. The yeast, Candida albicans, which is normal vaginal flora in women of childbearing age, is an example of a potentially pathogenic organism. Other bacterial flora in the vagina normally maintain a local pH of 3.4 to 4.5, keeping the population of yeast under control. When antibiotics are used to treat infection elsewhere in the body, the normal bacterial flora of the vagina are reduced, resulting in an altered mucosal pH, an overgrowth of yeast, and a vaginal yeast infection.⁷ The normally symbiotic relationship between host and flora is upset, and the flora become pathogenic.

Infection versus colonization

An imbalance between pathogen and host defenses can result in either infection or colonization. Colonization is the presence of resident flora or potentially pathogenic organisms in or on a host, occurring without tissue invasion or infection. Infection implies invasion of the host tissues, where pathogen multiplication and resulting inflammation of a normally sterile site then takes place.⁷

Colonized organisms can be present in or on the host, without the host exhibiting any apparent symptoms of infection. In these hosts, the potential exists for the covert spread of bacteria, tissue invasion, and resulting infection. Invasion by most microorganisms begins when microorganisms adhere to tissue cells. Whether the microorganism remains localized or spreads to other sites depends on other factors such as the production of toxins, enzymes, or other pathogenic substances.⁷

An example of covert spread of bacteria is that methicillin-resistant Staphylococcus aureus (MRSA) may still be intermittently colonized in the nares of patients who have completed treatment for the infection, as well as in the nares of healthcare workers who have been exposed to them. Additionally, transient colonization on the hands of healthcare workers can contribute to the transmission of disease-producing organisms. The added cost of treating even a single vancomycin-resistant enterococcal (VRE) nosocomial infection far exceeds the costs of prevention, using gowns, gloves, and screening.⁸ Preventive techniques, such as wearing a gown and gloves and washing hands before and after working with each patient, are essential to prevent the spread of resistant organisms. Vigorous control programs, including prevention techniques, represent cost savings over the cost of even one resistant-organism infection.⁹

Resistance to antimicrobial therapy

Inappropriate antibiotic use may result in the development of resistant organisms or resistant strains of an organism. Antimicrobial agents act selectively on specific types of organisms or on specific strains of organisms. This action of selectivity favors the survival of organisms that escape full-strength assault, or those capable of resisting the assault.

In general, the mechanisms of resistance used by pathogens fall into one of three categories —

• Enzymatic inactivation of the antimicrobial
• Prevention of intracellular accumulation
• Modification of the target site to which agents bind to exert an antimicrobial effect¹⁰

Resistance to some agents can be overcome by —

• Modifying the dosage regimens (e.g., using high-dose therapy)
• Inhibiting the resistance mechanism (e.g., b-lactamase inhibitors)¹⁰

However, other mechanisms of resistance can only be overcome by using an agent from a different class.¹²

Genetic alteration and evolution takes place in these stronger organisms or strains.¹³ Two methods of change are the microevolutionary and the macroevolutionary changes. Microevolutionary changes include point mutations in a nucleotide base pair, which alters the target site to which antimicrobials are directed, thereby interfering with the original antibiotic’s activity.¹⁰ Macroevolutionary changes involve wholesale rearrangement of sections of DNA, as a single event. Another method by which genetic variability is accomplished is the acquisition of segments of foreign DNA from plasmids, bacteriophages, or transposable genetic elements. The host organism takes on characteristics of the other organisms by virtue of the transposed DNA, thus permitting it to act like those organisms in resistance to specific therapies. Acquired genetic variation may be one pathway by which cross resistance to antimicrobial therapies from within one class, or to antibiotics from related classes, develops.¹²

An example of the role of these factors can be found in the current epidemic of drug resistance in S. pneumoniae. An interaction of factors related to the pathogen (e.g., the relative fitness of the resistant strains), to the prescription of antibiotic treatment (e.g., changes in selection pressure), and to the host (e.g., the ability to slow the transmission of S. pneumoniae) will decide whether the epidemic trend is sustainable or if it will succumb to current efforts to limit its spread.¹

Considerations for therapy in infectious disease

Healthcare providers must treat the infection invasion, not just the colonization. To identify which situation exists, several factors can assist the provider in making an accurate determination. The inflammatory response syndrome is the clinical presentation resulting from invasion and includes the following criteria:^13,14

• White blood count (WBC) of greater than 12,000/mm³, less than 4,000/mm3, or the presence of more than 10% neutrophils
• Heart rate higher than 90 beats per minute
• Respiratory rate higher than 20 breaths per minute or PCO2 lower than 32 mm Hg

Two or more of these criteria must be present to validate the presence of a systemic inflammatory response resulting from the invasion of microorganisms. In addition, accompanying the fever and other criteria listed above, inflammatory mediators are released into the systemic circulation, including activated complement product C3a, the cytokine interleukin-6 (IL-6), and the acute-phase reactant secretory phospholipase A(2) (sPLA[2]).^13,14

A normal WBC count is between 4,000/mm3 and 10,000/mm³. A WBC of greater than 10,000 is called leukocytosis. Because many conditions may prompt the development of leukocytosis, the differential — the percentage that each cell type of WBC contributes to the total count — must be assessed to determine the cause.¹⁴ Leukocytes originate in bone marrow from stem cells, which differentiate into five types of leukocytes as they develop. Each type plays a specific role in the inflammatory immune response.

The percentage of neutrophils or polymorphonuclear leukocytes (PMN) are important indicators of an inflammatory immune response to an infection. Neutrophils are phagocytic; they surround and engulf intruding organisms and then release enzymes to destroy the invader. With an acute infection, the supply of mature segmented neutrophils, or “segs,” may be exhausted, stimulating bone marrow to generate so many neutrophils in such a short time that less mature neutrophils — “bands” — proliferate. If that supply is depleted, even more primitive metamyelocytes and myelocytes are released. The presence of a high number of bands and especially meta- or myelocytes is called a “shift to the left.”¹⁴

• Culture reports that indicate the predominance of an organism or a large number of a single one suggest infection. However, reports need to be interpreted appropriately. For example, if a urine culture report listed three different organisms, and other signs and symptoms of a urinary tract infection were absent, you might conclude that the specimen was contaminated and no infection was present. Likewise, one day a report might indicate, “few gram negative diplococci seen,” and then on the next day, “no growth.” This report could simply reflect normal flora, such as with gram-negative Haemophilus influenzae, in numbers not large enough to mount an infection.
• The patient’s signs and symptoms also aid in infection diagnosis. The Centers for Disease Control and Prevention (CDC) combines clinical and diagnostic findings to form standard definitions for several categories of infections, such as bacteremia, pneumonia, and wound infection. For example, CDC criteria for a urinary tract infection requires that one of the following — fever (38 C), urgency, frequency, dysuria, or suprapubic tenderness — be present in addition to a urine culture of greater than or equal to 100,000 colonies/mL urine with no more than two species of organisms.¹⁵ These definitions are further applied to groups such as neonate, infant, and elderly populations.

Elderly patients with infections are a diagnostic and treatment challenge; the classic signs of infection may be absent or ill defined. The emergence of drug-resistant Streptococcus pneumoniae has led to empiric therapy considerations for the use of newer fluoroquinolones or the use of third- or fourth-generation cephalosporins in these patients. When a urinary tract infection is the culprit, multiresistant bacteria (e.g., MRSA or VRE) must be considered. New agents like quinipristin-dalfopristin, linezolid, and daptomycin may help in the management of such patients.¹⁶

Effective antibiotics

Antibiotics inhibit or kill microorganisms. They are either broad spectrum —effective against a wide range of both gram-positive and gram-negative bacteria — or narrow spectrum — targeted to only one group of organisms.^17,18 Antibiotics influence organisms by —

• Disrupting bacterial cell-wall synthesis (penicillins and cephalosporins)
• Alterring the permeability of the cell membrane (amphotericin B)
• Inhibiting protein or nucleic-acid (DNA, RNA) synthesis or binding within the organism (aminoglycosides, rifampin, fluoroquinolones,¹⁹ streptogramins,²⁰ oxazolidinones²¹)
• Interfering with synthesis of the organism’s essential metabolites (sulfanilamide, trimethoprim)¹⁷

The appropriate use of antibiotics falls into prophylactic, empiric, or therapeutic categories. Prophylactic antibiotics prevent infection. For example, the mouth supports high concentrations of bacteria that can cause bacterial endocarditis. In this case, a patient with valvular heart disease may be told to take prophylactic antibiotics to prevent infection during dental, surgical, and other invasive procedures involving damage to mucous membranes, the mucosal barrier system.

Antibiotics are empirically administered when a patient exhibits symptoms of infection and the pathogen is, as yet, unknown. For instance, a suddenly febrile patient may need immediate treatment in the middle of the night. After obtaining appropriate cultures, the physician may prescribe a broad spectrum antibiotic, which can be adjusted later by substituting a more narrow-spectrum agent after culture reports are available.

Ideally, antibiotics should be used therapeutically — that is, prescribed on the basis of culture and sensitivity test results, as treatment specific to the characteristics of the pathogen. A therapeutic intervention employs the least toxic, most cost-effective agent against an identified organism that has demonstrated vulnerability to the prescribed medication.

Mutant microbes

Inappropriate antibiotic use has contributed to the development of microorganisms that are resistant or unaffected by previously effective medications. In fact, the more antibiotics are used, the greater the likelihood that resistant strains will emerge.¹⁷ Cross-resistance between agents in the same category and between agents of different categories has been demonstrated. Mechanistically, resistance occurs with target alteration or reduced cell-membrane permeability, while drug inactivation occurs with chromosomal mutation and acquisition of new genetic elements.²²

Organisms resist the action of antibiotics through several common mechanisms:

1. The antibiotic may be unable to penetrate the microorganism when a reduction in permeability of the cell wall occurs.
2. The pathogen may employ a biochemical mechanism, such as an enzyme, to eliminate or inactivate the antibiotic.
3. The pathogen receptor no longer accommodates the drug, reducing drug-target interaction.
4. The organism may generate a metabolite that is antagonistic to the medication.^17,22

Resistance may occur through the mutation of the organisms’ chromosomal DNA, which becomes encoded with the ability to counter a specific antibiotic. Resistance may also come about when organisms transfer genetic information about drug resistance to each other. Small pieces of circular DNA, called plasmids, become encoded with an R factor, which stands for resistance to a particular antibiotic. A plasmid can carry R factors for several drugs at one time, not only transferring resistance from strain to strain of a single organism species, but also from one species to another.^12-14 Transmission of resistant bacteria can also amplify resistance of any type, but it is particularly important for complex resistance mechanisms that have evolved over time and for mechanisms that depend on infrequently occurring biologic events.²²

One example of cross-resistance between microorganisms involves VRE and MRSA. Until the emergence of VRE, vancomycin was a popular alternative for treating enterococci and one of the only effective agents against MRSA. Antimicrobial therapy is problematic for all VRE, but particularly when bactericidal activity is necessary. Quinipristin-dalfopristin and linezolid are two new approved antimicrobials for the treatment of recalcitrant infections caused by VRE.⁹ Also, it now appears that VRE may be capable of transferring its vancomycin resistance to MRSA and diminishing the effectiveness of the antibiotic.⁸

Our contribution to resistance

Several practices contribute to the development of drug resistance. One common mistake is not changing a broad-spectrum antibiotic to a more narrowly focused and specific drug when the results of a culture and sensitivity become known. Prolonged use of broad-spectrum antibiotics disrupt patients’ own normal flora, causing —

• Overgrowth of normal flora or other bacteria, which can result in a secondary infection or “superinfection”
• Colonization by drug-resistant strains
• Pseudomembranous colitis (PMC), usually caused by Clostridium difficile.²³

C. difficile can be present in the GI tract and produce a toxin leading to colitis if an antibiotic kills the bacteria that normally suppress its growth.

Another misuse is inadequate length of therapy that occurs when patients stop taking antibiotics because they no longer feel sick. Pathogenic microorganisms are extremely adaptive to their environment and genetically versatile. They “learn” about drugs through exposure. If therapy is stopped before all pathogens have been destroyed, the survivors then encode information about the medication, and a new resistant strain is born. The learning curve for microorganisms is also enhanced by the unnecessary use or overuse of common antibiotics, such as those prescribed to treat the “flu” or “colds,” viruses that are unaffected by bacteria-killing antibiotics. And the more organisms are exposed to antibiotics, the greater the chance of promoting resistance.¹⁷

Managing resistant infections

In recent years, SSTIs caused by multidrug resistant pathogens have become more common.³ While the majority of SSTIs are caused by Staphylococcus aureus or beta-haemolytic streptococci that are methicillin/oxacillin susceptible, the emergence of methicillin-resistant and vancomycin-resistant community-acquired and nosocomial Gram-positive pathogens has created a need for different therapeutic agents, such as linezolid, quinupristin/dalfopristin, daptomycin, and newer generation carbapenems and fluoroquinolones.

For pneumococcal infections with penicillin-sensitive strains, penicillin or an aminopenicillin in a standard dosage will still be effective for treatment.² In the cases of strains with intermediate resistance, beta-lactam agents are still considered appropriate treatment, although higher dosages are recommended.

Pneumococcal infections with isolates of high-level penicillin resistance should be treated with alternative agents, such as the third-generation cephalosporins or the newer antipneumococcal fluoroquinolones. Fluoroquinolones should not be used as a first-line therapy in community-acquired pneumonia, reserving this treatment instead for those with allergies to macrolides or those with documented resistance to standard therapy.² Some evidence shows beneficial effects on outcome with combination therapy, especially the combination of a beta-lactam agent and a macrolide given simultaneously to hospitalized patients with more severe pneumococcal pneumonia.²

Our role in fighting resistant strains

More and more healthcare facilities are winning the battle against MDROs by implementing combinations of the following control measures:

• Obtain administrative support for interventions that require fiscal and human resources. Interventions may include computer alerts, availability of ample alcohol-based hand sanitizers, and appropriate staffing.
• Facilitate behavior change by education on all levels to include control measures as well as hand hygiene compliance. The complete hand hygiene guideline is available at www.cdc.gov/mmwr/preview/mmwrhtml/rr5116a1.htm.
• Promote antibiotic stewardship through formulary restriction, preapproved indications, and other activities.
• Implement surveillance for MDROs to promote early detection, incidence rates, and asymptomatic colonization. Implement contact precautions for patients infected or colonized with an MDRO. This includes wearing gloves into the room and wearing a gown for contact with the patient and environment. A private room is preferred, but careful cohorting is also acceptable. Dedicated equipment should be used, or equipment should be cleaned after use. Additional information on isolation precautions can be found at the CDCs website (www.cdc.gov/ncidod/dhqp/gl_isolation.html).
• Environmental measures through enhanced environmental cleaning are also effective as MDROs may contaminate surfaces and items within the patient’s room. Routine environmental cultures are not recommended, but may be useful in outbreak situations.
• Decolonization is possible, but should be limited to use during outbreaks or high prevalence situations in special-care units. Decolonization is not recommended for healthcare providers who are asymptomatic and have not been epidemiologically linked to transmission.

The first step in eliminating MDROs is education. Healthcare personnel need to understand the importance of meticulous infection control measures. Sometimes enforcing infection control measures meets with resistance from some staff, who complain that they are too time-consuming. However, it takes less time and energy to prevent transmission of an MDRO than it does to treat it.