Antibiotic Resistance: Emerging Problem, Corrective Approaches

ABSTRACT: Resistance to antibiotics is increasing, and understanding the reasons can lead to more rational prescribing practices that affect susceptibility.

CME OBJECTIVE: Readers will better understand the current trend of increasing bacterial resistance to antibiotics and how emerging patterns affect antibiotic selection, as well as methods to slow resistance.

After 50 years of widespread use, antimicrobials are not as effective as they once were. Tuberculosis, gonorrhea, malaria, otitis media, pneumonia, and skin infections are now more difficult to treat than they were a few decades ago. While resistance occurs naturally, a variety of factors have amplified and accelerated the trend: overuse (21% of all prescriptions are antibiotics), incorrect use, underuse (too short a time, too low a dose, inadequate potency, poor adherence), and agricultural and veterinary use.

Bacterial infections that cause most human disease are those in which microbial resistance is most prevalent: diarrheal diseases, respiratory tract infections, meningitis, sexually transmitted infections, and hospital-acquired infections. It is no longer rare to encounter penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), and multidrug-resistant salmonellae or Mycobacterium tuberculosis.

Streptococcus Pneumoniae
S pneumoniae is the leading cause of community-acquired pneumonia (CAP), bacterial sinusitis, otitis media, meningitis, and other diseases. In 2005 the invasive disease rate was 14 cases per 100,000. At high risk are the elderly, children aged <2 years, blacks, Native Americans, Alaska natives, children who attend day care centers, and persons with underlying medical conditions. A 2003 study found 20% to 33% of isolates are no longer susceptible to penicillin, and 14% to 20% are not susceptible to >3 antibiotic classes (Pediatrics. 2003;112:862-869; 1095-1102) and (N Engl J Med. 2000;343:1917-1924).

The southeastern United States has the lowest pneumococcal antibiotic susceptibility in the nation. A 2005 study found that while penicillin resistance was stabilizing at around 34%, macrolide resistance was increasing. Quinolone resistance rates were <1%, but 21% of isolates had a first-stop mutation (Clin Infect Dis. 2005;41:139-148). “Resistance among bacterial pathogens is increasing at an alarming rate. We are seeing more and more resistance to cephalosporins, quinolones, macrolides, tetracycline, and clindamycin,” says UAB infectious diseases expert Craig J. Hoesley, MD. A 2005 study found that antibiotic therapy within the past 3 months is a risk factor for pneumococcal resistance. Recent therapy with penicillin, macrolides, and quinolones was associated with higher subsequent resistance to the same agent while the cephalosporins had no effect (Clin Infect Dis. 2005;40:1288-1297).

“The original quinolone, ciprofloxacin, was developed to treat enteric gram-negative infections like Pseudomonas and E coli,” says Hoesley. “By overusing the new quinolones to treat gram-positive infections — and we are flooding the human body with these drugs — we have impacted gram-negative bacteria living within us. Now multidrug-resistant, gram-negative nosocomial infections are common in the hospital.” The prevalence of resistant strains is increasing.

According to the Centers for Disease Control and Prevention (CDC), nearly 2 million US patients contract an infection in the hospital each year, and 90,000 of those die. More than 70% of bacteria that cause hospital-acquired infections are resistant to at least one commonly used antibiotic. Reliance on vancomycin has led to VRE infections and vancomycin-resistant S aureus.

“For nosocomial VRE and MRSA infections clinicians have an expanded arsenal of options, including IV daptomycin, IV tigecycline, and oral or IV linezolid. We need to be careful in the utilization of these newer compounds in an effort to preserve their durability and avoid resistance,” Hoesley says.

Prescribing Trends
Increasing resistance of pneumococcus and other organisms such as Haemophilus influenzae and even Mycoplasma pneumoniae can be explained partially by prescribing antibiotics for pneumonias and respiratory tract and ear infections that are viral. Between 20% and 25% of all human antibiotic consumption is for respiratory tract infections. The 2001 National Ambulatory Medical Care Survey estimated an annual 76 million primary care office visits for acute respiratory tract infections resulted in 41 million prescriptions. In adults antibiotic dispensing for pharyngitis and broad-spectrum agents for upper respiratory tract infections is rising (JAMA. 2003;289:719-725).

“The numbers are concerning, considering overwhelming evidence that antibiotics offer little or no benefit for upper respiratory infections,” says Hoesley. Numerous studies show widespread patient misconception about treatment of common respiratory illnesses.

Despite a secular trend showing improved knowledge among parents of commercially insured children (Pediatrics. 2007;119:698-706), most still believe antibiotics are indicated with green nasal discharge, uncomplicated cough, middle ear fluid, and bronchitis and that new, expensive medications are more effective than older agents.

Parents and patients exert economic pressure on busy practices and can influence well-meaning clinicians to prescribe antimicrobials in the absence of clinical indications. Half of pediatric providers report parental pressure to prescribe drugs even when not indicated (Pediatrics. 1999;103:395-401) and up to a third report providing the unnecessary antibiotic (Pediatrics. 1997;99[6]:e6).

Although some evidence shows prescribing for children decreased in late 1990s, the number of prescriptions for more expensive, broad-spectrum antibiotics has risen sharply. Prescriptions for second-generation macrolides increased 241% from 1996 to 2000. Broad-spectrum antibiotic prescriptions for pneumonia and bronchitis increased, and for children aged 3 months to <6 years, dispensing for otitis media increased 5.5 fold (Pediatrics. 2004;114[5]:1206-1211). Ear fluid and pain do not necessarily indicate infection. According to the CDC, avoiding unnecessary treatment of otitis media with effusion — and dispensing an antibiotic only for acute otitis media — would save as much as 8 million courses of antibiotics a year.

Even CAP may have a viral etiology, and mixed viral and bacterial infections are common (Thorax. 2008;63:42-48). To avoid contributing to resistance, says Hoesley, initiate appropriate empiric antibacterial therapy and utilize appropriate culture data to guide modifications in the antibiotic regimen such that the agent selected targets the specific bacterium.

“Using older drugs is not necessarily wrong. For example, doxycycline may be an effective alternative for CAP treatment as opposed to newer, more expensive, broader-spectrum antibiotics such as moxifloxacin or levofloxacin,” he says. “It is important for each clinician to develop an understanding of bacterial resistance patterns in their hospital and community and use this knowledge to make effective empiric antibiotic decisions for their patients.”

Significant risk factors for a multidrug-resistant infection are recent or current hospitalization; residence in a nursing home or facility; home infusion therapy; chronic dialysis within the past 30 days; home wound care; a family member with a multidrug-resistant pathogen; antibiotic therapy in the past 90 days; high incidence of antibiotic resistance in the community or hospital unit; or immunosuppressive disease or therapy.

If clinicians encounter resistance, Hoesley recommends susceptibility testing rather than doubling or tripling antimicrobials. Initial empirical therapy for suspected health care-associated pneumonia depends on risk factors and requires pathogen-specific data to allow prompt, targeted treatment.

Staphylococcus Aureus
CDC Active Bacterial Core Surveillance groups have found that MRSA is a tremendous burden. Recent US estimates indicate 90,000 deaths a year due to MRSA infections — more than HIV/AIDS. The CDC recently warned clinicians that 44% of pediatric influenza-related deaths between October 2006 and September 2007 occurred in the setting of bacterial coinfection. S aureus caused the majority of those deaths — MRSA in 15 of 22 cases. The CDC suggests taking cultures for those severely ill or suspected of having CAP and requests that all pediatric influenza-associated deaths be reported.

S aureus is present on the skin or in the noses of about 30% of healthy people, but these bacteria do not necessarily cause an infection. Approximately 5% of the population is colonized with MRSA, and 6% of community-acquired (CA) MRSA is invasive (N Eng J Med. 2005;352[14]:1436-1444). CA-MRSA strains have unique microbiologic and genetic properties compared with the traditional hospital-acquired strains and are resistant to beta-lactams. As a result, CA-MRSA is transmitted from person to person more easily and causes more skin disease than hospital-acquired (HA) MRSA. Recently another multidrug-resistant variant has emerged (Annals Intern Med. 2008;148[4]:249-257).

CA-MRSA now is widely disseminated in hospitals. At UAB Hospital, Hoesley and investigators found the majority of nosocomial infections were USA300 Panton-Valentine leukocidin (PVL)-positive MRSA rather than traditional USA100 PVL-negative MRSA (South Med J. 2008;101[1]:40-45). “We can no longer predict strain types solely on clinical factors. This shift could be disastrous if USA300 strains prove to be more pathogenic than traditional nosocomial MRSA,” he says.

The community-associated strains, which occur in individuals without conventional risk factors, often can be treated with incision and drainage. “Most cases of community-associated MRSA present as skin and soft tissue infections such as abscesses and furunculosis. Less frequently, invasive infections such as necrotizing pneumonia, fasciitis, and septicemia develop,” says Hoesley, “and these must be treated aggressively.”

S aureus is the main pathogen for health care-associated pneumonia and can be a cause of severe CAP, especially after a viral infection. It follows a rapid progressive course with shock, cavitation of lung parenchyma, and pleural effusion. Patients may have hemoptysis and necrosis on X-ray. “Treatment of such necrotizing pneumonia is difficult. MRSA remains sensitive to oral agents such as trimethoprim and sulfamethoxazole [Bactrim], clindamycin, and doxycycline, but additional options for bacteremic patients may include vancomycin or daptomycin,” Hoesley says.

Neisseria Gonorrhoeae
Gonorrhea affects 700,000 Americans annually and is the second most commonly reported infectious disease in the United States. Gonococcal strains may be resistant to penicillins, tetracyclines, spectinomycin, and fluoroquinolones.

The percentage of resistant N gonorrhoeae increased 11-fold in heterosexual men between 2001 and 2006 to almost 7%, such that the CDC no longer recommends fluoroquinolones for gonorrhea or for conditions such as pelvic inflammatory disease.

The CDC now recommends an injection of ceftriaxone as the preferred treatment for all types of gonorrhea infection (genital, anal, and pharyngeal). For genital and anal gonorrhea, physicians can consider some alternative oral cephalosporins, but there are no recommended alternatives for pharyngeal infection.

Strategies to Combat Resistance
“Vigilant infection control and prevention are a starting point,” Hoesley says. After the heptavalent pneumococcal conjugate vaccine (Prevnar) was introduced for children in 2000, antibiotic resistance and incidence of invasive pneumonia fell in children and adults — particularly those aged >65 years. The CDC recommends immunization with the 23-valent polysaccharide vaccine for adults aged >65 years. Vaccination of a large segment of an at-risk population lowers incidence and spread of invasive disease (N Engl J Med. 2003;348:1737-1746). Those with prior pneumococcal vaccination hospitalized with CAP have fewer complications and reduced length of stay and mortality (Clin Inf Dis. 2006;42:1093-1101).

Restricting antimicrobial use in hospital settings improves susceptibility. After observing increased resistance for selected gram-negative pathogens to ciprofloxacin and rising fluoroquinolone use at UAB Hospital, Hoesley and the Pharmacy and Therapeutics Committee implemented a formal fluoroquinolone restriction program. Hoesley restricted ciprofloxacin and moxifloxacin to use only with a culture-proven infection or in a patient intolerant of other agents and eliminated use of all other systemic fluoroquinolones. “Since 2006 we have seen improved susceptibility profiles of gram-negative bacteria in the hospital,” he says. “Different approaches are necessary in outpatient practices, but restricting use does have a positive impact.”

Other measures include avoiding antibiotic use when feasible, cycling antibiotics, and using first-generation drugs when possible. “Newer drugs are not necessarily better than old ones. Older drugs may have a higher incidence of resistance, but they work in a large percentage of patients, and the paradigm is to exhaust the existing agents before employing new agents with a broader spectrum of activity and larger potential impact on resistance,” he says.

To reduce antibiotic use, Hoesley advises physicians to augment patient education measures. In one study, patient and clinician education resulted in a 26% decline in antibiotic prescriptions for acute bronchitis (JAMA. 1999;281[16]:1512-1519). A handful of small studies have indicated that communicating with parents about appropriate antibiotic use does reduce the number of prescriptions. When included in medical decisions, parents often are willing to adopt a watchful waiting approach to otitis media (Pediatrics. 2005;115[6]:1466-1473).

Mechanisms of Resistance
UAB biochemist and molecular geneticist Dmitry G. Vassylyev, PhD, has discovered new information on the structure of a key enzyme in bacteria that could lead to improved antibiotics and less antibiotic resistance (Nature. 2007;7150:157-162;163-168). Using X-ray crystallography, Vassylyev’s team discovered how antibiotics bind to and affect their targets in bacteria. “RNA polymerase is the key enzyme regulating the transfer of genetic information from DNA to RNA,” Vassylyev says. “All living organisms use this enzyme to transmit the instructions stored in genes to messenger RNA, which in turn communicates those instructions to the cells.”

Without properly functioning RNA polymerase, a cell will die. Vassylyev’s team created a detailed image of the elongation complex, a structure formed by RNA polymerase, enabling them to determine the mechanism a certain antibiotic uses to block transcription. It prevents the normal operation of the elongation complex by freezing it in an inactive state. The RNA polymerase malfunctions and the cell dies.

Vassylyev’s discovery provides a foundation for producing drugs that will efficiently enter cells, bind to RNA polymerase, and destroy bacteria without inhibiting the growth of human cells. “Not only does this present a pathway for new antibiotics, it also should allow existing drugs to be improved to overcome drug-resistant bacteria,” he says.

For more information:
Dr. Craig Hoesley
Dr. Dmitry Vassylyev
1.800.UAB.MIST
mist@uabmc.edu