Community-Acquired Respiratory Tract Infections: Controversies in Resistance Patterns in Community-Acquired Pneumonia and Acute Exacerbations of Chronic Bronchitis

At an industry-sponsored symposium held in conjunction with CHEST 2003, the annual meeting of the American College of Chest Physicians in Orlando, Florida, four leading infectious researchers discussed recent developments in understanding of bacterial resistance and what clinicians can do to attenuate further increases in antibiotic resistance.

This program was supported by an unrestricted educational grant from Aventis Pharmaceuticals.

Evolving Bacterial Resistance: PROTEKT US — An Update

Stephen M. Brecher, PhD, Director of Microbiology at the VA Boston Healthcare System and Associate Professor of Microbiology at Boston University School of Medicine in Boston, MA, began the symposium with a brief history lesson. “Antibiotics have been used in the United States and throughout the world for only 62 years.” In comparison, homosapiens began to appear 125,000-200,000 years ago and bacteria, 3.85 billion years ago. “It becomes a no-brainer, 3.85 billion years (bacteria) versus 62 years (antibiotics): Bacteria will win,” said Dr. Brecher, adding, “I do consider them to be the dominant species on the earth and they’ll be around long after we have disappeared.” In regard to community acquired respiratory tract infections, S. pneumoniae is still the dominant pathogen, accounting for 35-55% of infections, followed by H. influenzae (15- 25%), and M. catarrhalis (2-8%). (Clin Ther. 1992;14: 214-229; Pediatr Infect Dis J. 1996; 15:955-962; N Engl J Med. 1999; 333:1618-1624). All three organisms show some resistance to antibiotics. In 1967, the first penicillin resistant S. pneumoniae was observed. Today, “about 35% of the strains are non-penicillin susceptible,” stated Dr. Brecher. There has been increasing macrolide resistance and we are also beginning to observe fluoroquinolone resistance (Table 1).

PROTEKT Studies
PROTEKT is an acronym for Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin study. It is an ambitious surveillance study that is currently in its third year and has looked at between 30,000 and 40,000 isolates. Minimum Inhibitory Concentrations (MICs) were determined at one location (Clinical Microbiology Institute in Portland, Oregon) and the pathogens studied include S. pneumoniae, H influenzae, and S. pyogenes. Among the plethora of antibiotics tested against S. pneumoniae, it was found that penicillin non-susceptible percentage was 30-35% and macrolide resistance was approximately 25%-30%. Fluoroquinolones resistance was 0.3-1.0% and the lowest resistance rate was seen with the new ketolide, telithromycin ( 0.02%). While resistance rates continue to rise for S. pneumoniae each year, the PROTEKT study found erythromycin resistance in S. pyogenes to be consistent at 5.4-5.7% over the three years.

Clinical Impact of in vitro Resistance in Community Acquired Pneumonia: Current Understandings

Continuing the discussion on bacteria resistance, Joseph P. Lynch III, MD, FCCP, Professor of Medicine at the David Geffen School of Medicine at UCLA in Los Angeles, CA, summarized some of the mechanisms of resistance.

Antibiotic-Resistant Pneumococci
“Bacteria divide about every 20 to 30 minutes, what happens at the end of the day, you’ve got close to a billion organisms,” said Dr. Lynch, adding, “one of the problems when you give antibiotics is you will select out those organisms which have already acquired resistance genes.”

Furthermore, antibiotic resistant pneumococci are not necessarily resistant to one antibiotic. Dr. Lynch said, “I think it’s important when you deal with a mutation that affects penicillin-binding proteins you’re going to have an impact on all b-lactam drugs since they all work by those penicillin- binding proteins and as you acquire penicillin resistance you will also require resistance to the cephalosporins.” To confirm this observation, Dr. Lynch discussed studies by Drs. Doerns (Clin Invest Dis. 1998; 27:764-770) and Jones (Clin Invest Dis. 2000;31:[suppl] S31) showing that many islets are multi-drug resistant.

Resistance mutation that leads to penicillin has now been spread worldwide by five dominate clones. These are the serotypes, 23F, 6, 14, 19 and 9. “These 5 clones have been responsible for more than 50 percent of all pneumococcal resistance in the world,” said Dr. Lynch.

Macrolide-Resistant Pneumococci
The two mechanisms of macrolide resistance are an efflux pump aberration or changes in the ribosome. Although the mechanisms are different from penicillin-binding protein alterations, there is a link between penicillin resistance and macrolide resistance. “The common theme here is exposure to antibiotics is what drives antibiotic resistance,” said Dr. Lynch.

Resistant rates for macrolides have dramatically increased over the past few decades. In 1978, rates were less than 1% but by 1998, rates were over 20% (J Infect Dis. 1991;163:1273-1278; JAMA. 1994;271:1831-1835; Antimi-crob Agents Chemother. 1994:38:2419-2425; Antimicrob Agents Chemother.1996;40:1208-1213; Diagn Microbiol Infect Dis. 1997;29:249-257; J Antimi-crob Chemother. 1999;44:749-759}.

With that being said, Dr. Lynch stated that the good news is resistance to ceftriaxone remains rare and only 0.2% of isolates were resistant to both ceftriaxone and levofloxacin, as well as the newer fluoroquin-olones.

Clinical Impact of High Grade Penicillin Resistance
A large retrospective study involving over 5800 patients with bacterial pneumococcal infections found that the major risk factor for death was not infection but age (Am J Public Health. 2000; 90:223). However, high resistance was also a mortality risk factor in patients with MIC > 4.0 (risk factor = 7.1). Fortunately, low and intermediate levels of resistance to antibiotics is currently not a risk factor for mortality when other factors are considered (i.e., age, severity of illness, comorbidities) but Dr. Lynch warned that continued improper use of antibiotics, especially in high density areas, could change that statistic.

Concluding Remarks
Dr. Lynch ended his presentation stating, “resistance is inevitably linked to antibiotic usage and certain classes of antibiotics will preferentially elicit resistance to those classes,” adding, “we have to be smarter about which ones we use.”

Clinical Impact of in vitro Resistance in Acute Exacerbations of Chronic Bronchitis:
Current Concepts

Two major issues of COPD exacerbation that need to be better recognized are the morbidity and mortality rates. Some studies have shown mortality rates ranging from 6-12% to as high as 24%. To discuss the effects of antibiotic treatment on exacerbations, Antonio Anzueto, MD, Associate Professor of Medicine at the University of Texas Health Science Center and Section Chief of the Texas Veterans Health Care System in San Antonio, TX provided the audience with an overview of COPD exacerbations and some of the common bacteria involved and the best treatment options available.

When an exacerbation of COPD occurs, it usually involves different pathogens than normally observed in community-acquired infections. Furthermore, only 40%-50% of exacerbations involve bacterial infections (Figure 1). The most common bacteria in COPD exacerbations are H. influenzae (49%), S. pneumoniae (19%), M. catarrhalis (14%), and other (18%) (Am J Manag Care. 1999;5:S677-S684; Semin Respir Infect..2000;15:234-247; Eur Resp J. 2001:18:541S).

The recurrence of bacterial infection in these were believed to be due to failure to eradicate them the first time, Dr. Anzueto said, “Once you get rid of that bacteria during an initial exacerbation, the haemophilus isolated during subsequent exacerbations, two or three months later, it’s a different haemo-philus.” It has been estimated that approximately 30% of the time when the patient has a recurrent exacerbation, it is produced by new stains of bacteria that can infect the airway.

Relapse Rates
Dr. Anzueto along with investigators have reported that exacerbation relapse rates are higher in patients that did not received antibiotics, 30% compared to less than 20% in patients receiving antibiotics (Chest 2000; 117:1345-1352). Further analysis show relapse rates were higher in patients given amoxicillin but much lower in patients given augmentin, macrolides, TMP/ SMX, ciprofloxaxin, or cephalosporins. Furthermore, one of the strongest predictors of relapse is the type of the antibiotic given. In a study by Dr. Pechere clinical failure rate was correlated to bacteriological failure rate in patients with COPD exacerbations (Int Med. 1998; 15:46). In other words, “the patients who have bugs still in the airway, they are very likely to fail and you need to get rid of those pathogens,” said Dr. Anzueto.

In summary, Dr. Anzueto said, “acute exacerbations continue to be a major problem in this patient population.” It has been well established that in vitro bacterial resistance has a significant impact on patient outcome and these may be improved and antimicrobial resistance slowed if guidelines are applied. Finally, physicians need to be more aware of the new strains of resist-ance that can quickly develop in these patients and therapy needs to address this problem as well as be tailored to the disease severity and the patient’s risk factors.

New Treatment Regimens for Community Acquired Pneumonia (CAP) and Acute Exacerbations in Chronic Bronchitis (AECB) and Future Therapies to Combat Resistance

How likely is my patient to have a resistant isolate and how do I treat them if they are at risk for resistance? Those were the two questions asked by Fernando Martinez, MD, MS, FCCP, Professor of Internal Medicine in the Division of Pulmonary and Critical Care Medicine at the University of Michigan, Ann Arbor, MI, to introduce his presentation on how to recognize patients at risk for resistance and how to treat them.

How Likely is a Resistant Isolate in My Patient?
Two key factors to estimating the likelihood of a resistant isolate in a patient are: the patient’s own risk factors (an older patient, a patient with immunocompromise, multiple medical conditions, a child in a daycare center, and whether the patient has received antibiotics in the past); where the patient lives (or traveled to) and what the resistant rates are in that community. To illustrate the importance of prior antibiotic therapy, Dr. Martinez discussed Victor Yu’s multicenter, multinational prospective study that showed prior antibiotic therapy was an important risk factor for resistance (Clin Infect Dis. 2003:2003;37:230-7). Ruhe and Hasbun have also shown that previous use of b-lactams, sulfonamides, or macrolides in the past month (or 6 months) increased the risk of developing bacteremic pneumococcal pneumonia that is penicillin nonsensitive (Clin Infect Dis. 2003: 36: 1132-8). As a general rule, Dr. Martinez said, “when I ask patients what antimicrobial agent they’ve used, I tend to ask, in the last four to six months.”

Treatment for Resistant ‘At Risk’ Patients
As bacteria develop resistance to the standard antibiotic treatment, newer treatments or older treatments that have been altered need to be employed.
Currently, there are several studies showing the newer quinolones to be effective in treating penicillin-resistant strains of S. pneumoniae. Among the quinolones, George Zhanel compared PK/PD data and found levofloxacin, gatifloxacin, and moxifloxacin to have 99.9% kill rate (3 log) at 6 hours (J Antimicrobiol Chemothe.r 2001;47:435-440).

Another treatment option is the combination amoxycillin/calvulonate. Dr. Martinez said, “the modification of this classic preparation of Amox/Clav was designed specifically to address the issue of strep pneumo resistance, even at MIC levels of four.” Clinical data supports its possible use in patients at risk for resistance (J Antimicrob. Agents 2003;20:235-247).

A third option is to use a new agent. “One of the sadder parts of what we’re dealing with is, there are not a lot of novel agents that are coming,” said Dr. Martinez, adding, “the only agent that is in the near future is telithromycin.” Telithromycin is a macrolide-based compound with three major modifications to lower the induction of resistance (an added keto group), improve acid stability (an added methoxy group), and enhance antimicrobial activity (an added carboxy group) (Clin Microbiol Infect. 2001;7[suppl 3]:11-17). Comparative studies show telithromycin to have lower MICs than b-lactams, macrolides, and flouroquinones. In vitro activity of telithromycin strains has been shown in penicillin-resistant, flouroquinone-resistant, and erythromycin -resistant strains of Streptococcus pneumoniae (Aventis Pharmaceuticals, data on file). Dr. Martinez stated there are several clinical trials showing telithromycin to be a safe and effective treatment option (J Antimicrobiol Chemother. 2003;51:947-955). Dr. Martinez further said when this drug becomes available (next year), it will be interesting to see how it is used by clinicians.

How to Minimize Future Resistance
Dr. Martinez finished his presentation with a brief discussion on how to minimize future resistance. According to him, there are 3 ways to minimize resistance: 1) appropriate use of antibiotics, 2) use of more potent agents, and 3) optimization of pharmacodynamics. The appropriate use of antibiotics is in response to the observation that if antibiotics are used more sparingly, resistance will decline. For example, a study by Seppela et al. (New Engl J Med. 1997;337:441-446) showed that decreased macrolide use led to a decrease macrolide resistance in group A streptococci. Using more potent agents is a controversial subject due to the fact that many contend that increased in vitro potency translates into lower resistant rates but the data supporting this hypothesis are not definitive. Finally, Dr. Martinez stated pharmacodynamics need to be optimized. To illustrate, Dr. Martinez mentioned a study by Jumbe et al .(J Clin Invest. 2003;112:275-285) that showed PK/PD modeling can be used to develop the optimal dose and inculum size to reduce induction of resistance.

Concluding Remarks
Prior to treating your patients, clinicians must determine the patient’s risk for resistance. Once that has been established, clinicians should provide antibiotics that the patient has not used in the recent past and clinicians should look at some of the newer antibiotics available and consider using them in an appropriate manner. “We’re going to try to use the appropriate doses of some of these agents with the ultimate goal of having a patient that does well and not accelerating this trend of resistance that these speakers have highlighted so nicely for you,” concluded Dr. Martinez.