Resistance of Streptococcus pneumoniae to beta-lactam antibiotics

INTRODUCTION — From the beginning of the antibiotic era to the mid-1970s, Streptococcus pneumoniae (pneumococcus) remained uniformly susceptible to all classes of antibiotics that had been active against this organism, with the possible exception of tetracycline. Thus, the medical profession had a rude awakening in 1977 and 1978 when outbreaks of infection due to antibiotic-resistant pneumococci occurred in Durban and Johannesburg, South Africa [1,2]. These outbreaks originated in infectious diseases hospitals where children with serious viral infections were routinely treated "prophylactically" with antibiotics. Although originally called penicillin-resistant pneumococci (PRP), these bacteria appeared to have acquired genetic material that encoded resistance to penicillin as well as to other commonly used antibiotics.

In the ensuing decades, resistance of pneumococci to a variety of antimicrobial agents has evolved from an ominous medical curiosity to a worldwide health problem. Pneumococcal resistance has increased to a point that it is clinically relevant in the following classes of antibiotics:

●Beta-lactams (penicillins, cephalosporins, and carbapenems)

●Macrolides (erythromycin, azithromycin, clarithromycin)

●Lincosamides (clindamycin)

●Tetracyclines

●Inhibitors of folate synthesis (trimethoprim-sulfamethoxazole [TMP-SMX])

●Fluoroquinolones (ciprofloxacin, levofloxacin, gemifloxacin, moxifloxacin)

A number of studies have addressed apparent risk factors for the acquisition of antibiotic-resistant pneumococcal strains [3-6]. These include:

●Previous antibiotic use

●Previous time spent in daycare (for children) or in an institutional setting, including nursing home, long-term care facility, or a shelter for people who are homeless (for adults)

●Recent respiratory infections

The mechanisms of action and resistance, definitions of resistance in relation to clinically achievable drug concentrations, and clinical data on the outcome of therapy in otitis, sinusitis, acute exacerbations of chronic bronchitis, pneumonia, meningitis, and bacteremia will be reviewed here for the beta-lactams. Resistance to the other classes of drugs is discussed separately. (See "Resistance of Streptococcus pneumoniae to the fluoroquinolones, doxycycline, and trimethoprim-sulfamethoxazole" and "Resistance of Streptococcus pneumoniae to the macrolides, azalides, and lincosamides".)

MECHANISM OF ACTION AND RESISTANCE — Beta-lactam antibiotics inhibit pneumococcal growth by irreversibly binding the active site of enzymes that are needed to synthesize peptidoglycan, the major constituent of the cell wall. When penicillin-susceptible pneumococci are incubated with low concentrations of radiolabeled penicillin and then subjected to protein electrophoresis and radioautography, five distinct bands, each representing a different enzyme that contributes to cell wall synthesis, are detected. These enzymes are often called "penicillin-binding proteins." In strains that have reduced susceptibility to penicillin, the affinity of the antibiotic for one or more of these enzymes is reduced; incubation with low concentrations of penicillin, followed by radioautography, detects reduced or absent labeling of one or more of the five bands (figure 1) [7]. However, labeling can generally be restored at higher antibiotic concentrations.

These observations explain the central clinical teaching that, in treating infections that do not involve the central nervous system (CNS), decreased susceptibility of pneumococci to penicillins is usually overcome with penicillin doses that are generally prescribed. The same principle applies to cephalosporins and carbapenems. However, there are differences in the capacity of these drugs to overcome the resistance, and clinicians need to know where each falls in the spectrum of efficacy at increased concentrations (table 1). Whether in vitro resistance to macrolides (depending upon the molecular basis for the resistance) or the fluoroquinolones can be overcome by increased doses of drug is controversial. Resistance to folate inhibitors or tetracyclines cannot be overcome by increasing the antibiotic dose. (See "Resistance of Streptococcus pneumoniae to the macrolides, azalides, and lincosamides" and "Resistance of Streptococcus pneumoniae to the fluoroquinolones, doxycycline, and trimethoprim-sulfamethoxazole".)

Definitions and prevalence of resistance — The definitions of susceptibility have been changed and can be confusing (table 2) [8,9]. Depending upon the parenteral dose being administered, penicillin levels in plasma and, therefore, in alveoli, soft tissues, sinuses, and perhaps the middle ear tend to exceed 2 mcg/mL for most of the treatment period. The peak levels attained with oral dosage are, of course, much lower, but amoxicillin has a much longer half-life, and 500 mg every six hours orally maintains levels above 2 mcg/mL for most of the treatment period. Because of the blood-brain barrier, cerebrospinal fluid (CSF) levels in children who are receiving 250,000 units/kg per day in six divided doses generally do not exceed 1 to 2 mcg/mL [10,11]. Thus, currently accepted definitions of resistance consider the site of the infection, the route of administration of the antibiotic, and the dosage, as discussed in the following section.

Penicillin — For non-CNS infections, when an infection is being treated with intravenous (IV) antibiotics, the following definitions for penicillin resistance apply:

●Susceptible – Minimum inhibitory concentration (MIC) ≤2 mcg/mL

●Intermediate – MIC >2 and ≤4 mcg/mL

●Resistant – MIC >4 mcg/mL

When oral penicillin is being used, the following definitions apply:

●Susceptible – MIC ≤0.06 mcg/mL

●Intermediate – MIC >0.06 and ≤1 mcg/mL

●Resistant – MIC >1 mcg/mL

For CNS infections, the following definitions apply:

●Susceptible – MIC ≤0.06 mcg/mL

●Resistant – MIC >0.06 mcg/mL

There is no intermediate category for CNS infections.

Resistance rates vary regionally:

●In the early 2000s, using older definitions of resistance, approximately 60 percent of pneumococci in the United States were said to be susceptible to penicillin, 20 percent intermediately resistant, and 20 percent resistant [12,13]. Using current definitions, rates of resistance are much lower. At present, when usual doses of parenteral penicillin are used to treat pneumococcal infection that does not involve the CNS, 96 percent of isolates are susceptible, 2 percent are intermediate, and 2 percent are resistant [14].

●Higher rates of penicillin resistance have been described in other countries. For example, among 685 S. pneumoniae isolates from 14 centers in 11 Asian countries that were collected from January 2000 to June 2001 [15], 52 percent were reported as not susceptible to penicillin, with rates of resistance as high as 74 percent in Vietnam. However, using definitions of susceptibility, resistance rates are quite similar to those in the United States [16].

Despite the improved rates of penicillin susceptibility reported for pneumococcal isolates in the United States, it is important to note that rates of penicillin susceptibility may fluctuate, largely related to the effects of widespread use of the pneumococcal conjugate vaccine and local habits of antibiotic prescribing. In Spain, for example, emergence of strains with reduced susceptibility to penicillin has been attributed to increased uptake of PCV13 [17].

Impact of the pneumococcal conjugate vaccine — Use of pneumococcal conjugate vaccines in children reduces carriage of vaccine strains and therefore reduces the spread of these strains to adults. Many of the strains included in the original 7-valent conjugate vaccine had reduced susceptibility to penicillin. In the United States, widespread use of PCV7, a protein conjugate pneumococcal vaccine that contains polysaccharides from seven serotypes that commonly colonized and infected young children, was followed by a >90 percent reduction in invasive disease caused by vaccine serotypes in both children and adults and, therefore, by a reduction in the overall rate of nonsusceptibility [18].

As a result of widespread vaccination of children with conjugate pneumococcal vaccine, most vaccine strains have largely disappeared, and new strains have emerged (called "replacement strains") [19]. On the one hand, those that were targeted by the vaccine and have largely disappeared tended to be resistant ones carried by toddlers and young children. On the other hand, some of the replacement strains have been resistant to penicillin and other antibiotics. Serotype 19A emerged so promptly after introduction of 7-valent pneumococcal vaccine that it was added to the 13-valent vaccine. Since the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) in 2010, other emerging serotypes that are not contained in either PCV13 or the pneumococcal polysaccharide vaccine (PPSV23) and that exhibit a substantial degree of antimicrobial resistance have been reported; examples of these serotypes include serotypes 15B, 23A, 23B, and 35B [20,21]. PCV20 is now available, and will cover serotype 15B, but new capsular types will continue to emerge.

Amoxicillin — Most clinicians prescribe amoxicillin instead of penicillin because of its more reliable absorption from the gastrointestinal tract and longer half-life. These pharmacologic considerations help to explain the discrepancies between definitions of susceptibility to penicillin and amoxicillin (table 2).

Cephalosporins — Similar concepts that are operative in the mechanisms for penicillin resistance apply to the cephalosporins [12]. With ceftriaxone, for example, 50 mg/kg given intravenously yields peak serum levels of 250 mcg/mL and peak CSF levels of 2 to 5 mcg/mL (figure 2) [22]. The drug declines in the bloodstream with a half-life of six hours. Clearly, treatment of non-CNS infections in adults with 1 g ceftriaxone given every 24 hours (approximately 12.5 mg/kg) should be effective against all but the most highly resistant isolates. Virtually all pneumococcal isolates reported are highly susceptible to ceftaroline [23,24].

Definitions of susceptibility to cefotaxime or ceftriaxone for non-CNS isolates of S. pneumoniae are as follows [8]:

●Susceptible – MIC ≤1 mcg/mL

●Intermediate – MIC >1 and ≤2 mcg/mL

●Resistant – MIC >2 mcg/mL

According to these definitions, in the United States, 96.6 percent of pneumococci are susceptible, 2.8 percent are intermediate, and 0.6 percent are resistant to ceftriaxone and cefotaxime [25]. Ceftaroline, a newer cephalosporin, appears to be particularly effective in vitro against pneumococcal isolates [24]. The reader should conclude that nonmeningeal infections caused by pneumococcus are very likely to respond to currently used doses of ceftriaxone, cefotaxime, cefepime, or ceftaroline. The same applies to imipenem or ertapenem. Even in Asia, only 3 percent of pneumococcal isolates are resistant to ceftriaxone [15].

Current definitions of susceptibility for CNS isolates of S. pneumoniae to cefotaxime or ceftriaxone are:

●Susceptible – MIC ≤0.5 mcg/mL

●Intermediate – MIC >0.5 and ≤1 mcg/mL

●Resistant – MIC >1 mcg/mL

Carbapenems — Resistance to carbapenems, including meropenem, appears to parallel that of third-generation cephalosporins, based upon rising MICs in the United States [26] and reports from countries such as Italy [23] and Japan [27].

RESISTANCE AND THE OUTCOME OF THERAPY — Resistance of pneumococci to beta-lactam antibiotics is relative and, in the treatment of pneumonia, can generally be overcome by the doses currently in use. In cases other than meningitis, approximately 95 percent of pneumococcal infections will respond to treatment with standard-doses of beta-lactam antibiotics (eg, 1 gram of ceftriaxone daily for an average adult). However, in treating meningitis, one needs to pay particular attention to the measured susceptibility of the infecting organism.

Otitis media — After young children with otitis receive 30 mg/kg of amoxicillin orally, mean concentrations in the middle ear fluid are approximately 4 to 7 mcg/mL [28,29]. Meticulous studies have shown that the outcome of amoxicillin treatment for pneumococcal otitis media correlates well with the amoxicillin susceptibility of the infecting organism [30]. These data validate the current recommendations to administer 80 to 90 mg/kg per day of amoxicillin orally in two divided doses, which is effective for all but the most resistant pneumococci [31,32]. In contrast, a drug such as cefaclor (table 1), which has a high MIC for penicillin-resistant pneumococci relative to achievable serum levels, is much less likely to produce a cure [33]. (See "Acute otitis media in children: Treatment", section on 'Initial antibiotic therapy'.)

Acute purulent rhinosinusitis — Similar data are not available to relate the outcome of treatment for acute purulent rhinosinusitis to antibiotic resistance. Nevertheless, it seems likely that the same considerations would apply as for otitis media. Rhinosinusitis responds very well to treatment with amoxicillin [34] and recommendations for treating rhinosinusitis are nearly identical to those for otitis. The increasing prevalence of beta-lactamase-producing Haemophilus influenzae in the United States has led to a preference for amoxicillin-clavulanic acid in treating these upper respiratory conditions. (See "Uncomplicated acute sinusitis and rhinosinusitis in adults: Treatment".)

Pneumonia and bacteremia — In the preantibiotic era, pneumococci caused 85 to 95 percent of all community-acquired pneumonia (CAP). Studies in the United States have implicated S. pneumoniae in no more than 5 to 8 percent of CAP [35,36]. However, one subsequent study suggests that among hospitalized patients able to provide a sputum sample at admission, S. pneumoniae was detected alone or with a respiratory virus in 20 percent of cases and together with a bacterial infection in an additional 5 percent [37]. In Europe, pneumococcus almost certainly causes a higher proportion of CAP [38-40]. (See "Treatment of community-acquired pneumonia in adults in the outpatient setting" and "Treatment of community-acquired pneumonia in adults who require hospitalization".)

In summary, at present, nearly all pneumococcal infections other than those involving the central nervous system appear to respond to currently recommended doses of beta-lactam antibiotics.

Meningitis — Because of the limited ability of beta-lactams to cross the blood-brain barrier, only about 80 percent of pneumococcus isolates are fully susceptible at achievable concentrations. There is substantial risk that meningitis caused by pneumococci that are not fully susceptible to beta-lactam antibiotics will not respond to treatment with these drugs [41]. For example, meningitis caused by strains with a ceftriaxone MIC >2 mcg/mL are likely to fail to respond to treatment with recommended doses of this drug [42], whereas those with MIC = 1 mcg/mL may or may not respond (table 2) [42-44].

These findings justify the recommendation that initial empiric therapy of pneumococcal meningitis be with vancomycin in addition to ceftriaxone or cefotaxime [41,45], until the results of susceptibility testing are known. When susceptibility studies are completed, vancomycin can be discontinued if the infecting organism is susceptible to beta-lactam antibiotics. However, if the organism is intermediate or resistant, vancomycin should be continued for the entire treatment period. (See "Treatment of bacterial meningitis caused by specific pathogens in adults", section on 'Streptococcus pneumoniae' and "Bacterial meningitis in children older than one month: Treatment and prognosis", section on 'Streptococcus pneumoniae'.)

SUMMARY

●Mechanisms of resistance – Early in the antibiotic era, pneumococci were uniformly susceptible to penicillin. Resistance to penicillin and other beta-lactams arose when mutations appeared in enzymes that are needed to synthesize the cell wall, the active site at which beta-lactams block the replication of pneumococci. (See 'Introduction' above and 'Mechanism of action and resistance' above.)

●Dose-dependent nonsusceptibility – Nonsusceptibility of pneumococci to beta-lactam resistance antibiotics is dose dependent; when non-central nervous system (CNS) infections are being treated, it can be overcome by the doses of beta-lactams in use. In cases other than meningitis, approximately 95 percent of pneumococcal infections will respond to treatment with beta-lactams. (See 'Resistance and the outcome of therapy' above.)

●Limited penetration of beta-lactams to CNS – Because of the limited ability of beta-lactams to cross the blood-brain barrier, only about 80 percent of pneumococcus isolates are fully susceptible at concentrations achievable in the CNS. Therefore, resistance is of much greater consequence in cases of meningitis than in cases of disease outside the CNS. (See 'Meningitis' above.)

●Susceptibility thresholds vary by site of infection – Accordingly, microbiology laboratories report pneumococcal susceptibility to beta-lactams based on the site of infection, distinguishing between isolates that cause meningitis and those that cause infections at other sites (table 2). (See 'Meningitis' above.)