Chapter 128. Pneumococcal Infections (Part 6) pdf

At present, ~20% of pneumococcal isolates in the United States exhibit intermediate resistance to penicillin [minimal inhibitory concentration MIC 0.1– 1.0 μg/mL], and 15% are resistant

Chapter 128 Pneumococcal Infections

(Part 6)

Pneumococcal Infections: Treatment

Antibiotic Susceptibility

β-Lactam antibiotics, the cornerstone of therapy for serious pneumococcal

infection, bind covalently to the active site and thereby block the action of

enzymes (endo-, trans-, and carboxypeptidases) needed for cell-wall synthesis

Because these enzymes were identified by their reaction with radiolabeled

penicillin, they are called penicillin-binding proteins Until the late 1970s,

virtually all clinical isolates of S pneumoniae were susceptible to penicillin (i.e.,

were inhibited in vitro by concentrations of <0.06 µg/mL) Since then, an

increasing number of isolates have shown some degree of resistance to penicillin

Resistance results when spontaneous mutation or acquisition of new genetic

material alters penicillin-binding proteins in a manner that reduces their affinity

for penicillin, thereby necessitating a higher concentration of penicillin for their

saturation The genetic information that renders pneumococci resistant to

penicillin is acquired from oral streptococci and is transmitted along with genes

that convey resistance to other antibiotics as well Selection of antibiotic-resistant

strains worldwide—especially in countries where antibiotics are available without

prescription and in loci of high antibiotic use, such as day-care centers—greatly

contributes to the prevalence of multidrug resistance

At present, ~20% of pneumococcal isolates in the United States exhibit

intermediate resistance to penicillin [minimal inhibitory concentration (MIC) 0.1–

1.0 μg/mL], and 15% are resistant (MIC ≥2.0 μg/mL; Fig 128-3) The rate of

resistance is lower in countries that, by tradition, are conservative in their

antibiotic use (e.g., Holland and Germany) and higher in countries where usage is

more liberal (e.g., France) In Hong Kong and Korea, resistance rates approach

80% These definitions of resistance, however, were based on drug levels

achievable in CSF during treatment of meningitis, whereas levels reached in the

bloodstream, lungs, and sinuses are actually much higher Thus the MIC needs to

be interpreted in light of the infection being treated Pneumonia caused by a

penicillin-resistant strain is likely to respond to conventional doses of β-lactam

antibiotics, whereas meningitis may not The recently revised definition of

amoxicillin resistance (susceptible, MIC ≤2 µg/mL; intermediately resistant, MIC

= 4 μg/mL; and resistant, MIC ≥8 μg/mL) is based on susceptibility to serum

levels, with the assumption that no physician would knowingly treat meningitis

with this oral medication Pneumonia due to a pneumococcal strain with

intermediate amoxicillin resistance is still likely to respond to treatment with this

drug, whereas that due to a resistant strain may not On the assumption that

antibiotic concentrations in middle-ear fluid or sinus cavities approach those in

serum, similar inferences can be made about the treatment of otitis or sinusitis

Figure 128-3

The e-strip method currently used by most laboratories to determine

the susceptibility of S pneumoniae to antibiotics After the plate is streaked

with a suspension of pneumococci, a strip impregnated with graded concentrations

of the antibiotic under study (penicillin in the example shown) is placed on the

surface, and the plate is incubated overnight at 37°C The organism on the left is

inhibited by a penicillin concentration of 0.016 µg/mL and is fully susceptible to

this drug The organism on the right is inhibited only by a penicillin concentration

of 0.25 µg/mL and is intermediately resistant to this agent

Penicillin-susceptible pneumococci are susceptible to all commonly used

cephalosporins Penicillin-intermediate strains tend to be resistant to all first- and

many second-generation cephalosporins (of which cefuroxime retains the best

efficacy), but most are susceptible to certain third-generation cephalosporins,

including cefotaxime, ceftriaxone, cefepime, and the oral cefpodoxime One-half

of highly penicillin-resistant pneumococci are also resistant to cefotaxime,

ceftriaxone, and cefepime, and nearly all are resistant to cefpodoxime Just as in

the case of penicillin, susceptibility to cefotaxime and ceftriaxone is defined on the

basis of achievable CSF levels Thus pneumonia caused by intermediately

resistant strains (MIC = 2 µg/mL) still responds well to usual doses of these drugs,

and pneumonia due to a resistant organism (MIC ≥4 µg/mL) is likely to respond

Meningitis due to intermediately resistant strains may not respond, and meningitis

due to a resistant strain is likely not to respond to treatment with cefotaxime or

ceftriaxone

About one-quarter of all pneumococcal isolates in the United States are

resistant to erythromycin and the newer macrolides, including azithromycin and

clarithromycin, with much higher rates of resistance among penicillin-resistant

strains This resistance will certainly affect empirical therapy for bronchitis,

sinusitis, and pneumonia In the United States, the majority of macrolide-resistant

pneumococci bear the so-called M phenotype (erythromycin MIC = 1–8 µg/mL)

and are susceptible to clindamycin In this case, resistance is mediated by an efflux

pump mechanism; to some extent, M-type resistance can be overcome by

clinically achievable levels of macrolides In Europe, most macrolide resistance is

due to a mutation in ermB, which confers high-level resistance not only to

macrolides but also to clindamycin; >90% of pneumococcal isolates in the United

States are susceptible to clindamycin Rates of doxycycline resistance are similar

to those observed for macrolides One-third of pneumococcal isolates are resistant

to trimethoprim-sulfamethoxazole The newer fluoroquinolones remain effective

against pneumococci; the rate of resistance is generally <2–3% in the United

States but is higher elsewhere and may be much higher in closed environments

where these drugs are heavily prescribed, such as nursing homes and

assisted-living facilities Ketolides (such as telithromycin) appear to be uniformly effective

against pneumococci, as does vancomycin