A Perspective of Cephalosporins in Pneumonia

Abstract

Several important considerations must be taken into account when selecting antibiotic therapy. In all situations the most appropriate drug is one that: (1) is highly active against the etiologic agent; (2) reaches effective concentration at the site of the infection; (3) does not lead to emergence of resistant microorganisms; (4) has low toxicity; and (5) can be administered by the desired route. The cost of an antibiotic is also a factor, but is secondary to efficacy and toxicity factors. The cephalosporin class is highly active against a wide spectrum of bacteria, reaches effective concentrations against most pathogens in respiratory secretions, rarely leads to the emergence of resistant microorganisms, has an acceptable therapeutic-toxic ratio, and can be delivered by all three routes at a range of dosage schedules. Therefore, cephalosporins will continue to have a principal role in the treatment of pneumonia and deserve discussion of their relative value to the current penicillins and aminoglycosides and the newer carbapenems, quinolones and monobactams in this setting. The first cephalosporin, cephalothin, became available in the United States in 1964. Initially, cephalosporins were limited to two parenteral dosage forms, cephalothin and cephaloridine. These were followed by oral as well as new parenteral formulations that are less painful on intra-muscular injection, more capable of reaching higher blood levels and have a longer half-life (ie, cefazolin), but the microbiologic properties and toxicities are similar (Table 1).Table 1Classification of CephalosporinsFirst-generationSecond-generationThird-generationCephalothinCefoxitinCefotaximeCefazolinCefamandoleMoxalactamCephapirinCefuroximeCefoperazoneCephradineCeforanideCeftizoximeCephaloridineCefotetanCeftazidimeCephalexinCefmetazoleCeftriaxoneCefadroxilCefonicidCefmenoximeCefotiamCefsulodinCefbuperazoneCefpiramid Open table in a new tab The second-generation cephalosporins emphasized extension of the antibacterial spectrum not only against Enterobacteriacae, but also beta-lactamase producing H influenzae and B fragilis (Table 1). The third-generation cephalosporins are represented by a very diverse group of potent, broad-spectrum beta-lactam antibiotics. The agents have a broader spectrum of activity and more stability to several of the beta-lactamase enzymes than do first- or second-generation cephalosporins. Since the release of cefotaxime in the United States in 1981, there are now ten or so available third-generation agents with several more under investigation (Table 1). Because there are more commonalities in each generation than significant differences, it seems most practical for clinicians to become knowledgeable about one agent in each of the first-, second- and third-generation categories. Beta-lactam antibiotics (ie, penicillins, cephalosporins, carbapenems, monobactams) act by interfering with a terminal step in cell wall synthesis which requires linking of peptidoglycan synthesis. The cephalosporin nucleus consists of the beta-lactam ring attached to a dihydrothiazine ring (Fig 1). The activity will occur only if the cephalosporin can bind to penicillin-binding proteins (PBP), enzymes located on the inner cell membrane that catalyze the peptidoglycan synthesis. However, binding of the cephalosporin to a PBP does not necessarily result in inhibition of bacterial growth. This may occur because: (a) some PBPs that may be very sensitive to cephalosporins may have no role in cell wall metabolism, (b) other PBPs that do govern cell wall synthesis and are sensitive to cephalosporins have little to do with the direct antimicrobial effects, and yet, (c) other PBPs that are not only involved with cell wall synthesis and are sensitive to cephalosporins resist the inhibitory effects of the drug. The killing and lyses of bacteria by a beta-lactam drug still require other steps subsequent to the antibiotic-PBP binding reaction that are less completely understood. Clinical and/or bacteriologic failure of appropriate therapy reflects one or several concomitant factors: (a) compromised host's systemic immune defense mechanisms; (b) abnormal local immune defense mechanisms; (c) non-immune local defense disorder (eg, abscess, necrosis, obstruction, foreign material); (d) superinfection (eg, candidiasis); (e) failure of antibiotic to reach the site of infection (eg, blood-brain barrier, vascular insufficiency); (f) bacterial resistance to the antibiotic. Bacterial resistance to cephalosporins may occur by several mechanisms. First of all, failure of the drug to penetrate through the outer wall porin channels of some bacteria will restrict the drug from reaching its target site on the PBP. Gram-positive organisms have more permeable cell walls than Gram-negative organisms so this is not an important mechanism of antibiotic resistance for Staphylococcus and Streptococcus. A second mechanism of resistance occurs from the production by many Gram-positive and Gram-negative organisms of beta-lactamases that act predominantly as penicillinases or cephalosporinases. The basic reaction of beta-lactamase with a cephalosporin is hydrolysis of the beta-lactam ring causing the ring to open and result in inactivation of the drug (Fig 2). This is a very important mechanism of bacterial resistance to cephalosporins. These enzymes are genetically mediated through chromosomes or plasmids and vary in their location, characterization, concentration and enzymatic activity. Staphylococcus sp excrete their beta-lactamase outside the cell wall as an exoenzyme, whereas all Gram-negative organisms contain the enzyme in their periplasmic space. Characterization of the beta-lactamases is confusing because of the varied classification systems proposed by different investigators. The TEM beta-lactamases are the most common enzymes found in clinical isolates, although a number of other beta-lactamases, such as OXA and PSE found in some Enterobacteriaciae and Pseudomonads may also contribute to resistance. The concentration of beta-lactamase in some bacteria is small, but in certain situations, the enzyme may be induced to greater amounts. Other bacteria make large amounts of beta-lactamase constitutively. Some cephalosporins (eg, cefoxitin) are known to be a very effective inducer of beta-lactamase, but are minimally susceptible to hydrolysis, while others are much more susceptible to hydrolytic action. An important principle to remember is that an inducible beta-lactamase may cause self-destruction or inactivate other cephalosporins. Alteration of PBPs in another important mechanism of bacterial resistance to cephalosporins and other beta-lactam antibiotics. These PBPs are biochemically and functionally distinct, show considerable species variation, and are preferentially sensitive to individual beta-lactam antibiotics. There is a wide range of difference in the pharmacokinetic properties of the cephalosporins which effect blood and tissue concentrations. The peak blood level gives little indication of the peak tissue level. The peak blood level should be some small multiple of the MIC of the infecting organism. By convention, the blood levels of two- to four-fold the MIC of the organism is thought to be appropriate for treatment of bacterial pneumonia and most other infections. It is possible that, despite a high blood level, the tissues may not receive an adequate concentration of the drug. In order to achieve effective tissue levels, most antibiotics which are excreted rapidly should be administered either frequently or at sufficiently large doses to ensure tissue levels equilibrated with adequate blood levels. However, the exact duration of the therapeutic concentration is not clear. The relationship of protein-binding to therapeutic efficacy is still controversial. The degree of protein-binding of cephalosporins may vary from 15 to 95 percent and the relative antimicrobial activity of the antibiotic while it is protein bound is still unknown. Adverse effects due to cephalosporins are infrequent. The most common side-effects are hypersensitivity reactions in 1-5 percent and nonspecific gastrointestinal reactions in 5-10 percent. Superinfection has been reported in 5-10 percent of patients treated with cephalosporins. Coagulopathy and disulfiram-like reactions have been observed in several cephalosporins that possess an N-methylthiotetrazole (MTT) group at the 3- position of the dihydrothiazine ring (Fig 3). Moxalactam, cefamandole, cefoperazone, cefmenoxime and cefotetan all contain this MTT side group. Risk factors for bleeding include severe illness, malnourishment, hyperalimentation, renal failure, hepatic disease and high-prolonged dosages. These patients should receive prophylactic vitamin K, and all patients receiving one of these agents should be monitored for prolonged bleeding time. The cost element is indeed an extremely important factor of managing the infected patient. Federal and corporate policies have directed our attention to this element, but should not subordinate the importance of efficacy and toxicity factors. The injectable antibiotic market in the United States was $1.3 billion in sales in 1985. Fifty-six percent of these sales was for cephalosporins, penicillin (3.8 percent), ampicillin (2.6 percent), broad-spectrum penicillins (10.8 percent), aminoglycosides (9.5 percent), clindamycin, vancomycin and metronidazole (13.6 percent) and all others (3.7 percent). Fifty-six percent of the usage in the hospital was for infectious disease therapy, 33 percent directly for surgery, and 10.7 percent for nonsurgical prophylaxis. The newer cephalosporins are expensive on a per-gram basis. However, the per-gram (acquisition) cost of an antibiotic is not the only, nor is it the major, determinant of the overall cost of treating the hospitalized infected patient. Other important determinants are “hidden costs” of the pharmacy and laboratory, costs of diagnosing and treating adverse effects or complications, and costs of hospital care. Many of the “more expensive” cephalosporins have longer serum half-lives and greater potency on a weight-to-weight basis allowing for less frequent and lower dosing. Therefore, the total drug expense would be lessened. “Hidden” laboratory costs can be observed when antimicrobials such as aminoglycosides or vancomycin are used. These drugs require regular monitoring of blood levels and renal function to assure effective therapy, but yet to avoid toxicity. From this standpoint alone, these drugs can become more costly to use than cephalosporins. The costs of diagnosing and treating complications of antimicrobial treatment are very difficult to estimate. What are the additional costs of an antibiotic-associated renal failure, anaphylactoid reaction, severe exanthem or work-up for a drug fever masquerading as a fever of unknown origin? Organisms that possess inducible beta-lactamases can rapidly develop resistance to the newer cephalosporins. This phenomenon is most closely associated with Pseudomonas aeruginosa, Enterobacter cloacae and Serratia marcescens infections treated with second- or third-generation cephalosporins. The extent of this problem of resistance emerging during therapy is undetermined, but close attention to these organisms and patients is required. Patients with the usual community-acquired pneumonia, atypical pneumonia syndrome or chronic pneumonia generally should be treated with agents other than cephalosporins. However, there are four pneumonia syndromes in which cephalosporins are attractive therapeutic agents: pneumonia associated with immunoincompetency, gastric aspiration, hospitalization, and the aged. Except when a cellular immune defect is singularly operative, bacteria are the most common etiologic agents of pneumonia in the immunocompromised hosts. Pseudomonas, Klebsiella, Enterobacter, Serratia, E coli, Acinetobacter and Legionella are the most common Gram-negative pathogens, whereas S aureus is the most common Gram-positive pathogen in these patients. Rational empiric therapy must be selected based on the existing epidemiologic and immunologic circumstances. Because most Pseudomonas and Acinetobacter and many Enterobacter and Serratia are either resistant or minimally sensitive to cephalosporins or possess type 1 chromosomal beta-lactamases that allow resistance to develop, monotherapy with a cephalosporin is to be discouraged. An aminoglycoside combined with a broad-spectrum penicillin or cephalosporin is the conventional therapy. Ceftazidime is more active than the other available cephalosporins against P aeruginosa and Serratia sp. Modification of this empiric regimen may be appropriate depending on the immunologic status of the patient, epidemiologic circumstances, and precise microbial sensitivity data. The microorganisms of aspiration pneumonia are representatives of usual pharyngeal and gastric flora. Streptococcus viridans, microaerophilic Streptococcus and Bacteroides non-fragilis groups predominate, so moderate-dose penicillin is appropriate treatment. Gastric or intestinal motility disorders, gastrointestinal surgery or cimetidine/ranitidine therapy may enhance bacterial concentration in the stomach and allow for more pathogenic Bacteroides organisms to colonize the upper gastrointestinal system. Additionally, hospitalized or institutionalized patients or the debilitated aged have a propensity for Gram-negative organisms to colonize their hypopharyngeal region. Treatment in these situations may need to be more broad-spectrum with a newer cephalosporin combined with penicillin or clindamycin. Cephalosporins (ie, cefoxitin, cefotetan) that have good to excellent activity against most anaerobes, including B fragilis, may be used alone, but there are no comparative studies to support this. The 1984 National Nosocomial Infection Surveillance (NNIS) program showed that pneumonia accounted for 17.8 percent of all hospital-acquired infections, exceeded only by urinary tract infections responsible for 38.5 percent. The surgical wound infection rate was 16.6 percent. Nosocomial pneumonia confers the highest mortality rate at 25-50 percent of the major nosocomial infections. Efforts to effect prevention and early recognition, as well as more effective treatment regimens will have a major impact on hospital-associated morbidity and mortality. Gram-negative bacillary aerobes make up about 60 percent of nosocomial pneumonias. The frequency of various pathogens from the NNIS data is P aeruginosa (16.9 percent), Klebsiella (11.6 percent), Enterobacter (9.4 percent), E coli (6.4 percent), Serratia (5.8 percent), Proteus (4.2 percent) and S aureus (12.9 percent). Conditions or diseases that in particular predispose to Gram-negative aerobic bacillary pneumonia are prolonged hospital stay, recent antibiotic exposure, serious illness, immunosuppression, debilitation, and tracheal intubation. Traditionally, an aminoglycoside in conjunction with an anti-staphylococcal agent has constituted appropriate initial therapy in this situation. There is now excellent evidence that monotherapy with a third-generation cephalosporin is as efficacious as combination therapy in non-neutropenic patients. At best, curative therapy for nosocomial Gram-negative pneumonia is 65-85 percent. Cefotaxime and ceftriaxone have better activity than other third-generation agents against Staphylococcus and Streptococcus, while ceftazidime shows superior activity against Pseudomonas and Serratia. Acinetobacter calcoaceticus is frequently resistant to all cephalosporins. Imipenem, the new carbapenem, is now the drug of choice for this organism, with an aminoglycoside as an alternate agent. Serious Gram-negative pneumonias due to P aeruginosa, Serratia or Enterobacter may still require combination therapy with an aminoglycoside plus a broad-spectrum penicillin or third-generation cephalosporin. Combined beta-lactam therapy should be avoided due to the problem of inducible and transferable resistance or drug antagonism. Eleven percent of the population in the United States is over 65 years of age. This group consumes over 30 percent of the health care dollars due partially to an increased prevalence, morbidity and mortality of infectious diseases. Aerobic Gram-negative bacillary organisms (ie, H influenza, Klebsiella, Enterobacter, E coli, Legionella) are more often the etiologic agents than in younger patients. This is because 30-50 percent of aged patients residing in hospitals or skilled nursing homes have pharyngeal colonization with Gram-negative bacilli. Appropriate empiric therapy must be broad in spectrum or be based on a most probable organism(s) as ascertained from examining acceptable respiratory secretion samples obtained rarely by expectoration and more commonly by minor invasive procedures (ie, nasotracheal aspiration, transtracheal aspiration, bronchoscopy). Many antimicrobials have adverse effects that age can potentiate. The nephrotoxicity reported from aminoglycosides ranges from 5-10 percent and ototoxicity at 2 percent. These complications may be significantly greater in the elderly. Carbenicillin contains nearly 5 mEq Na+/g which can precipitate heart failure. Long-acting sulfa drugs may potentiate the hypoglycemic effects of oral diabetic agents. Erythromycin may induce theophylline toxicity in COPD patients. Tetracyclines and isoniazid show more toxicity in the aged. Therefore, a third-generation cephalosporin would be an appropriate drug as initial therapy unless the clinical situation or microbiologic specimen would direct a more narrow antibiotic agent. The diagnosis of pneumonia rests on the chest roentgenogram, examination of the lower respiratory secretions, and assessment of the patient. Blood or pleural fluid cultures, when positive, are definitive for the etiologic agent, but only 20 percent of Gram-negative pneumonias will show positive on blood cultures.