Fourth-generation cephalosporins: a review of in vitro activity, pharmacokinetics, pharmacodynamics and clinical utility

Fourth-generation cephalosporins: a review of in vitro activity, pharmacokinetics, pharmacodynamics and clinical utility Javier Garaul , Walter Wilson2, Martin Wood3 and Jean Carlefl Department of Medicine, Hospital M u t u a d e Terrassa, Barcelona, Spain; 2Division of Infectious Diseases, M a y o Clinic, Minnesota, LISA; 3Department of Infection & Tropical Medicine, Birmingham Heartlands Hospital, Birmingham, England; 4Service de R t a n i m a t i o n Mkdicale, H6pital Saint Joseph, Paris, France

Antimicrobial resistance to antibiotics is a significant problem in the treatment of serious nosocomial infections. Antibiotic therapy is often empiric, until a specific pathogen and its antibiotic susceptibility are known, after which time adjustments in initial therapy may be made as necessairy. The increasing prevalence of Gram-positive bacteria as a cause of serious nosocornial infections, together with the increasing incidence of resistance among Gram-negative bacilli, require the use of compounds with broad-spectrum antimicrobial activity. The third-generation cephalosporins are widely used for empiric therapy but their effectiveness has been limited by the increasing prevalence of strains of Enterobacteriaceae and Pseudomonas spp. that produce derepressed ArnpC p-lactamases. The fourth-generation cephalosporins are structurally related to the third-generation cephalosporins but, in addition, they possess a quaternary ammonium group at the C-3’ position. They are zwitterionic compounds, which facilitates rapid penetration through the outer membrane of Gram-negative bacteria. This, together with their low affinity for clinically important P-lactamases, results in potent activity against many Gram-negative pathogens, including strains producing derepressed class I (AmpC) P-lactamase, resistant to most third-generation cephalosporins. In addition, some fourthgeneration cephalosporins exhibit excellent activity in vitro against Gram-positive bacteria, including methicillinsusceptible staphylococci, penicillin-resistamnt pneumococci and viridans group streptococci. Among the fourth-generation cephalosporins, only cefpirome and cefepime are widely available. A review of clinical studies published to date indicates that they are potentially useful as a first line empiric therapy for serious infections, including severe community-acquired and nosocomial pneumonia, bacteremia, febrile episodes in neutropenic patients and meningitis. Key Words: Fourth-generation cephalosporin, cefpirome, cefepime, zwitterion, pneumonia, neutropenia, sepsis

INTRODUCTION

The third-generation cephalosporins were introduced in the early 1980s and were poorly hydrolyzed by these enzymes, but Gram-negative microorganisms resistant to these compounds have emerged [6,7]. Until recently, the third-generation cephalosponns represented one of the most significant developments in the discovery of new p-lactam antibiotics [S]. These c o nip o u n ds ( c e fo taxi m e , c e ft r i ax o n e , ceftizoxime) possess a C-7 2-amino-5-thiazolyl methoximino side chain, which confers greater stability against broad-spectrum plasmid-mediated P-lactamases. They exhibit enhanced activity against Gram-negative bacteria when compared with earlier generation cephalosporins [9]. However, the emergence of new, extended-spectrum p-lactamases (ESBLs) and the prevalence of stably derepresscd mutants of ciitcric Gram-ncgative bacilli producing inducible chromosomally-mediated class I P-lactamases represent

Antimicrobial resistance t o currently available antibiotics is a significant problem world-wide in the treatment of serious nosocomial infections [ 1-31, The problem is particularly important with the p-lactam antibiotics because of their widespread use [4].Betalactamase production is the most prevalent mechanism of resistance among Gram-negative bacteria. The plasmid-mediated broad-spectrum P-lactamases found in Escherichia coli and Klebsiella pneumoniae confer resistance to the first-generation cephalosponns [5].

Corresponding author and reprint requests to: J. Garau, Department of Medicine, Hospital Mutua de Terrassa, Barcelona, Spain Tel:

+ 34 3 783 5111

Fax:

+ 34 3 736 50:37 S87

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a threat to the activity of the third-generation cephalosporins [3,10,11]. Some Gram-negative bacilli that produce these enzymes, for example Pseudomonas aeruginosa and Enterobacter cloacae, also have a less permeable outer membrane [6]. More recently, Gram-positive bacteria have become the predominant cause of serious nosocomial infections, particularly bacteremia in neutropenic patients and in intensive care units (ICUs) [12-141. Current resistance problems among Gram-positive bacteria include penicillin and multi-drug resistance among pneumococci and viridans group streptococci, methicillin resistance in staphylococci and multiple drug resistance in enterococci [2,15-171. The increasing incidence of Gram-positive pathogens as the cause of serious nosocomial infections emphasizes the need for compounds with potent, broad-spectrum activity against both Gram-positive and Gramnegative bacteria, which may be used for empiric therapy. Among the p-lactam antibiotics, only the carbapenems (imipenem and meropenem) and the fourth-generation cephalosporins possess an antibacterial activity in vitro that encompasses most Gram-positive and Gram-negative bacteria. The fourth-generation cephalosporins are chemically closely related to third-generation cephems. They differ by having a C-3' quaternary ammonium group in position 3 of the cephem nucleus. These molecules are zwitterionic compounds, by virtue of a positive charge on the nitrogen of the C-3' group and a negative charge on the C-4 carboxylic group of the cephem nucleus [6]. Due to these zwitterionic properties they penetrate the outer membrane of Gram-negative bacteria rapidly [18,19]. In addtion, they have poor affinity for P-lactamases which are located in the periplasmic space [18] and, like other 2-amino-5-thiazolyl derivatives, they have a high affinity for penicillin-binding proteins (PBPs) of both Gram-negative and Gram-positive bacteria. There are two fourth-generation cephalosporins that are currently widely available: cefpirome and cefepime [20].

ANTIBACTERIAL SPECTRUM Cefpirome and cefepime have a well-balanced antibacterial spectrum, including Gram-negative bacteria as well as Gram-positive cocci. They exhibit a greater antibacterial spectrum in vitro than thirdgeneration cephalosporins because they are active against Enterobacteriaceae which produce class I p-lactamases [21-251, which may inactivate third-generation cephalosporins. Additionally, they are more active in vitro than third-generation cephalosporins against

Gram-positive cocci, including methicillin-susceptible Staphylococcus aureus. Finally, fourth-generation cephalosporins, unlike third-generation cephalosporins, are active in vitro against Gram-negative bacilli which produce derepressed amounts of AmpC P-lactamases (3,181. The in vitro antibacterial spectrum of the fourthgeneration cephalosporins includes many of the pathogens involved in hospital-acquired infections, such as Enterobacteriaceae, P. aeruginosa, Acinetobacter spp., Haemopkilus inzuenzae, methicillin-susceptible S. aureus, coagulase-negative staphylococci (CNS), pneumococci and viridans streptococci. Activity against Gram-positive pathogens

In a review of the activity of third- and fourthgeneration cephalosporins, cefpirome was the most active agent tested against Gram-positive bacteria [23]. In contrast to most of the third-generation cephalosporins, cefpirome had good activity in vitro against methicillin-susceptible staphylococci. Indeed, methicivin-susceptible S. auyeus and CNS were inhibited by cefpirome at < 1 mg/L (geometric mean MIC,,) (Table 1). This level of activity was two-fold greater than that of cefepime, four-fold greater than cefotaxime and eight-fold greater than ceftazidime [23]. Pneumococci are important pathogens in community-acquired pneumonia, meningitis and bacteremia/septicemia and the treatment of these infections is complicated by an increasing risk of encountering penicillin- and multidrug-resistant organisms [ 151. The fourth-generation cephalosporins demonstrate excellent activity in vitro against pneumococci, including penicillin-resistant strains. Studies have shown cefpirome and imipenem to be the most active p-lactams against Streptococcus pneumoniae [15,26,27,28]. I n o n e study, cefpirome inhibited penicillin-resistant strains with MIC,, and MIC90 values of 0.5 and 1 mg/L, respectively, which was two-fold superior to cefotaxime and cefepime [27]. In another study, cefpirome was more active than some of the newer fourth-generation cephalosporins, such as cefclidin and cefozopran against penicillin-intermediate and penicillinresistant strains (Table 2) [28]. Viridans group streptococci are becoming more frequent pathogens in the hospital environment, particularly in neutropenic and immunocompromised patients [29]. The incidence of strains exhibiting intermediate- and high-level penicillin resistance is increasing, up to 45% of isolates are resistant in certain countries [16]. In a study of 410 penicillin-resistant viridans group streptococci recovered from blood

G a ra u:

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Table 1 Antimicrobial activity of third- and fourth-generation cephalosporins against micro-organisms involved in serious infectionsa

Organism S . aiir~ns CNS S . pneumuniae Enterococcus spp. 1221 H . inflnenzae E . coli Klebsivlla spp. Entevobacter spp C .frenndii Serratia spp. Prouidencia spp. M . morganii

P.aevic@mw B. cepacia Acinetobacter spp

Intrinsic potency (mg/L)b Cefotaxime Cefepime

Ceftazidime

8.00 9.08 0.27 >32 0.06 0.15 0.14 0.52 0.74 0.29 0.17 0.11 1.83 2.30 3.33

1.90 1.54 0.02 >32 0.01 0.06 0.01 0.32 0.21 0.50 0.07 0.05 22.6 6.73 6.46

Cefpirome

2.10 1.34 0.03

0.65 0.50 0.03 3.60 0.06 0.05 0.04 0.07 0.05 0.11 0.08 0.03 3.70 8.00 0.94

-

0.06 0.04 0.04 0.06 0.05 0.15 0.04 0.03 2.83 7.13 1.73

aAdapted from [23], unless otherwise stated. hExpressed as the geometric mean MIC,,, i.e. concentration required to inhibit 50% of organisms.

Table 2 Activity of third- and fourth-generation cephalosporins against Streptococcus pneumoniae Pen-S (MIC: < 0.12 nig/L) n = 60

Pen-I (MIC 0.12-1 .0 mg/L) n = 60

MICY, penicillin G cefotaxime cefpirome cefepime cefclidin cefozopran cefluprenam cefoselis

0.03 0.03 0.01 0.03 0.25 0.03 0.03 0.03

0.03 0.03 0.03 0.03 0.5 0.06 0.03 0.125

0.25 0.25 0.12 0.25 1.0 0.25 0.5 0.125

Pen-R (MIC > 1.0 mg/L) n = 60

MICX,

MIC;,,

MIC90

1.0 1.0 0.5 1.0 4.0 1.0 1.0 0.5

2.0 1.0 0.5 1.o 8.0 2.0 1.0 1.0

4.0 2.0 1 .o 2.0 8.0 2.0 1 .0 1.0

Adapted from Frt-maux et al. [28]

cultures, the activity of cef@ironie(MIC,,, 1 mg/L and MIC,,, 4 mg/L) was second only to thalt of imipenem [16]. In this study, the MIC,, and MIC,, values for cefotaxime were 4 and 8 mg/L, respectively, and MICso and MIC,, values for ceftazidime were 2 32 mg/L. In contrast to other cephalosporins which are inactive, cefpirome exhibits moderate activity in vitro against enterococci. In one study, the MIC,, of cefpirome for E .faecalis was 3.6 mg/L [:22]. In another study of ICU and hematology isolates, 55% of E . faecalis isolates were inhibited by < 8 mg/L of cefpirome [30]. Although this level of activity is probably inadequate for the treatment of infections, it

may be sufficient for the prevention of colonization or superinfection, or for the treatment of polymicrobial infections which include enterococci. Activity against Gram-negative pathogens The fourth-generation cephalosporins exhibit similar activity in vitro to the third-generation cephalosponns, cefotaxime, ceftriaxone and ceftazidime, against Enterobacteriaceae which produce non-inducible P-lactamases, such as E . coli, Klebsiella spp., Proteus mirabilis and Salmonella spp. (Table 1) [23]. O f greater significance is the enhanced activity of fourthgeneration cephalosporins against Enterobactenaceae and

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P. amginosa, which produce inducible and derepressed AmpC p-lactamases [3,31]. Such p-lactamases confer considerable resistance to ceftazidime and other thirdgeneration cephalosporins. The incidence of strains with AmpC varies geographically and the incidence of stably derepressed mutants has increased since the widespread introduction of the third-generation cephalosporins (Table 3) [32-361. Indeed, in two studies, the percentage of derepressed strains of E. cloacae increased from 14.4% to 23.6% between 1983 and 1994, and in P. aeruginosa increased from 5.0% to 9.2% during the same period [36]. Cefpirome and cefepime display similar activities in vitro against Enterobacteriaceae which produce inducible and derepressed AmpC p-lactamases [3,37]. O f 97 ceftazidime-resistant Enterobacteriaceae (MIC > 16 mg/L), 74% of strains were inhibited by cefpirome (MIC I 8 mg/L) [24]. In an 11 nation study of cefiazidime-resistant Enterobacteriaceae, > 80% of strains were inhibited by cefepime (MIC 5 8 mg/L) [37]. T h e plasmid-mediated, extended-spectrum 0-lactamases (ESBLs), although clinically less important than the chromosomally-mediated Class I p-lactamases, are produced by Gram-negative bacteria from patients in the ICU and with serious infections [2,5,12]. These enzymes are produced by strains of K. pneumoniae and E . coli. Whilst the fourth-generation cephalosporins are active against many strains which produce some of the ESBLs, they are less active against strains which produce TEM-4, SHV-2, SHV-3 and SHV-4 [23,38]. The potent in vitro activity of the fourthgeneration cephalosporins is generally lower against non-fermentative Gram-negative bacilli than against Enterobacteriaceae. The in vitro activity of cefpirome and cefepime is greater than that of cefotaxime against P . aeruginosa, but less than the activity of ceftazidime (Table 1) [23]. Previous studies have shown that cefpirome and cefepime have moderate activity against Peptostreptococcus spp. and Fwobacteriwx spp., although the fourthgeneration cephalosporins have generally demonstrated

limited activity against other anerobic Gram-negative bacilli such as P-lactamase-producing strains of Bacteroidesfvagilis (MIC > 8 mg/L) [39]. A major concern is the emergence of strains resistant to the fourth-generation cephalosporins; Gram-negative bacteria resistant to cefpirome and cefepime may be selected in vitro by serial passage experiments. However, this is more likely to occur as a result of modification of the outer membrane proteins than by p-lactamase selection and inactivation [ 11,401. Resistance was attributable to derepression of inducible chromosomal p-lactamases (although in these experiments this was more common with ceftazidime) and outer membrane porin changes [40]. The cefpirome MICs, although higher, remained below the proposed breakpoint of 8 mg/L. The risk of selecting resistant strains of Enterobacteriaceae among hospital isolates to fourth-generation cephalosporins may be lower than for the third-generation cephalosporins in the clinical setting, as demonstrated by in vitro studies, but more data are necessary [11,40].

HUMAN PHARMACOKINETICS AND PHARMACODYNAMICS The pharmacokinetic properties of cefpirome and cefepime have been investigated following intravenous (iv) dosing [41,42] (Table 4). Both compounds have an elimination half-life ( t y J of approximately 2 hours [41-431 and this is prolonged in elderly patients [42,44,45]. As the pharmacokinetic and pharmacodynamic properties of the fourth-generation cephalosporins are similar, we chose to present specific data on ceEpirome, as follows. In both healthy and infected elderly patients, the ce$irome tllz was 1.7 to 2.2 times longer than in healthy and infected younger patients, respectively [44,45]. This also resulted in trough concentrations in the elderly that were about 12fold higher than those observed in younger patients (Table 5). This slower t y 2 was related to alterations in renal function, associated with increasing age [41,44].

Table 3 Prevalence of stably derepressed AmpC mutants among Enterobactenaceae and Psetrdomonas aemginosa &om 1983-1994 Keference

Fuster (1991) Liu (1992) Goldstein (1993) Reeves (1993) Lopez-Yeste (1994) ND = No data.

Enterobacteriaceae n % ~321 1331 [34] [35] [36]

130 830 9038 ND

510

17.0 13.2 14.7 ND 15.1

Enterobacter spp.

P . aemginora

n

%

n

%

387 ND 348 163 267

10.8 ND 17.6 8.7 18.7

ND 170 ND ND 916

ND 1.2 ND ND 9.2

Ga ra u : Fo u r t h - g e n era t i o n c e p h a I o s p o r i ns

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Table 4 Pharmacokinetics of cefpirome and cefepime following a 2 g intravenous dose to healthy volunteers Parameter

Cefpirome 2 g iv

Cefepime 2 g iv

175 4.8 1.9 130 70-90 <10

133 4.5 1.8 263 80 19

Adapted from [41,42]

Table 5 Effect of age and infection on the pharmacokinetics of cefpirome Status

tvz

Age < 50 Age > 65 Infection Infection

+ age < 40 + age 40-65

Infection + age > 65 Age < 40

Trough levels (range) at 12 h (mg/L)

(h)

1.8-2.0 3.1-3.4 2.0 2.9 4.4 2.0

1.2 (0.25-3.0) 5.5 (1-13) 14.2 (2-32)

Adapted from [41,44,45]

Following parenteral administration, cefpirome distributes primarily into the intravascular compartment and potentially therapeutic concentrations are achieved in most tissues, including cerebrospinal 5uid (CSF) [41]. Cefpirome is extensively excreted via the kidneys and the compound has no detectable metabolites [41]. For the treatment of serious nosocornial infections, the recommended dosage regimen for cefpirome is 2 g twice daily (bid). Pharmacodynamic calculations have shown that concentrations in serum following 1 g and 2 g doses of cefpirome are above the MIC for common pathogens, including Enterobacteriaceae, staphylococci and streptococci, for at least half of the 12-hour dosing interval [41]. The time above MIC:,, values for common bacterial pathogens following a 2 g dose of cefpirome in normal volunteers, are shown in Figure 1. Since the MICs for most Enterobacteriaceae, staphylococci and streptococci are 1 mg/L or less, cefpirome concentrations in serum remain above the M I C for these organisms for at least 12 hours. Paradis et al. [46] used the serum bactericidal test to demonstrate that a 2 g iv dose of cefpirome provided bactericidal activity against strains of E . cloacae arid methicillinsusceptible S. aureus for more than 12 hours and 8 hours, ~ ~ in respectively. For P. aevuginosa, the I V I I Cvalue most studies has varied &om 4-1 6 mg/L [22-241. Serum concentrations of cefpirome exceed the MIC values for only 4.5-8 hours. Therefore, a 2 g dose of cefpirome

250 100

2

-E c

50

25

v)

0

.= !

10

c

c

$

K

5&

v)

5

2.5 l

. - -MIC

- - - Stap - - .. hyococcus\ ...- -

90

0.5 0

2

,_

--

....

I

..

Enterobacteriaceae Streptococcus

4

6

8 1 0 1 2

Time (hours)

Figure 1 Relationship between serum levels of cefpirome and the MIC,, for common bacterial pathogens following a 2 g iv dose. With permission from the Scandinavian University Press (411.

bid may not be adequate for the treatment ofinfections caused by P. aeruginosa.

POTENTIAL CLINICAL INDICATIONS A number of studies have demonstrated the efficacy of cefpirome and cefepime in the treatment of upper and

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lower respiratory tract infections, complicated and acute uncomplicated urinary tract infections, skin and soft tissue and gynecological infections [47,48]. However, it is likely that the real place for fourthgeneration cephalosporins is in the treatment of severe hospital- or community-acquired infections (mainly pneumonia and bacteremia) and in the treatment of febrile episodes in patients with chemotherapy-induced neutropenia (Table 6).

SEVERE INFECTIONS Nosocomial and community-acquired pneumonia

Nosocomial pneumonia represents t h e most problematic nosocomial infection and may be caused by, among others, methicillin-resistant S . aureus (MRSA), Legionella pneumophila, Enterobacteriaceae or non-fermentative Gram-negative bacilli. When choosing empiric therapy for the treatment of nosocomial pneumonia before microbiologcal results are available, it is important to consider where the infection was contracted. Nosocomial pneumonia acquired in the adult or neonatal ICU, burns unit or hematology unit is more likely to be associated with complicating risk factors than nosocomial pneumonia acquired in general medical or surgical wards. Other factors, such as the local prevalence of particular microorganisms and recent outbreaks, should also be taken into account. In intubated patients, early-onset pneumonia is usually caused by normal inhabitants o f t h e oropharyngeal cavity, such as S. pneumoniae, methicillin-

susceptible S. aureus and H . injuenzae [49]. In contrast, late-onset nosocomial pneumonia is more likely to be caused by pathogens such as hospital Enterobacteriaceae or P. aeruginosa. Non-fermentative Gram-negative bacilli, e.g. Acinetobacter baumannii or Stenotrophomonas maltopkilia and MRSA, are encountered in some geographic locations [49]. Patients with early-onset ventilator-associated pneumonia together with no underlying risk factors such as prior antibiotic therapy, recent hospitalization, aspiration or a severe underlying condition, may be treated initially with agents such as p-lactams plus P-lactamase inhibitors, or second- or third-generation cephalosporins [50]. For patients with late-onset pneumonia, or early-onset pneumonia plus associated risk factors, a broader-spectrum antibiotic is recommended, such as a fourth-generation cephalosporin, a broad-spectrum p-lactam/p-lactamase inhibitor with anti-pseudomonal activity such as ticarcillin-clavulanate or piperacillin-tazobactam, or a parenteral carbapenem. Fourth-generation cephalosporins, such as cefpirome or cefepime, may be considered as single agent therapy because of their high potency against Gram-positive pathogens ( S .pneumoniae and S . aureus) and Gram-negative bacilli [2,3,49]. If P. aeruginosa is recovered from the cultures, an aminoglycoside or fluoroquinolone should be added to fourth-generation cephalosporin therapy. The fourth-generation cephalosporins may also be considered for the treatment of some cases of severe community-acquired pneumonia (CAP), particularly in areas with a high incidence of S . aureus or cases where Enterobacteriaceae are suspected (i.e. in chronic

Table 6 Potential uses and limitations for cefpirome and cefepime Category

~~~~

Indications

Severe infections

Pneumonia Nosocomial pneumonia Severe conmunity-acquired pneumoniaa Neutropenia and fever Nosocomial sepsis

Other severe nosocomial sepsis

Complicated urinary tract infections Intra-abdominal infectionsb Polyniicrohial skin and skin structure infectionsC

Potential

Bacterial meningtis

Limitations

Anaerobes MRSAIMRSE ESBL producers

~

~

~

aIn areas with a high prevalence of S. aureus community-acquired pneumonia infection (e.g. elderly nursing home patients and following influenza outbreaks). bIn combination with metronidazole. CMixed infections caused by S . auieus and Gram-negative bacilli.

G a ra u : F o u r t h - g e n e r a t i o n c e p h a Io s 1) o r i n s

obstructive pulmonary disease (COPD) patients or patients with previous courses of antibi'otics) and are an alternative to third-generation cephalosporins as empiric first-line therapy (Table 6). The predominant etiological agents in patients with severe-communityacquired pathogens are S. pneumoniae, S . aureus, H . influenme, Moraxella catarrhalis or enceric bacteria (especially in COPD patients), which are susceptible to ce@irome and cefepime. P. aeruginoso infection is rarely encountered except in patients with cystic fibrosis, and would not require consideration in other patients with community-acquired pneumonia, when choosing an empiric regimen. The clinical efficacy of cefpirome 2 g bid was compared with that of ceftazidime 2 g three times daily (tid), in a large randomized multicenter study in the treatment of I C U patients with severe pneumonia [51]. Pneumonia was hospital-acquired in 75% of patients. Patients received monotherapy with either cefpirome or ceftazimme, or combination therapy with either cephalosporin together with an aininoglycoside or nietronidazole, depending on the severity of pneumonia. The mean APACHE I1 score was 16, and 75% and 63% of the patients receiving cefpirome or ceftazidime, respectively, were mechanically ventilated. A satisfactory clinical response was achieved in 57% of evaluable patients and the bacteriological success rate was 68% for patients receiving cefpirome o r ceftazidime. There was no difference in treatment outcome between the groups given monotherapy or combination therapy. O f a total of 471 causative pathogens isolated from patients (mainly S. aureus, H . inJuerzzae, P. aeruginosa and S. pneurnoniae), 81.5% were susceptible to cefpirome and ceftazidime. Cefepime 2 g bid has also been shown to be effective in the treatment of severe community-acquired or nosocornial pneumonia [52,53]. In a comparative study, a satisfactory response was reported in 75% of the cefepime patients and 74% of patients receiving ceftazidime or cefotaxime 2 g tid [53:1. I n a further study of severe community-acquired pneumonia, clinical cure rates were 87% in the cefepime group and 86% in the ceftazidime group [54]. When P. aeruginosa is not the most likely first causative agent and in severe cases, a fourth-generation cephalosporin is an adequate choice as empiric initial monotherapy. However, combination antimicrobial therapy should be used when P. aevtrginosa has been identified. Bacteremiahepticemia

Morbidity and mortality resulting from bacteremia can be a serious problem in the young, the elderly and

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in immunosuppressed and neutropenic individuals. In some studies mortality associated with bacteremia has ranged from 2&30% of affected patients and more than 50% in patients with severe sepsis or septic shock [55,56], although mortality is in part due to the underlying disease. Prompt recognition of the infection and empiric antibiotic treatment are essential before the microbiological results are available, to avoid complications such as septic shock and multi-system organ failure. The predominant microorganisms responsible for bacterernia include S . aureus, CNS, Enterococcus spp., S. pneumoniae, viridans group streptococci and Enterobacteriaceae ( E . coli, Klebsiella spp., Enterobacter spp. and Proteus spp.). P. aeruginosa and anaerobes are less frequently encountered. Gram-positive cocci have now replaced Gramnegative bacilli as the predominant pathogens responsible for single-organism bacteremia [ 13,561. Indeed, in the EPIIC study (European Prevalence of Infection in Intensive Care), 70% of bacteremia/septicemia cases in the ICU were caused by Gram-positive species [13]. S. aureus is a serious nosocomial pathogen, particularly in the ICU where it may cause catheter-related sepsis, pneumonia, wound infections and primary bacteremia. The management of infections caused by S. aureus is further complicated by the relative likelihood of encountering methicillin-resistant strains. Therefore, it is important to take into account the local prevalence of MRSA, as this will dictate the need for vancomycin as initial empiric therapy. CNS are also a frequent cause of bacteremia. However, it is often difficult to assess whether CNS are responsible for the infection or whether they are an environmental contaminant. The use of intravascular catheters in seriously ill patients could account for the increase in frequency of CNS as a cause of bacteremia in the ICU [13]. The best treatment for these cases is uncertain, but removal of the catheter, together with antimicrobial therapy, has been recommended by several investigators [57]. S. pneumoniae and other streptococci are also relatively common causes of bacteremia. The aminoglycosides have been widely used for empiric therapy of Gram-negative nosocomial infections, but have now been replaced with thirdgeneration cephalosporins and fluoroquinolones. Ceftazidime was used frequently as a first line agent, but the emergence of AmpC derepressed mutants of Enterobacteriaceae in up to 50%)of strains has diminished the utility of third-generation ceplialosporins in the I C U (Table 7) [30,36,58,59]. I n addition, cases of progressive sepsis and death caused by penicillinresistant pneumococci in patients treated with ceftazidime (ceftazidime MICs of high level penicillin

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Table 7 Prevalence of stably derepressed AmpC mutants among Enterobacteriaceae and Pseudomonas aerugirrosa of nosocomial origin Number of strains studied (n)/% stable derepressed mutants Reference

Enterobacter SPP' n

%

Citrobacter SPP. n %

33

14

M. morganii

Sewatia

P . aemginosa

SPP. n

%

n

%

n

%

7

26

8

ND

ND

143

19

Buirma (1991)

[58]

105

Verbist (1991)

1301

153

37

32

53

ND

ND

78

8

326

12

Syndman (1991)

[59]

154

23

48

50

49

6

16

25

177

18

Lopez-Yeste (1994) [36]

267

25

100

17

45

4

57

0

916

12

ND = No data.

resistant pneumococci can be 2 64 mg/L) have been reported [26]. A fourth-generation cephalosporin, such as ceEpirome or cefepime, with activity against Grampositive cocci and Enterobacteriaceae and stability to AmpC p-lactamase, may be considered for first-line empiric therapy of these infections, before microbiological results are available, when infections are likely to be polymicrobial or in cases where there is no information regarding the strains colonizing the patient. In a retrospective analysis of 4,180 patients entered in 15 phase I1 and 111 trials [60], the efficacy of cefpirome 1 g or 2 g bid was assessed in the treatment of confirmed severe bacteremia in patients in ICUs. Satisfactory clinical responses were achieved in 97% of cefpirome recipients and in 90% of patients treated with cefiazidime. Bacteriological eradication occurred in 89% of patients treated with cefpirome and in 90% of patients treated with cefiazidime. The most common pathogens were S.pneumoniae and E. coli, all strains were susceptible to cefpirome and cefiazidime. Only four out of a total of 230 bacterial isolates were resistant to cefpirome, and four out of 60 bacterial isolates were resistant to cefiazidime. Similar clinical response rates have also been obtained in 192 patients with suspected bacteremia receiving cefepime 2 g bid (79%) or ceftazidime 2 g tid (73%) (611. febrile episodes in severe neutropenia

Gram-positive cocci are the predominant microorganisms causing infections in granulocytopenic patients. In the Gimema Infection Programme conducted in 1991, Gram-negative bacilli were responsible for 36% of single-organism bacteremia, while Gram-positive cocci accounted for 64% of cases [62]. In 1994, the incidence of bacteremia due to Gram-positive cocci had risen to 89% [63]. The most

frequently isolated species were staphylococci, CNS (associated with the high use of intravascular catheters in these patients) and a-hemolytic streptococci. The streptococci were associated with septic shock and acute respiratory distress syndrome with up to 45% of viridans group streptococci resistant to penicillin [15,16]. The main Gram-negative bacteria responsible for febrile neutropenia infections in cancer patients are Enterobacteriaceae and P. aeruginosa, which are ofien rapidly fatal. Efforts to reduce this mortality by early empiric antimicrobial therapy have been successful, but have resulted in significant antibiotic exposure and development of bacterial resistance. Ceftazidime has been used successfblly as sole therapy, but the emergence of strains with derepressed AnipC production together with poor Gram-positive coverage has limited its use

~41. During the last 10 to 20 years, empiric antibiotic therapy has been designed for optimal coverage of infections caused by Gram-negative bacteria, but with the increase in incidence of Gram-positive organisms this is no longer satisfactory. Empiric therapy of fever in granulocytopenic patients could be achieved using a single antibiotic, provided that the compound affords adequate coverage against both Gram-negative and Gram-positive infections. ComGared with the third-generation cephalosporins, including ceftazidime, the fourth-generation cephalosporins are more active both in vitro and in vivo and possess enhanced activity against Grampositive bacteria and Enterobacteriaceae. Accordingly, fourth-generation cephalosporins may potentially replace cefiazidime for empiric therapy in selected patients. The fourth-generation cephalosporin, cefepime, has been studied in one open and five comparative randomized trials [64]. Overall, 334 neutropenic patients received cefepime monotherapy

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(2 g tid) and 212 received cefepime (2 g bid) in combination with amikacin (7.5 mg/kg bid). The results showed cefepime monotherapy and combination therapy to be as effective as standard regmens of ceftazidime monotherapy (2 g tid) or combination therapy with broad-spectrum penicillins. In a recent multicenter, randomized, comparative study performed in 353 patients, the Combination of cefepime plus amikacin showed equivalent efficacy to ceftazidime plus amikacin in febrile neutropenic patients [65]. In an international, multicenter, Ispen labeled, randomized trial, a total of 270 neutropenic patients were treated empirically with either cee’irome 2 g hid or cefiazidime 2 g tid [66]. Positive blood cultures were obtained from 41% of cefpironie and 36% of cefiazidinie-treated patients, respectively. The clinical response rate in both groups was ;’4%, but the bacteriological cure rate was higher in the cefpirome group (89%) than in the ceftazidime group (74%). The predominant causative pathogens in both groups were the Gram-positive organisms, S. epidevmidis and S . nureus. Surty-eight percent of patients in the ceEpirome group and 65% in the ceftazidime group received at least one additional systemic antibiotic at some time, either during or at the end of the study. The authors concluded that cefpirome 2 g bid was at least as effective and well-tolerated as ceftazidi,me 2 g tid in the empiric management of neutropenic patients.

attained a concentration of 2.3 mg/L in the CSF following a 50 mg/kg/h iv infusion, representing 4.3% penetration. A number of studies have found that the MICs and minimum bactericidal concentrations (MBCs) of cefpirome for penicillin-resistant pneumococci are generally one- to two-fold lower than those for cefotaxime, ceftriaxone or cefepime [15,74,75]. Although small, such differences may be critical in the treatment of meningtis, when the CSF/cephalosporin concentration is similar to the MIC. In another animal model study [74], the efficacy of several agents was compared against pneumococcal infections, involving penicillin-sensitive and -resistant strains in rabbits. The excellent CSF penetration of cefpironie compared with meropenem, rifampicin, clinafloxacin and vancomycin was confirmed and cefpirome was more effective than meropenem or ceftriaxone. Preliminary results in children, using a dose of 50 nig/kg of cefpirome were very encouraging. The mean CSF penetration (ratio CSF to plasma concentration) was 39% at 2 hours and CSF concentrations remained above the MIC,,, of common meningeal pathogens (including penicillinresistant pneumococci) for at least 8 hours 1761. Finally, in a recent comparative study, cefepime was at least as effective as cefotaxime in the treatment of acute bacterial meningitis in children [72]. Additional studies are required to support the use of fourth-generation cephalosporins in this setting.

Bacterial meningitis

Combination Therapy

Acute bacterial meningitis is a life-threatening infection needing urgent empiric treatment. Community-acquired pathogens such as Neisreria rneningitidis, H . influenzae and S . pneumoniae are the predominant causes, accounting for 75% of cases, followed by nosocomial pathogens such as Gramnegative bacilli, s. atireus and Listeria monorytogenes. The emergence of penicillin-resistant and multidrugresistant S. pneumoniae has severely limited the available therapeutic options. Recent reports of therapeutic failures with some third-generation cephalosporins have further complicated the matter [67,68]. Cefpirome and cefepime have excellent activiq against these organisms in vitro, with the exception of L. monocytogener [26,27,69] which, coupled with excellent penetration into the CSF in man, offers considerable therapeutic potential [70-721. In a penicillin-susceptible, pneumococcal meninptis model in rabbits, following iv infusion of cefepime (25 mg/kg/h) or cefpironie (10 mg/kg/h), antibiotic concentrations of 9.6 and 6.6 mg/l,, respectively, were achieved in CSF, resulting in 16.2% and 19.3% penetration, respectively [73]. In contrast, cefotaxime

Although the fourth-generation cephalosporins offer broad-spectrum activity, they have some deficiencies in their antimicrobial spectrum. Methicillin-resistant staphylococci and vancomycin-resistant enterococci (VKE) pose increasingly serious clinical problems. Fourth-generation cephalosporins alone have only modest activity against both these organisms. Accordingly, if infection? caused by these microorganisms are suspected, it is necessary to initiate empiric combination therapy with a glycopeptide for MRSA. Similarly, if anerobes such as Bactevoidesfva
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is effective, based upon results of cultures, antimicrobial

therapy may be changed to less expensive agents with a narrow spectrum of activity. For example, empiric therapy with a fourth-generation cephalosporin should be switched to an earlier generation cephalosporin if E. coli is isolated. Similarly, empiric therapy with a fourth-generation cephalosporin plus a glycopeptide for a suspected MRSA infection should be changed to nafcillin or oxacillin, if methicillin-susceptible staphylococci are isolated. Thus, the empiric antibiotic therapy must be supported by two complementary contracts, the first initially with the patient (i.e. the most appropriate antibiotic according to the case and the severity) and secondly, 2 to 3 days later with the ‘community’ (providing antibiotics which have the least negative impact upon future potential patients).

streptococci, emphasizes the persistent need for new agents with potent activity against both Gram-positive and Gram-negative bacteria. The broad-spectrum activity of cefpirome and cefepime indicates that they could be useful for empiric treatment of febrile episodes in neutropenic patients, either alone or in combination. Initial studies have shown encouraging results when compared to ceftazidime [49, 62-66]. Thus, cefpirome and cefepime, with their broadspectrum activity, are valuable additions to the treatment of severe infections in hospitalized patients. Further comparative studies are required to establish the true value of the fourth-generation cephalosporins in the treatment of serious nosocomial infection and to determine whether they induce less selective pressure upon Gram-negative hospital strains.

CONCLUSION

DISCUSSION

Severe infections, both community-acquired and nosocomial continue to be a major problem in hospitals with regard to treatment and costs. The incidence of nosocomial infection is particularly high in ICUs and in neutropenic and other immunocompromised patients [13]. These infections are usually severe and are associated with high morbidity and mortality. The treatment of these serious infections has been complicated by the increasing incidence of drug-resistant microorganisms, including Gram-positive bacteria. Pneumonia is the second most common nosocomial infection in the world and is associated with the highest mortality and morbidity. T h e fourth-generation cephalosporins, with their broad antibacterial spectrum, would be an attractive therapeutic alternative, administered empirically, either as monotherapy or as part of a combination regimen. Initial studies utilizing fourth-generation cephalosporins in patients suffering from severe nosocomial pneumonia in the ICU are encouraging [52,53]. Cefpirome is one of the most potent p-lactam antibiotics against penicillin-resistant pneumococci and staphylococci [15,26,27,74] and should be usefd for the treatment of hospitalized patients with severe, community-acquired pneumonia or earlyonset nosocomial pneumonia. In neutropenic patients receiving cancer chemotherapy, mortality is significantly reduced by empiric treatment with broad-spectrum agents or by combination therapy, at the onset of infection [77]. In this setting ceftazidime, imipenem/cilastatin and meropenem have been successfully used as monotherapy in febrile neutropenic patients over the last decade [65,78,79]. The increasing prevalence of Gram-positive pathogens, including CNS, S. aureus and viridans

Prof. W. Wilson: There has been a lot of discussion about the use of fourth-generation cephalosporins such as cefpirome in the treatment of patients with severe CAP. There are geographic differences with respect to the spectrum of microorganisms recovered from severe CAP. In the USA, S. aureus is the second most common cause of severe CAP after S . pnarrnoniae, in elderly nursing home patients or patients who are post influenza with a secondary bacterial infection. In this setting, cefpirome would be a good choice for empiric therapy, before the microbiological results become available. Prof. J. Garau: Cefpirome exhibits good in vitro activity against methicillin-susceptible S. aureuj. In Spain, however, S . aureus as a cause of primary CAP is uncommon. However, in areas with a high incidence of S . aureus pneumonia, fourth-generation cephalosporins would be an alternative to the thirdgeneration cephalosporins. For the treatment of nosocomial pneumonia, when P.aeruginosa infection is indicated, then ce@irome would not be considered for first-line empiric therapy. P. aeruginosa pneumonia is mainly seen in the ICU, therefore for nosocomial pneumonia outside of the ICU, fourth-generation cephalosporins could be considered for empiric therapy. Prof. K. Klugman: Cefpirome has a good theoretical indication in the treatment of meningitis, and it could become the drug of choice, however clinical data are needed to support this. In a CSF penetration study, cefpirome showed excellent penetration in children (analogous to the rabbits). However, this study was only performed in a limited number of children.

G a r a u : F o u r t h - g e n e r a t i o n c e p h a I0 s p o r i n s

Prof. J. Garau: Was a 50 mg/kg dose used? Prof. K. Klugman: I believe so. There was some reluctance to proceed with the study because of the potential for seizures. Some of the children had seizures before they received the drug, indeed, 10-20% of children with meningitis have seizures without antibiotic therapy. Therefore, there is no evidence that the drug was related to seizures. The mean CSF penetration ofcefpirome in children was > 10-15 mg/L. Prof. B. Wiedemann: Are there any data on the in vitro activity of cefpironie against ceftriaxone-resistant S. pneumoniae? Prof. K. Klugman: Yes, there are somc unpublished data. Approximately 40% of penicillin-resistant pneumococci exhibit MIC values to cefotaxime or cefiriaxone 2 1 mg/L, and 8% exhibit MICs to cefpirome of 1 mg/L. None of strains tested exhibited MICs to cefpirome > 1 mg/L. In terms of the current NCCLS breakpoints no strains were resistant to cefpirome i.e. MICs > 1 mg/L. For cefpirome, the CSF penetration is approximately 15 mg/L, and using a maximum MIC of 1 mg/L pharmacodynamic calculations would predict that for tid dosing, the MIC would be exceeded for the whole dosing interval in CSF. Prof. B. Wiedemann: Would this concentration be sufficient to exhibit a killing/bactericidal effect? Prof. K. Klugman: Yes, we would predict that. Prof. A. Bryskier: Is there any difference between the PBP affinity for cefpirome, cefotaxime and ceftriaxone in S . pneumoniae? Prof. K. Klugman: To my knowledge there are no studies that have specifically looked at );he affinity for PBPs. However, differences in the binding affinities could explain the improvement in in v:itro potency. Prof. J. Garau: Professor Klugman, are there data comparing the bactericidal activity of ceftriaxone, cefotaxime and cefpirome? Prof. K. Klugman: Yes, cefpimme is highly bactericidal. Prof. J. Garau: Is cefpirome more ba.ctericida1 than the other cephalosporins, as they are less bactericidal than penicillin? Prof. K. Mugman: Yes, at comparative concentrations cefpirome is more bactericidal. Synergy with vanconiycin has also been demonstratcd in time-kill studies. Prof.J. Garau: Are there any data regarding the activity of cefpirome against cefotaxime-resistant pneumococci (MICs of 16-32 mg/L), described in the USA? Prof. K. Klugman: These strains have currently only been described in Tennessee, however they may pose a problem in the future.

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Prof. R. Jones: In the geographic areas where there is a high incidence of penicillin-intermediate and particularly penicillin-resistant pneuniococci, the fourth-generation cephalosporins, like cefpirome, could have a significant role in the treatment of CAP. Prof. J. Garau: There is no clinical data to support the use of fourth-generation cephalosporins rather than the third-generation cephalosporins. It would be difficult to justify a fourth-generation cephalosporin for CAP. In Spain, 40% of cases of pneumococcal pneumonia are caused by penicillin-resistant strains, and these are still treated with cefotaxime, even if the cefotaxime MIC is 2 mg/L. It would be difficult to justifji fourth-generation cephalosporins for CAP based on in vitro activity alone. The main advantage of cefpirome over the third-generation cephalosponns is activity against S . aureus. This would not be achieved with cefotaxime, unless using a high dosing regimen. Prof. R. Jones: Among the methicillin-susceptible staphylococci, cefotaxime and ceftriaxone exhibit an MIC,, of 2 mg/L, and well over 98-99% of strains exhibit MICs 5 8 mg/L. In a comparative study conducted in the USA, there was a four-fold potency advantage for cefpirome against staphylococci, however the absolute number and percentage of susceptible strains was essentially the same as for the third-generation cephalosporins. A similar potency advantage would be observed for cefpirome against pneuniococci. Current doses of third-generation cephalosporins are being increased to cover the more resistant endemic strains. An alternative to coiisider could be the fourthgeneration cephalosporins, because of a two-fold or four-fold advantage against pneumococci. Prof. J. Garau: However, penicillin is still used for the treatment of penicillin-resistant pneumococcal infection, except in the case of meninatis. Prof. K. Klugman: It would be difficult to extrapolate arguments for the treatment of meninatis to pneumonia, as the third-generation cephalosporins reach peak serum concentrations of 100 nig/L, with concentrations remaining above the M I C for the entire dosing interval. There is no objective evidence that third-generation cephalosporins are not effective for the treatment of pneumococcal pneumonia. Indeed, the data suggests that penicillin is still effective for the treatment of pneumococcal pneumonia. Prof. R. Jones: I agree, routine doses of thirdgeneration cephalosporins are still utkzed in the USA for the treatment of pneumococcal pneumonia. In 1995, for a period of time, over 50% of strains in hospitalized patients with significant invasive pneumococcal disease (meningitis or pneumonia with bacteremia) were caused by non-susceptible pneuniococci. I n all cases,

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a clinical response was obtained with third-generation cephalosporins at modest normal dosing for pneumococcal pneumonia. However, there are potency advantages for the fourth-generation cephalosporins and they should be considered for wider use. Dr. J. Turnidge: O n pharmacodynamic grounds, conventional doses of cefotaxime alone should susciently cover S . aureus and most strains of penicillin-intermediate and -resistant pneumococci. A fourth-generation cephalosporin may not be necessary to cover the current resistance levels. Prof. M. Glauser: Professor Garau, can you discuss when cefpirome could be used as monotherapy, or when it should be used in combination? Prof. J. Garau: It would not be advisable to use combination therapy initially, unless P. aeruginosa infection is indicated. If P. aeruginosa was the most likely pathogen, then a more potent antipseudomonal agent combined with an aminoglycoside or ciprofloxacin is recommended. Prof. M. Glauser: Would you consider cefpirome for monotherapy in all the indications mentioned, except for documented infections caused by P. aeruginosa? Prof. J. Garau: Yes, and for intra-abdominal infections caused by a mixture of aerobes and anerobes, combination therapy would be used to expand the spectrum of activity. When combination therapy is used to enhance the bactericidal activity, by the addition of an aminoglycoside or a fluoroquinolone to the regimen, I would recommend cefiazidime or another more potent antipseudomonal agent plus an aminoglycoside, against P . aeruginosa infection. However, if cefpirome was the initial empiric therapy for nosocomial pneumonia in the ICU, and the microbiological results confirmed that P. aeruginosa had been identified and was susceptible to cefpirome, I would continue therapy with cefpirome in combination with an aminoglycoside. Professor Bryskier, which drug would you recommend ifboth cefpirome and ceftazidime exhibited an MIC value against P. aeruginosa of 1 mg/L? Prof. A. Bryskier: There is often a wide variation in the susceptibility of P. aeruginosa, on one culture they exhibit MIC values of 1 mg/L and on retesting exhibit MICs of 4 mg/L. In France, combination therapy with a p-lactam plus an aminoglycoside for at least three weeks is recommended for the therapy of Pseudomonas infections. Monotherapy for the treatment of Pseudomonas infections is not recommended. Ceftazidime is a dianionic compound and if the inoculum level is increased it does not exhibit bactericidal activity. In contrast, cefpirome is a zwitterionic compound and exhibits bactericidal activity

if the inoculum is increased. The same principle also applies to cefepime. Therefore, the quaternary ammonium cephems would have an advantage over ceftazidime. Prof. J. Garau: If a patient has a P. aeruginosa infection with a low cefpirome MIC, then combination therapy with an aminoglycoside could be considered. Prof. W. Wilson: For most infections caused by Pseudomonas, combination therapy would be recommended, although there are some infections where combination therapy would not be necessary. References 1. Neu HC. The crisis in antibiotic resistance. Science 1992; 257: 1064-73. 2. Spencer R C , Bauernfeind A, Garcia-Rodriguez J , et al. Surveillance of current resistance of nosocomial pathogens to antibiotics. [This supplement]. 3. Jones R N , Baquero F, Privitera G, Inoue M, Wiedemann B. Inducible P-lactamase-mediated resistance to thirdgeneration cephalosporins. [This supplement]. 4. Jones R N . The current and future impact of antimicrobial resistance among nosocomial bacterial pathogens. Diagn Microbiol Infect Dis 1993; 15: S3-10. 5. Livermore DM. Mechanism of resistance to p-lactam antibiotics. Scand J Infect Dis 1991; 78 (suppl): S7-16. 6. Pechere J-C, Wilson W, Neu H. Laboratory assessment of antibacterial activity of zwitterionic 7-methoxyimino cephalosporins.J Antimicrob Chemother 1995: 3 6 757-71. 7. Sanders CC. p-lactamases of Gram-negative bacteria: New challengesfor new drugs. Clin Infect Dis 1992; 14: 1089-99. 8. Neu HC. The place of cephalosporins in antibacterial treatment of infectious diseases. J Antimicrob Chemother 1980; 6 (suppl A): 1-10. 9. Neu HC. p-lactam antibiotics: Structural relationships affecting in vitro activity and pharmacologic properties. Rev Infect Dis 1986: (suppl 3): S287-359. 10. Sanders CC. Inducible p-lactamase and non-hydrolytic resistance mechanisms.J Antimicrob Chemother 1984; 13: 1-3. 11. Sanders WE, Sanders CC. Inducible P-lactamases: clinical and epidemiological implications for use of newer cephalosporins. Rev Infect Dis 1988; 10: 83@8. 12. Livermore DM and Yuan M. Antibiotic resistance and production of extended-spectrum P-lactamases amongst Klebriella spp. from intensive care units in Europe. J Antimicrob Chemother 1996; 38: 409-24. 13. Wolff M, Brun-Buisson C, Lode H, Mathai D, Lewi D, Pittet D. The changing epidemiology of severe infections in the ICU. [This supplement]. 14. Jarvis WR, Martone W. Predominant pathogens in hospital infections. J Antimicrob Chemother 1992: 29 (suppl A): S19-24. 15. Klugman K, Goldstein F, Kohno S, Baquero F. The role of fourth-generation cephalosporins in treatment of infections caused by penicillin-resistant streptococci. [This supplement].

Garau: Fourth-generation cephalosporins 16. Alcaide F, Linares J, Pallares R. In vitro activities of 22 p-lactam antibiotics against penicillin-resistanl; and penicdhnsusceptible viridans group streptococci isolated from blood. Antimicrob Agents Chemother 1995; 39: 2243-7. 17. Arthur M, Courvalin P. Genetic mechanisms of glycopeptide resistance in enterococci. Antimicrob Agents Chemother 1993; 37: 1563-71. 18. Hancock R E W , Bellido F. Antibacterial in vitro activity of fourth-generation cephalosporins. J Chemother 1996; 8: 31-6. 19. Pucci MJ, Boice-Sowek J, Kessler RE, et al. Comparison of cefepime, cefpirome and cefclidine binding affinities for penicillin binding proteins in Escherichia coli K-12 and Pseudornonas aeruginosu SC8329. Antimicrob Agents Chemother 1991: 35: 2312-7. 20. Bryskier A, Aszodi J , Chantot J-F. Parenteral cephalosporin classification.Expt Opin Invest Drugs 1994; 3: 145-71. 21. Jones RN, Pfaller MA, M e n SD, Gerlach EH, Fuchs PC, Aldridge KE. Antimicrobial activity of cefpirome. An update compared to third-generation cephalosporins against nearly 6000 recent clinical isolates from five medlcal centres. Diagn Microbiol Infect Dis 1991: 14: 361--4. 22. Schafer V, Shah PM, Doerr HW, Zieman M , Hellwich S, Seibert G and Study Group. In vitro activity of cefpirome against isolates from patients with urinary tract, lower respiratory tract and wound infections. J Antimicrob Chemother 1992; 29 (suppl A): S7-12. 23. Sanders CC. Cefepime: the next generation? Clin Infect Dis 1993; 17: 369-79. 24. Cheng AFB, Ling TKW, Lam AW, Fung KSC, Wise R. The antimicrobial activity and beta-lactainase stability of cefpirome, a new fourth-generation cephalosporin in comparison with other agents. J Antimicrob Chemother 1993; 31: 699-709. 25. Sader HS, Jones R N . In vitro antimicrobial activity of cefpirome against ceftazidme-resistant isolates fiom two multicenter studies. Eur J Clin Microbiol Infect Dis 1994; 13: 675-9. 26. Linares J , Alonso T, Perez JL, et al. Decreased susceptibility of penicillin-resistant pineumococci to twenty-four beta-lactam antibiotics. J Antiniicrob Chemother 1992; 30: 279-88. 27. Fremaux A, Sissia G, Geslin P. In vitro antibacterial activity of cefotaxime, cefpirome and four other beta-lactam antibiotics against penicillin-resistant Streptococcus pneurnoniue. 6th lilt Congr Infect Dis Prague 1994; PCS 26. 28. Fremaux A, Sissia G, Bryskier A, Geslin P. In vitro activity of cefpirome and six other parenteral [l-lactams against penicillin susceptible and penicillin-resistant pneumococci. gfh Eur Congr Clin Microb Infect Dis, Vienna 1995. 29. Glauser MP, Boogaerts M, Cordonnier C, Palmblad J, Martino P. Empiric therapy of bacterial infections in severe neutropenia. [This supplement]. 30. Verbist L, for the International Study Group. Epidemiology and sensitivity of 8625 ICU and hemotology/oncology bacterial isolates in Europe. Scand J Infect Dis 1993; (suppl 91): 14-24.

s99 31. Jones R N , Fuchs PC. Activity of cefepime @MY-28142) and cefpirome ( H R 810) against Gram-negative bacilli resistant to cefotaxime or ceftazidime. J Antimicrob Chemother 1989; 23: 163-5. 32. Fuster C, Raya C , Tirado M, Teruel D , Garnelo AM, Roy C. Enterobacteriacea. hslamientos y scnsibilidad a 10s antibi6ticos Betalactamicos en un hospital comarcal. Rev Esp Microbiol Clin 1991: 6: 497-503. 33. Liu PYF, Gur D, Hall LMC, Livermore DM. Survey of the prevalence of p-lactamases amongst 1000 Gramnegative bacilli isolated consecutively at the Royal London Hospital. J Antimicrob Chemothcr 1992; 30: 429-47. 34. Goldstein FW, Pean Y, Rosato A, Gerther J, Gutman L, Vigil ROC Study Group. Characterization of ceftnaxoneresistant Enterobacteriaceae: a mulncenhic study in 26 French Hospitals. J Antimicrob Chemother 1993; 32: 595-603. 35. Reeves DS, Bywater MJ, Holt HA. The activity of cefpirome and ten other antibacterial agents against 2858 clinical isolates collected form 20 centrec. J Antimicrob Chemother 1993; 31: 345-62. 36. Lopez-Yeste L, Xercavins M, Lite J , Cuchi E, Garau J. Resistencia a fluoroquinolonas y aminoglucosidos en cepas hiperproductoras de cefalosporinasa cromosomica de bacilos Gram-negativos con p-lactamasa inducible. Enf Inf Microbiol Clin 1996; 14: 211-4. 37. Jones R N , Marshall SA. Antimicrobial activity of cefepime tested against Bush group 1 P-lactamase-producing strains resistant to ceftazidime. A multilaboratory national and international clinical isolate study. Diagn Microbiol Infect Dis 1994; 19 (1): 33-8. 38. Jacoby GA, Cameras I. Activities of p-lactam antibiotics against Escherichia roli strains producing extended spectrum beta-lactamases. Antimicrob Agents Chemother 1990; 34: 858-62. 39. King A, Boothman C, Phillips I. Comparative ~n vitro activity of cefpirome and cefepimc, two new cephalosporins. Eur J Clin Microbiol Infect Dis 1990; 9: 677-85. 40. Piddock LJV, Traynor EA. Beta-lactamase cxpression and outer membrane protein changes in cefpirome-resistant and ceftazidime-resistant Gram-negative bacteria. J Antimicrob Chemother 1991; 28: 209-19. 41. Craig WA. The phamiacokinetics of cefpirome-rationale for a twelve-hour dosing regimen. Scand J Infect Dis 1993: (suppl 91): 33-40. 42. Barbhaiya R H , Forgue ST, Gleason CK. Safety, tolerance and pharmacokinetic evaluation of cefepime aftcr administration of single intravenous doses. Antimicrobial Agents Chemother 1992; 36: 552-7. 43. Malerczyk V, Maas L, Verbo M, Hajdu N, Rangoonwala R. Single and multiple dose pharmacohnetics of intravenous cefpirome, a novel cephalosporin derivativc. Infection 1987: 15: 211-4. 44. Wilcox M H , Pithie A, Smith G, Moreland TA. Relationship between cefpirome clearance. serum creatimnc, weight and age in patients treated for infection.J Antimicrob Chemother 1991: 28: 291-9. 45. CollinsJ, Badian M, Lehr KH, Luus HG, ct al. Multiple dose pharmacokinetics of 2 g cefpirome iv in young and elderly

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