Antimicrobial activity of 11 newer and investigational drugs tested against aerobic isolates from spontaneous bacterial peritonitis

ELSEVIER

NOTES

Antimicrobial Activity of 11 Newer and Investigational Drugs Tested Against Aerobic Isolates from Spontaneous Bacterial Peritonitis Helio S. Sader, Bruce A. Runyon, Meridith E. Erwin, and Ronald N. Jones

The in vitro susceptibility of 124 aerobic bacterial pathogens isolated from patients with spontaneous bacterial peritonitis (SBP) were tested against 11 antimicrobial agents, including parenteral or oral cephalosporins and f7uoroquinolones. Most SBP isolates were Gram-negative organisms, and Escherichia coli and KIebsiella pneumoniae were responsible for 63% of the episodes evaluated. The fluoroquinolones (ciprofloxacin and ofloxacin) and the “fourth-generation” cephalosporin cefpirome were the most active agents against the Gram-negative bacteria. Commonly used cefotaxime and cefotaxime-desacetylcefotaxime (DES-CTX) combinations were also very active against Gram-negative bacteria with only fewEnterobacter cloacae

isolates being resistant (minimum inhibitory concentrations > 32 kglml). All streptococci were susceptible to cefotaxime, cefpirome, and cefdaloxime and to the cefotaxime-DES-CTX combinations, whereas only ofloxacin demonstrated acceptable activity against the enterococci. The widest spectrum of activity versus SBP isolates was found for ofloxacin (98% susceptibility) among the fluoroquinolones. For the @lactams, the widest spectrum of activity was demonstrated by cefpirome and the 2:l cefotaxime-DES-CTX combination (93% susceptibility). These results indicate that the role of ofloxacin and newer parenteral or orally administered cephalosporins in the treatment of prophylaxis of SBP should be further evaluated.

Spontaneous bacterial peritonitis (SBP) is a frequent and life-threatening complication in cirrhotic patients with ascites. The mortality attributed to infection is usually high, and prompt antimicrobial therapy is required to prevent uncontrolled sepsis (Almdal and Skinhoj, 1987; Arroyo et al., 1994). In addition, culture of the ascitic fluid has a relatively low sensitivity unless specific procedures are followed (Runyon et al., 1990). Thus, empiric therapy is usually initiated based on elevated ascitic fluid neutrophil counts and/or symptoms of infection (Westphal et al., 1994). Empiric SBP treatment originally used a combination of ampicillin and an ami-

TABLE

1 Distribution

of 124 Aerobic Bacterial Pathogens Isolated from Patients with Spontaneous Bacterial Peritonitis

Organism Escherichia coli Klebsiella spp. Streptococcus pneumoniae Streptococcus, viridans gr. Enterococcus spp. Enterobacter cloacae Streptococcus agalactiae Streptococci,

From the Departments of Pathology (H.S.S., R.N.J., and M.E.E.) and Internal Medicine (B.A.R.), University of Iowa College of Medicine, Iowa City, Iowa, USA. Address reprint requests to Dr. R.N. Jones, Department of Pathology, 5232 RCP, University of Iowa College of Medicine, Iowa City, IA 52242, USA. Received 28 October 1994; revised and accepted 21 December 1994. DIAGN MICROBIOL INFECT DIS 1995;21:10%110 0 1995 Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

nonhemolytic

Aeromonas sobria Citrobacter freundii Listeria monocytogenes Pseudomonas aeruginosa Salmonella arizonae Salmonella typhimurium Shigella spp.

No. of Isolates

%

61

49

17

14

12

10

7

6

6 5 5

5 4 4

4

3

1

1

1 1 1

1 1

1

1

1

1

1

1

1

0732~&393l95l$9.50 0732-8893(94)00148-I

H.S. Sader et al.

106

TABLE 2

In vitro Antimicrobial Activity of 11 Antimicrobial Agents Tested Against 89 Gram-Negative Organisms Isolated from Spontaneous Bacterial Peritonitis Patients MIC (kg/ml)

Organism (No. Tested)

Antimicrobial Agents”

50%

90%

Range

Escherichia coli (61)

Cefotaxime +DES-CTX (1:l) + DES-CTX (2:l) + DES-CTX (4:l) DES-CTX alone Cefodizime Cefpirome Ceftazidime Cefdaloxime Cefpodoxime Cefuroxime Cefaclor Ofloxacin Ciprofloxacin

0.06 0.03 0.03 0.03 0.25 0.12 0.03 0.12 0.25 0.5 4 1 0.06 0.015

0.12 0.06 0.12 0.06 1 0.25 0.06 0.25 0.5 1 4 4 0.12 0.03

~0.015-1 ~0.015-0.5 ~0.015-1 SO.O&1 GO.Ol5-8 0.064 so.o15-8 0.06-0.5 0.12-2 0.12-8 1-16 0.25-8 0.03-0.12 ~0.00~0.06

Klebsiella spp. (17)b

Cefotaxime + DES-CTX (1:l) + DES-CTX (2:l) + DES-CTX (4:l) DEX-CTX alone Cefodizime Cefpirome Ceftazidime Cefdaloxime Cefpodoxime Cefuroxime Cefaclor Ofloxacin Ciprofloxacin

0.06 0.015 0.03 0.03 0.12 0.12 0.03 0.12 0.12 0.12 2 0.5 0.06 0.03

0.12 0.03 0.06 0.06 0.12 0.25 0.06 0.5 0.5 0.25 4 1 0.25 0.06

~0.0158 so.015-4 so.0154 SO.0158 0.06-16 0.06->32 0.03-0.12 0.06-16 0.12->16 0.06>16 l->16 0.25-8 0.06-0.25 ~0.00&0.12

Enterobucter cloacue (5)

Cefotaxime +DES-CTX (1:l) + DES-CTX (2:l) + DES-CTX (4:l) DES-CTX alone Cefodizime Cefpirome Ceftazidime Cefdaloxime Cefpodoxime Cefuroxime Cefaclor Ofloxacin Ciprofloxacin

Other species

Cefotaxime + DES-CTX (1:l) + DES-CTX (2: 1) + DES-CTX (4:l) DES-CTX alone Cefodizime Cefpirome Ceftazidime Cefdaloxime Cefpodoxime

(6)

0.25 0.12 0.12 0.12 8 1 0.25 0.5 >16 4 >16 ~16 0.12 0.06

-

0.06>32 0.03->32 0.06->32 0.06->32 OS-->32 0.12->32 0.034 0.06->16 l->16 0.5->16 P>16 16->16 0.12-0.25 0.03-0.25

0.06 0.03 0.03 0.06 0.25 0.25 0.03 0.12 0.12 0.12

-

sO.O1>16 ~0.01516 ~0.01>16 ~0.01~16 0.06->32 0.12->32 =Zo.o15-2 0.06-2 0.12-2 0.03>16 (Continued)

Note

TABLE 2

107

(Continued)

Organism (No. Tested)

Antimicrobial Agents”

Am 64fW) 50% 4 0.5 0.12 0.12

Cefuroxime Cefaclor Ofloxacin Ciprofloxacin

90% -

Range 0.12->16 OS>16 SO.O04-2 SO.OO&l

“DES-CTX, Desacetylcefotaxime. (l:l), (2:1), and (4:1), Ratio testing of cefotaxime and desacetylcefotaxime concentrations. Cefotaxime concentration alone is listed as the minimum inhibitory concentration (MIC). qncludes Klebsiellu pneumoniae (14 strains), KZebsieZZaoxytocn (two strains), and KZebsieZZaozaenae (one strain). includes Aeromonas sobrio (one strain), Citrobacter freundii (one strain), Pseudomonas aeruginosa (one strain), Salmonella nrizonae (one strain), Salmonella typhimurium (one strain), and ShigeZZa spp. (one strain).

noglycoside

(usually gentamicin).

However,

the use

of this combination in patients with cirrhotic ascites was demonstrated to be problematic because of the unpredictable aminoglycoside volume of distribution, and the resulting difficulty in selecting an appropriate dose has been responsible for excessive nephrotoxicity (Westphal et al., 1994). More recently, the use of a “third-generation” cephalosporin was proven to be superior to the ampicillinaminoglycoside combination in randomized trials and consequently became a commonly used drug class for the treatment of SBP (Felisart et al., 1985). However, data regarding susceptibility testing of a large series of SBP isolates remains limited, especially for newer alternative compounds with a reduced risk of nephrotoxicity. In the present study, we evaluated the in vitro susceptibility of a large collection (124 aerobic bacterial pathogens) of strains isolated from patients with SBP. We tested 11 antimicrobial agents, including nine parenteral and oral cephalosporins and two fluoroquinolones, to confirm that the activity previously described for these drugs was applicable against SBP isolates. The investigation was performed at the University of Iowa Hospitals and Clinics (Iowa City, Iowa, USA), a 1000-bed tertiary care referral center. Abdominal paracentesis was routinely performed in all ascites patients: (a) at admission to the hospital, (b) if ascites developed during hospitalization, or (c) if the patient developed clinical deterioration consistent with bacterial infection. A total of 10 ml of ascitic fluid was inoculated into each bottle of a pair of blood culture bottles at bedside (Runyon et al., 1990). The following antimicrobial agents were tested: cefotaxime, desacetylcefotaxime (DES-CTX), various combination ratios of cefotaxime and DES-CTX (l:l, 2:1, and 4:1), cefdaloxime, cefodizime, and cefpirome provided by Hoechst-Roussel Pharmaceuticals (Somerville, NJ, USA) ceftazidime and cefuroxime received from Glaxo (Research Triangle Park, NC, USA), cefaclor

obtained from Eli Lilly (Indianapolis, IN, USA), ofloxacin given by McNeil Ortho Pharmaceuticals (Raritan, NJ, USA), and ciprofloxacin obtained from Miles Pharmaceuticals (West Haven, CT, USA). Minimum inhibitory concentrations (MICs) were determined by reference broth microdilution as recommended by the National Committee for Clinical Laboratory Standards (NCCLS) using cation-adjusted Mueller-Hinton broth (Difco, Detroit, MI, USA) or medium modifications approved for testing fastidious species (NCCLS, 1993). All SBP episodes involved pure growth of a single pathogen; Table 1 shows the distribution of the aerobic bacteria isolated during the study. Staphylococcus epidermidis, Bacillus species, and coryneform bacteria (diphtheroids) were considered to be contaminants, and only three anaerobes were isolated. Most strains were Gram-negative species (89 of 124 strains), and the enteric species Escherichiu coli and Klebsielh pneumoniue were responsible for 63% of the episodes evaluated. Among the Gram-positive organisms, Streptococcus pneumoniue was the most common species and was responsible for 23% of the clinical cases. The in vitro activity of the 11 antimicrobial agents against Gram-negative and Gram-positive isolates are shown in Tables 2 and 3, respectively. The fluoroquinolones ciprofloxacin and ofloxacin were the most active agents against the Gram-negative bacteria tested, with all organisms inhibited by both agents. The so-called “fourth-generation” cephalosporin cefpirome was also very active (100% susceptibility at ~8 pg/ml) against the Gram-negative bacteria, and only a few Enterobucter cloucue isolates were resistant to cefotaxime or to the cefotaximeDES-CTX combinations. The cefotaxime-DES-CTX combination were usually two-fold more active than cefotaxime alone, which in turn was two- to 16-fold more active than the DES-CTX metabolite alone. The other parenteral cephalosporins evaluated (cefodizime and ceftazidime) were routinely less active

H.S. Sader et al.

108

TABLE 3

In vitro Activity of 11 Antimicrobial Agents Tested Against 35 Gram-Positive Isolated from Spontaneous Bacterial Peritonitis Patients

Organisms

MIC (kg/ml) Organism

(No. Tested) (12)

Streptococcus pneumoniae

Enterococcus spp.

Streptococcus,

Antimicrobial Agents“

Cefotaxime + DES-CTX (1:l) + DES-CTX (2:l) + DES-CTX (4:l) DES-CTX alone Cefodizime Cefpirome Ceftazidime Cefdaloxime Cefpodoxime Cefuroxime Cefaclor Ofloxacin Ciprofloxacin

(6)b

viridans gr.

Streptococcus agalactiae

Cefotaxime + DES-CTX (1:l) + DES-CTX (2:l) + DES-CTX (4:l) DES-CTX alone Cefodizime Cefpirome Ceftazidime Cefdaloxime Cefpodoxime Cefuroxime Cefaclor Ofloxacin Ciprofloxacin

(5)

(7)

50% 0.015 0.008 0.008 0.008 0.06 0.03 0.015 0.25 0.06 0.03 0.015 0.25 2 1 >32 >32 >32 >32 >32 >32 >16 >16 >16 >16 >16 16 2 1

90%

Range

0.03 0.03 0.03 0.03 0.06 0.06 0.06 0.5 0.06 0.06 0.12 0.5 2 2

0.004-0.03 0.004-0.03 0.008-0.03 0.004-0.03 0.015-0.12 0.015-0.06 0.015-0.06 0.06-l 0.03-0.12 0.01>0.06 ~0.008-0.12 0.12-0.5 l-2 OS-2

-

32->32 32->32 1&>32 16->32 >32 16->32 8-->32 >16 >16 >16 >16 &>16 2-4 0.!+4 0.01%2 0.015-2 0.015-2 0.015-2 0.06->2 0.0%>4 0.015-2 0.25->8 0.03-0.12 0.0%>16 0.03->4 O.O!?-~16 l-2 0.54

Cefotaxime + DES-CTX (1:l) + DES-CTX (2:l) + DES-CTX (4:l) DES-CTX alone Cefodizime Cefpirome Ceftazidime Cefdaloxime Cefpodoxime Cefuroxime Cefaclor Ofloxacin Ciprofloxacin

0.06 0.03 0.06 0.06 0.25 0.25 0.03 0.5 0.25 0.12 0.12 0.5 2 2

-

Cefotaxime + DES-CTX (1:l) + DES-CTX (2:l) + DES-CTX (4:l) DES-CTX alone Cefodizime Cefpirome Ceftazidime Cefdaloxime Cefpodoxime

0.03 0.015 0.03 0.015 0.12 0.12 0.03 0.25 0.03 0.03

-

0.015-0.03 0.015-0.03 0.015-0.06 0.015-0.03 0.06-0.12 0.06-0.12 0.015-0.06 0.12-0.5 0.01~0.03 0.015-0.03 (Continued)

Note

TABLE 3

109

(Continued)

Organism (No. Tested)

Other species

(5)’

WC (&ml)

Antimicrobial Agents’

50%

90%

Range

Cefuroxime Cefaclor Ofloxacin Ciprofloxacin

0.03 0.5 1 0.5

-

0.015-0.03 0.06-0.5 1-2 0.5-l

Cefotaxime + DES-CTX (1:l) + DES-CTX (2:l) + DES-CTX (4:l) DES-CTX alone Cefodizime Cefpirome Ceftazidime Cefdaloxime Cefpodoxime Cefuroxime Cefaclor Ofloxacin Ciprofloxacin

0.06 0.015 0.03 0.06 0.25 0.5 0.03 0.5 0.25 0.12 0.06 0.5 2

-

0.015->32 0.015->32 0.015->32 0.015-~32 0.06->32 0.0~>32 0.05->16 0.25-~16 0.03->16 0.03-~16 0.015->16 0.03->16 l->8 l->8

“Abbreviationsas in Table 2. Cefotaxime concentration alone is listed as the minimum inhibitory concentration (MIC). “Includes Enterococcus fuecium (three strains), Enterococcus avium (two strains), and Enterococcus spp. (one strain). Includes

nonhaemolytic

streptococci

(four strains) and Listeria monocytogenes

than cefotaxime against the Gram-negative species tested. In general, the orally administered cephalosporins (cefpodoxime, cefdaloxime, cefuroxime, and cefaclor) possessed similar in vitro activities against the Gram-negative bacteria. The pneumococci and Streptococcus agalactiae (serogroup B) isolates were very susceptible to all cephalosporins, whereas viridans gr. streptococcal isolates possessed relatively elevated MICs compared to other Streptococcus species (Table 3). All streptococci were susceptible to cefotaxime, cefpirome, and cefdaloxime and to the cefotaximeDES-CTX combinations. Although the majority of streptococci were susceptible to both fluoroquinolones (all were susceptible to ofloxacin), the MICs were usually close to recognized break-point concentrations (NCCLS, 1993). In contrast, only the fluoroquinolones showed acceptable in vitro activity (ofloxacin > ciprofloxacin) against enterococci (Table 3). Overall, the fluoroquinolones exhibited the widest spectrum of activity versus the aerobic SBP isolates. The total percentage of susceptible strains was 98% and 90% for ofloxacin and ciprofloxacin, respectively. In addition to the in vitro activity, the penetration of the antimicrobial agents into ascitic fluid and their pharmacokinetics in patients with hepatic failure are important considerations in defining an efficacious treatment for SBP. Published data addressing these points are very sparse for fluoroquinolones. It ap-

(one strain).

pears that both ciprofloxacin and ofloxacin have satisfactory penetration in the ascitic fluid of cirrhotic patients, reaching levels close to that of the plasma (Montay and Gaillot, 1990; Dan et al., 1992). The levels that these fluoroquinolones achieve in the ascitic fluid are well above the MICs for the vast majority of Gram-negative isolates evaluated in the present study. However, they may be borderline when compared to the MICs obtained for some of the Gram-positive isolates (Westphal et al., 1994). Previous studies with ciprofloxacin have shown that its pharmacokinetics is not significantly altered in cirrhotic patients, and no dosage adjustment appears to be needed. However, results obtained with ofloxacin in alcoholic patients with ascites indicated that the ofloxacin pharmacokinetics is markedly influenced, and dosage may need to be adjusted (decreased) because the drug excretion is delayed by the altered renal tubular function of these patients (Silvian et al., 1989; Montay and Gaillot, 1990). Because tubular secretion is involved in the renal excretion of fluoroquinolones (unchanged drugs or metabolites), care must be taken in cases of associated hepatic and renal dysfunction. In addition, although the fluoroquinolones have proven to be quite safe, when used at high doses in cirrhotic patients, some may cause adverse effects (Westphal et al., 1994). Among the B-lactams, the widest spectrum of activity was demonstrated for cefpirome and the 2:l cefotaxime_DES-CTX combination. The overall per-

110

centage of susceptible isolates was 93% for these compounds. The pharmacokinetics of both cefotaxime and DES-CTX in ascitic fluid has been evaluated in several studies (Hary et al., 1989; Ko et al., 1991; Runyon et al., 1991). Cefotaxime freely diffuses into and accumulates in ascitic fluid to an appreciable degree. Its metabolite, DES-CTX, which has shown significant antimicrobial activity and an enhancing effect with cefotaxime, displayed pharmacokinetic behavior similar to that of the parent drug. At the usual doses, these p-lactams yield concentrations in the ascitic fluid that are adequate for inhibition of most Gram-negative strains (Westphal et al., 1994). In contrast to the fluoroquinolones, the levels achieved by cefotaxime in the ascitic fluid are also well above the MICs for most streptococci, especially pneumococci (Table 3). Among the oral cephems, the newer “third-

H.S. Sader et al.

generation” drugs (cefdaloxime and cefpodoxime) showed overall in vitro spectrums similar to that of the older oral compounds (cefaclor and cefuroxime) (Tables 2 and 3). These compounds were active against 85% to 89% of the strains tested. In summary, some fluoroquinolones (ofloxacin) appear to have a wide spectrum of in vitro activity against the prevalent SBP isolates. However, more animal models studies and clinical trials (Silvian et al., 1989; Arroyo et al., 1994) are necessary to evaluate the role of these compounds in the treatment of SBP. Our results confirmed the satisfactory activity of cefotaxime against SBP isolates reported in previous studies, and indicate the potential role of some newer parenteral (cefpirome) and oral (cefdaloxime and cefpodoxime) broad-spectrum cephalosporins and fluoroquinolones in the treatment of prophylaxis of SBP.

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