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N.V. Dmitrieva
Blokhin Russian Cancer Research Center, Moscow, Russian Federation
Cefpirome. Literature review
Author Affiliation:
Natal’ya Vladimirovna Dmitrieva, MD, PhD, Professor, head of the laboratory of
microbiological diagnosis and oncological infection treatment at the Blokhin Russian Cancer
Research Center (Federal State Budgetary Research Institution)
Address: 24 Kashirskoye Hw., Moscow, 115478; tel.: +7 (499) 324-18-40;
e-mail: prof.ndmitrieva@mail.ru
Article received: 17.07.2014. Accepted for publication: 17.09.2014.
Researchers around the world acknowledge a continuing growth of antibiotic resistance. Thus, it
is especially important to select from a wide range of antibacterial agents in the pharmaceutical
market the ones appropriate for specific regional sensitivity, only in accordance with clearly
defined indications and in order of priority for each specific case. The most frequently used are
wide range drugs, including the 4th-generation cephalosporins active against gram-positive and
gram-negative microbes and most anaerobes. This review is dedicated to a representative of this
group – cefpirome. The authors indicate the primary indications for use thereof and present a
comparative effectiveness analysis. Cefpirome is as effective as cefepime, which is important,
particularly because of growth of bacterial resistance against the 3rd-generation cephalosporins.
Its significant advantage is activity against several enterococci and anaerobes. Cefpirome
penetrates various body tissues fairly well and establishes there bactericidal concentrations
against most known clinically significant microbes. The trials have demonstrated clinical
effectiveness of the drug for various nosocomial infections, such as sepsis (62-77%), febrile
neutropenia (53-84%), intra-abdominal infections (83%), complicated urinary infections (100%)
etc. The drug features low toxicity: it does not exceed the one in cefepime and the 3rd-generation
cephalosporins, which makes it possible to use cefpirome as the drug of the 1st choice for severe
hospital-acquired infections given its wide antibacterial range and clinical significance.
Keywords: cefpirome, cefepime, nosocomial infections, sepsis, febrile neutropenia, antibiotic
resistance, treatment of gram-negative infections, 4th-generation cephalosporins.
INTRODUCTION
Cefpirome is a 4th-generation cephalosporin highly active against both gram-positive and
gram-negative (including Pseudomonas aeruginosa) microbes. Compared to the 1st-, 2nd- and
3rd-generation cephalosporins, 4th-generation cephalosporins (cefpirome and cefepime) are more
effective against gram-positive microbes and pseudomonas aeruginosa and are sufficiently stable
against class 1 chromosomal cephalosporinases (usually produced by Enterobacter spp.).
Cefpirome features a high level of safety and an extremely low risk of nephrotoxicity [1-3].
Comparative studies have demonstrated high clinical effectiveness of the drug for bacteremias
[1]. Cefpirome’s wide antibacterial spectrum, low toxicity and anti-staphylococcal activity are
the advantages thereof for severe sepsis, febrile neutropenia and other nosocomial infections,
which are difficult to treat with routine antibiotics.
Microbiological activity
Methicillin-resistant Staphylococcus aureus (MRSA)-induced infections are among the most
clinically significant and difficult to treat infections. Glycopeptides vancomycin and teicoplanin
(only vancomycin is available in Russia) are the drugs of choice therefor; however, the therapy is
not always successful [4].
Several studies have demonstrated synergism of a vancomycin (MIC 0.25-1) or teicoplanin
(MIC 0.125-1) combination with cefpirome (MIC 0.125-0.5) determined by the time of bacterial
death [5]: thus, an in vitro study of 12 MRSA strains demonstrated spread of the synergic effect
to glycopeptide-intermediate strains.
Similar results were obtained in a prospective randomized study of the vancomycin-cefpirome
combination’s effect on the microbial death rate in the treatment of the MRSA-induced infections
at a resuscitation and intensive care unit [6]. The study involved 20 patients with severe
pneumonia or bacteremia. The first group (n = 10) was treated with vancomycin (2 g/day), the
second (n = 10) – with a combination of vancomycin (2 g/day) and cefpirome (4 g/day).
Although the parameters under analysis were better in the 2nd group (microbial death rate – 40
and 60%, serum’s bactericidal properties [at a 1/16 dilution] – 68 and 88.8%), the difference was
not significant except for decrease in the concentration of inflammatory markers – 119.5 and
198.6 mg/l (p < 0.05) on day 3.
In general, the 4th-generation cephalosporins (cefpirome and cefepime) are especially effective
against gram-negative microbes. However, several studies have demonstrated a surprisingly high
cefpirome activity against gram-positive aerobes [7, 8]: thus, out of the 434 coagulase-positive
(CPSs) and coagulase-negative staphylococci (CNSs) extracted from clinical biomaterials,
81.3 and 91.6%, respectively, were sensitive to cefpirome (compared to 35.1 and 26.5%
sensitivity to oxacillin (sensitivity was measured by means of Mueller-Hinton agar dilution; the
minimal inhibiting concentration for cefpirome varied from 0.5 to 8 mg/l) [8]. Other authors
compared this drug with the 3rd-generation cephalosporins (ceftazidime, cefoperazone,
ceftizoxime, ceftriaxone) using 1,300 gram-positive and gram-negative microbes obtained from
13 medical centers [7]. Bacterial identification was performed using semi-automatic
microbiological systems; sensitivity to antibiotics was measured by means of a modified Kirby-
Bauer test and assessed in compliance with the CLSI (NCCLS) standards. Cefpirome
demonstrated higher activity against both gram-positive (enterococci, MRSA and β-hemolytic
streptococci) and gram-negative strains (escherichiae coli, klebsiellae, enterobacters, protei and
Salmonella typhi). In general, the share of Escherichia coli-sensitive strains was 87% for
cefpirome and 61% for the 3rd-generartion cephalosporins; Klebsiella spp.-sensitive – 84 and
56%; Enterobacter spp.-sensitive – 88 and 59%; Proteus spp.-sensitive – 97 and 92%; S. typhi-
sensitive – 98 and 96%; Staphylococcus spp.-sensitive – 86 and 59%; Enterococcus spp.-
sensitive – 82 and 72%, respectively. The activity of cefpirome and ceftazidime against
pseudomonas aeruginosa was comparable [7]. Thus, the authors have concluded that cefpirome
features a wider spectrum and higher activity against most clinically significant nosocomial
microbes.
A study (Japan, 2008) of 4,228 nosocomial microbial strains from 51 medical centers was
dedicated to comparative analysis of sensitivity of the 3rd- (ceftazidime and
cefoperazone/sulbactam, as well as piperacillin and imipenem) and the 4th-generation
cephalosporins (cefpirome and cefepime) [9]. CNS and CPS non-methicillin-resistant strains
were 100% sensitive to all β-lactams (except for ceftazidime). Escherichia coli strains were the
most resistant against piperacillin (24.6%), whereas the resistance thereof against other β-lactams
(including cefpirome) was below 4.5%. Pseudomonas aeruginosa resistance was slightly higher –
from 9.1% against piperacillin to 16.3% against cefpirome. According to the obtained data, the
proportion of resistant strains slightly decreased from 2006; the authors concluded that this fact
totally reflected policies of consumption of specific antibiotics at the centers involved in the
study [9].
However, most authors mention increase in pseudomonas aeruginosa resistance to β-lactam
antibiotics around the world [3]. The study performed in Bulgaria analyzed 203 pseudomonas
aeruginosa strains obtained from different patients in the course of 6 years. The resistance rate
was high: 56.8-93.1% for penicillins (including piperacillin + tazobactam), 59.1-79.7% for
aminoglycosides, 42.3-45.5% for carbapenems and 45.8-58.2% for anti-pseudomonas aeruginosa
3rd-4th-generation cephalosporins (including cefpirome). 49.8% of the pseudomonas aeruginosa
strains were multi-resistant. β-lactamases bla (OXA-group) – 41.3% - and bla (VEB-1) – 33.1% -
were prevalent. Carbapenemases IMP and VIM were not observed. The authors concluded that
carbapenem resistance was likely associated with protein OprD deficiency and active efflux [10].
Klebsiella strains were equally sensitive (97.6-99.6%) to the analyzed β-lactams, as well as
enterobacter, citrobacter and serratia strains. However, an earlier study performed by the same
authors demonstrated higher sensitivity of Klebsiella strains to cefpirome, cefepime and
imipenem [10]. Results of a similar study performed in Japan confirm equal activity of
cefpirome, the 3rd-generation cephalosporins and cefepime [11].
Another study [12] was aimed at comparing Klebsiella spp.-sensitivity of cefpirome and
cefepime due to increasing resistance of the 3rd-generation cephalosporins against the
β-lactamase-producing Enterobacteriaceae. 342 microbes obtained from different pathological
materials of the patients admitted to Western Romanian clinics were analyzed. Activity of both
drugs was the same; the average minimal inhibiting concentration (MIC) was 1 mg/l; MIC of
more than 60% of the strains was below 8 mg/l; therefore, the authors stated high activity of the
4th-generation cephalosporins – cefpirome and cefepime – against the klebsiella-induced
infections [12].
Huang et al. [13] analyzed sensitivity of 588 microbial strains extracted from blood of oncology
patients (476 bacteremia episodes): E. coli – 22.4%, Klebsiella pneumoniae – 17.6%,
Staphylococcus aureus – 9.7% (MRSA – 55.8%); coagulase-negative staphylococci were
primarily represented by methicillin-resistant variants. Sensitivity of gram-negative microbes to
the analyzed antibiotics (cefpirome, cefepime, piperacillin/tazobactam and carbapenems) was
comparable – 85% among patients with and without febrile neutropenia. The authors stated equal
value of the aforementioned drugs for empiric treatment of blood flow infections in oncology
patients.
Pharmacokinetic peculiarities
As most cephalosporin antibiotics, cefpirome is poorly absorbed from the gastrointestinal tract
and is thus used only parenterally (intravenously or intramuscularly). The drug’s bioavailability
is high in the event of intramuscular administration. The elimination half-life is ca. 2 hours (1.8-
2.2 hours in patients with normal renal function); it does not depend on the dose and duration of
use. The antibiotic is found in blood in therapeutic concentrations for 12 hours, which is why it is
prescribed BID. The average drug’s concentration in blood plasma 5 minutes after i/v
administration of 1 g is 81 mg/l. Binding with plasma proteins is ca. 10%. Cumulation at
repeated administration is not observed. Cefpirome is primarily eliminated by kidneys by means
of glomerular filtration (80-90% of cefpirome is extracted with urine within the first 24 hours).
The average drug’s concentration in blood plasma of over-65 patients 5 minutes after i/v
administration of 1 g may be as high as 127.1 mg/l; the elimination half-life increases up to 4.5
hours. Cumulation at multiple administration is not observed. Joukhadar et al. performed a
pharmacokinetic comparison of cefpirome use in 12 patients with septic shock and 6 volunteers:
they analyzed permeability of the drug’s dose (2 g) into interstitial fluid of skeletal muscles [14].
Results were comparable: 16.0 ± 1.1 and 18.8 ± 1.1 mg/ml per minutes in patients and
volunteers, respectively (p > 0.05). The drug’s concentration in plasma and interstitial fluid
exceeded 28 mcg/ml within the observation period of 240 minutes and еру MIC for most
clinically significant pathogens. The authors state reasonability of using cefpirome for empiric
treatment of sepsis. Other authors have come to the same conclusions by measuring extracellular
concentration in normal lung tissue and inflamed lung tissue of patients with sepsis [15]. They
demonstrated that cefpirome concentration in both normal lung and inflamed lung and blood
plasma were equal and that the drug’s concentration exceeded MICs for most microbes within 12
hours after 30 mg/kg dose administration.
Indications for use: infectious inflammatory diseases induced by sensitive bacteria:
sepsis/bacteremia; complicated urinary infections, including pyelonephritis, pyelitis, urethritis,
cystitis; respiratory infections, including pneumonia; lung abscess; pleural empyema; skin and
soft tissue infections; wound infections; infections in patients with neutropenia.
Contraindications: intense allergy to cephalosporins, pregnancy, lactation, under-12 children.
Care must be exercised when prescribing the drug to patients with gastrointestinal diseases,
including ulcerative colitis, regional enteritis and severe renal failure.
CLINICAL STUDIES
Febrile neutropenia
Progress in antitumor chemotherapy may be leveled off by infectious complications, especially
by febrile neutropenia (FN), which often comes secondary to the primary disease. FN is
especially aggressive and difficult to treat in patients with oncohematological diseases due to
duration and intensity of neutropenia. Fever is often the only clinical manifestation of FN. Broad
antimicrobial action spectrum antibiotics ought to be prescribe as soon as possible. Infection is
microbiologically confirmed rather rarely (25-40%).
3rd-4th-generation cephalosporins featuring anti-pseudomonas aeruginosa activity (ceftazidime or
cefepime), carbapenems or “protected” anti-pseudomonas aeruginosa penicillins
(ticarcillin/clavulanate or piperacillin/tazobactam) are the 1st line drugs for FN. Supplementation
of the aforementioned drugs with aminoglycosides does not improve treatment results [16, 17].
F. Bauduer et al. [17] assessed results of a randomized multicenter study, where cefpirome
(4 g/day) or piperacillin/tazobactam (12 g/day) were used as the 1st line drugs for
chemotherapy-induced FN in patients with oncohematological diseases. 208 FN episodes were
analyzed: 10 cases out of them concerned allotransplantation of stem cells, 38 – autologous
transplantation thereof. The average duration of neutropenia was 17 days. The infection was
microbiologically confirmed in 27% of the cases. The obtained clinical effects of cefpirome
surpassed clinical effects of piperacillin/tazobactam, although the difference was not significant:
fever disappearance after 2 days of therapy and negative results of bacteriological analysis were
obtained in 62; 61 and 50; 55% of the cases, respectively. Use of cefpirome did not require shift
to other antibiotics (no superinfection) in 59% of the cases (50% - fir piperacillin/tazobactam).
Incidence of these side effects was insignificant in both groups.
The authors stated similar effectiveness of the drugs; they may be recommended as the 1st line
drugs for FN.
Other authors empirically used cefpirome to treat FN in 140 patients [18]. Microbes
(13 gram-positive and 9 gram-negative) were detected in 20 patients. On the average, fever
disappeared after 3.1 days of therapy in 84.1% of the patients. The average time of microbial (if
present) eradication was 5 days. The authors recommend using cefpirome as the 1st line highly
effective and financially sound drug for FN.
G.J. Timmers et al. [19] analyzed 154 FN episodes in 106 patients with oncohematological
diseases and demonstrated high effectiveness of cefpirome. The average fever duration was
4.5 days; the infection was microbiologically confirmed in 36% of the cases (44% of the strains
were cefpirome-resistant); infection was clinically detected in 26% of the patients, idiopathic
fever – in 38% of the patients. The average clinical effect was 53%; it was the highest at
idiopathic fever – 76%; at clinically proven infections – 53%; at microbiologically confirmed
infections – 27% (weak effect may be caused by resistance of some microbes to the analyzed
antibiotic). No adverse effects were registered. The authors recommend prescribing cefpirome as
the 1st line drug for FN; however, high risk of pseudomonas aeruginosa resistance (2 strains were
identified in this study; both were cefpirome-sensitive) requires multimodal therapy.
Genitourinary infections
A comparative multicenter study (2004-2005) of patients with complicated and non-complicated
urinary infections was performed in 14 medical centers in Japan [20]. The highest activity of
cefpirome and cefotiam was observed against strains of escherichia coli – common causative
agents of urinary infections.
A.M. Nikolovski et al. [21] achieved a 100% clinical effect and complete eradication of
causative agents in 20 patients with acute and severe urinary infections, which is why they
recommended cefpirome as the 1st line drug for this disease.
High clinical effectiveness of the drug was demonstrated in 88 patients with different
gynecological infectious diseases, as well as for prevention of postoperative infections after
vaginal hysterectomy. Clinical effect was 77%; bacterial eradication was observed in 67.8% of
the cases [22].
Japanese authors [23] demonstrated effectiveness of cefpirome against a range of anaerobic
microbes (Bacteroides spp., Prevotella spp., Porphyromonas spp.) in 146 patients of
obstetric-gynecological clinics. Clinical effect was registered in 122 cases. Eradication of
Bacteroides spp. was observed in 37 out of 54 patients, of Prevotella spp. – in 38/49, of
Porphyromonas spp. – in 5/5. Adverse effects were observed in 4.76% of the cases. On the basis
of these results, the authors state safety and effectiveness of cefpirome for use at
obstetric-gynecological clinics.
Intraabdominal infections
Cefpirome takes precedence over other cephalosporins not only in the high antianaerobic activity
regard. Thus, Giamarellou [24] demonstrated its uniqueness in respect of enterococci. Surgical
infections are rather versatile: intraabdominal infections, obstetric and gynecological infections,
musculoskeletal and soft tissue infections. Due to the peculiarities thereof, antimicrobial
chemotherapy usually plays a supporting role. The most commonly used drugs are the
1st-2nd-generation cephalosporins combined with antianaerobic drugs and aminoglycosides in
order to broaden the combination’s antimicrobial spectrum. The 4th-generation cephalosporins
were more or as effective as cefotaxime and ceftazidime [25]. MRSA and Bacteroides fragilis are
not covered by the 4th-generation cephalosporins; however, some strains are cefpirome-sensitive.
Moreover, cefpirome is the only effective cephalosporin against enterococci. According to the
author, cefpirome and cefepime are highly indicated for empirical therapy of severe surgical
infections; combination with nitroimidazoles (metronidazole) may be useful.
Sepsis and bacteremia
A group of researchers performed a multicenter comparative study of effectiveness of cefpirome
(4 g/day) and ceftazidime (6 g/day) for empirical therapy of 100 patients with severe
community-acquired sepsis [1]. Clinical effect of cefpirome and ceftazidime was 77 and 67%,
respectively; bacteriological effect – 90 and 86% (non-significant difference). The average
treatment duration was 9 days: 1-23 days in the cefpirome group and 0-25 days in the
ceftazidime group. Drug monotherapy was performed in 82% of the cases in the cefpirome group
and in 78% of the cases in the ceftazidime group. Other patients were additionally prescribed
metronidazole and/or vancomycin and/or antifungal drugs. The most commonly observed
microbes were escherichia coli (35%), pneumococcus (12%) and staphylococcus aureus (23.8%).
In total, 11 microbes were cefpirome-resistant, 10 – ceftazidime-resistant. Adverse effects were
observed in 29 and 22% of the cases. In a randomized study of 3,103 cefpirome-treated patients,
adverse effects (probably associated with treatment) were also observed in 22% of the cases [2].
Adverse effects were observed in 26% of the 1,134 ceftazidime-treated patients. All the other
parameters, including mortality (9-12%) were almost the same (non-significant difference). The
authors state effectiveness and safety of cefpirome for bacteremia. Broad antibacterial spectrum
against gram-positive microbes and a possibility of administering the drug BID make it not only
effective, but also more financially sound than other drugs.
Use of cefpirome in pediatric practice
Cefpirome is not indicated for under-12 children in Russia, the USA and European countries.
However, experience of Japanese researchers demonstrates the safety and high activity thereof
for treating various infections induced by sensitive microbes in children aged from 1 month to
12 years. The authors observed high cefpirome concentration in cerebrospinal fluid when
treating purulent meningitis (general clinical effect – 93%) and absence of adverse effects [26-
28].
CONCLUSION
Thus, one of the most important properties of cefpirome is broader antibacterial activity
spectrum (stability against various β-lactamases) than in the 3rd-generation cephalosporins,
which covers gram-positive and gram-negative microbes and most anaerobes. Combination of
cefpirome with vancomycin improves its clinical effect against MRSA; high activity against
enterococci and anaerobes positively sets it apart from other 3rd-4th-generation cephalosporins.
Cefpirome is as active as cefepime and other 3rd-generation cephalosporins: several studies have
demonstrated the clinical effectiveness thereof for treating patients with febrile neutropenia and
sepsis. Cefpirome penetrates various body tissues well and establishes there in the concentrations
bactericidal to most clinically significant microbes. The drug is easily metered, which makes it
financially sound; it features low toxicity (not higher than that of cefepime and the 3rd-generation
cephalosporins). The antibiotic’s effectiveness against various severe nosocomial infections has
been proved; broad microbiological spectrum allows using it for monotherapy.
CONFLICT OF INTEREST
The author has indicated she has no financial relationships relevant to this article to disclose.
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