The major concern associated with antibiotic today is the development of the resistant
bacteria. Due to this, disease of hospital acquired infections and severe infection like
septicemia and neutropenia accounts high mortility rate. The increasing rate of the bacterial
resistance and the life threatening diseases in the hospitals have developed the need of the
new advance antibiotic with better stability against B-lactamase and higher bacterial
eradication rate against many pathogens responsible for Nosocomial infection.
The evolution of the cephalosporin class of the antibiotic, through modification of the basic
cephem structure, has resulted into a new generation with improved antibacterial activity
and stability against common chromosomally and plasmid mediated B-lactamase.
Cefpirome, the fourth generation cephalosporin have an excellent efficacy against the gram-
positive and gram-negative micro-organism with a high stability against the B-lactamase.
The growing number of the mortality due to the infectious disease is a big threat to the
health care society. The major causes of this are:
• Bacterial resistance
' Nosocomial infection
1) Bacterial resistance
Major concern in the medical sciences is to cure the infection. The resistance acquired by the
micro-organism isa big barrier in the treatment. In case of the treatment with cephalosporins
the production of the B-lactamase results into the development of resistance by preventing
the drug to reach their target site by tightly combining with the drug inthe periplasm. These
enzymes could be specific, like penicillinases, or broad spectrum B-lactamases, which can
hydrolyze several B-lactam antibiotics. ICU patients are more resistant towards the
antimicrobial compare to the non-ICU patients.
Resistance acquired by micro-organism ( % )
Microbes ICU patient Non-ICU Out-patient
Coagulase- negative 75 60.4 44.5
MRSA 35.2 31.9 17.7
VRF 13 11.8 2.5
Cefotaxime resist. 25 22.3 10.1
The above table shows that the ICU patients are more prone to the bacterial resistance. The
B-lactamase produced by the micro-organism against antibiotic is a big threat in curing the
disease or infection.
2) Nosocomial infection
The Nosocomial infection is a major cause of concern today which accounts for 5-15% of the
infection and can lead to the complications of 25-33% of patient admitted to ICU. Due to
impaired host defense critically ill patients are susceptible to a rapid colonization byendemic
pathogens.
Responsible pathogens: MRSA, VRE, ESBL, Pseudomonas spp, Enterobacter spp., Citrobacter
etc.
Nosocomial infection threat
• Ventilatorassociated pneumonia
' Surgical site infection
• Urinary catheter infection
These all infections account for 80% of the Nosocomial infection today. ICU infections are
very serious and life threatening. It can infect any part of the body.
Studies shows that respiratory tract is more prone to the infections followed byUTI.The most
Common disease in this is nosocomial pneumonia & UTI.
Description
Cefpirome is a new C-3' quaternary ammonium cephalosporin which bears a 2,3-
cyclopentano pyridinium at the C-3 position of the cephem nucleus and has been classified
as a fourth generation cephalosporin.
a.CEFOVIN™ features
CEFOVIN'" is:
• Active against the gram-positive organisms including staphylococci and streptococci.
• Highly active against gram-negative organisms including Pseudomonasaeruginosa.
' Stable to both plasmid and chromosomal mediated B-lactamases.
• Active against de-repressed mutants producing high level of cephalosporinase
• Shows synergistic activity with aminoglycosides against many bacteria.
b. Pharmacodynamics
CEFOVIN™ is a bactericidal B-lactamase-stable cephalosporin antibiotic. As a B-lactam,
acts by disturbing the synthesis of the main bacterial cell-wall polymer, peptidoglycan b
interfering the final stage of synthesis by inhibiting the enzyme transpeptidase. It
bactericidal at low concentrations against gram-negative and gram-positive pathogens
because it penetrates the cell wall of bacteria extremely rapidly and binds to the target
enzymes ( penicillin binding proteins ) with high affinity
c. Pharmacokinetics
Absorption
Bioavailability after IM administration is greater than 90%. Plasma peak values close to 80-90
mg/l are found after an IV injection of 1 g.
Distribution
The average peak (c,,,,) serum level after single IV dose of 1 g is 80-90 mg/L.
Pharmacokinetics is dose linear. The volume of distribution is 14-19L. No accumulation is
seen after multiple dosing. The elimination half-life in serum is 1 .8-2.2h.
Serum protein binding is less than 10% and is dose independent. Rapid penetration into the
following body tissues and fluids is observed :
Tissue/ Fluid Dose ( g) Mean concentration Time ( mg/L ) Fluid : serum ratio
2h <8h 12h 2h <8h 12h
Tissue (mg/Kg )
Prostate 1.0 12.9 6.1 1.7 0.3 0.4 0.6
Bronchial mucosa 1.0 33.0 15.7 - 0.6 0.6 -
Fluid ( mg/L )
Interstitial 1.0 32.9 13.3 2.9 1.9 2.3 0.3
Peritoneal 1.0 46.3 10.6 - 1.1 1.0 -
Peak plasma level is above MIC for commonly encountered pathogens.
Biotransformation
Minimally metabolized to the extent of 5-10% of the dose in liver.
Excretion
Principally eliminated by the kidney. 80-90% of the administered drug is recovered in the
urine. Radioactive counts recovered in the urine consisted of 98-99% unchanged cefpirome.
The average elimination half-life in renal impairment increases with time. Dose adjustment
are required in renally impaired patients only at creatinine clearance levels below 50 ml/min
2. Antibacterial coverage and
B-lactamase stability
The following organ isms show sensitivity to cefpirome:
Gram positive
• Enterococcus faecalis
' Clostridiumspp.
• Staphylococcusaureus
' Coagulase -negative Staphylococcus spp
' Streptococcus pneumoniae
• Streptococcus pyogenes
• Streptococcus agalactiae
' Streptococcus viridians
' Corynebacterium diphtheriae
' Corynebacterium pyogen
gram negative
• Pseudomonas aeruginosa
' Acinetobacterspp.
• Bacteroides fragilis
' Citrobacterspp.
• Escherichiacoli
• Salmonellaspp.
• Klebsiellaspp.
• Enterobacterspp.
' Serratiaspp.
• Proteus mirabilis
• Neisseria meninaitides
1) The Cefpirome is having a good activity against Enterococcusfaecalis where MIC range is
as follows:
(J.chemother 1992.dec.4 (6) 338
2) Cefpirome inhibited 70% of the clinically isolated Staphylococcus aureus and
Staphylococcus epidermis strains when used at 0.59-0.84 mcg/ml .
(Antimicrob agents chemother.l 985 july.,28(1). 160-162
3) The activity of cefpirome against Enterobacteriaceae members based on the MlC
inhibiting the 90% of the bacterial growth (MIC,,))) which is 4 to 64 folds lower than the
values of the other antibiotics.
(Antimicrob agents chemother.l 985 july.,28(1).160-162
4) Cefpirome is very stable against the B-lactamase like TEM-1,TEM-2, PSE-1, SHV-1 and the
chromosomal mediated P99 and K-1.
(Antimicrob Chemother.l 993mav,31(5):699-709
micro-organisms MIC ( mg/l )
Enterobacteriacea 1
Salmonella spp. 0.5
N.gonorrhoeae 0.5
H.influenzae 0.25
Campylobacter spp. 2
Coagulase negative staph. Cocci 0.5
B-Lactamase Stability of CEFOVIN'
B-lactamase has been considered responsible for resistance in bacteria against
cephalosporins that are intrinsically stable to hydrolyse by the enzyme that results into the
inactivity of the drug.
The resistance occurs as B-lactamase prevents B-lactam from reaching their true target sites
by tightly combining with the drug in the periplasm. The other mechanism of resistance has
been reported including the decreased penetration of B-lactam across the outer membrane.
Cefpirome is one of the drug which is highly stable to hydrolyse by various B-lactamase. The
compound had a very low affinity for cephalosporinase from Enterobacter cloacae,
Citrobacter freundii, Serratia marcescens and Proteus vulgaris. A relative low affinity of
cefpirome for B-lactamase is considered to be one of the reason for its high antimicrobial
activity against such enzyme producing strains.
1 .In a study conducted by research and development laboratories, Hoechst Japan
limited, Cefpirome was examined for their stability to various B-lactamase including R-
plasmid mediated (type III a, Va/b, and Vc), Chromosomally mediated penicillinase (type IV b)
from Klebsiella pneumoniae and chromosomal cephalosporinase.
Organism MIC ( mcg / ml )
Type of enzyme Cefpirome Ceftazidime Cefoperazone
Escherichia coli IIIa <0.4 <0.4 7.8
w3630/Rms212
Klebsiella pneumoniae IVb <0.3 <0.3 7.5
Pseudomonas aeruginosa Vc <0.3 <0.3 <0.5
In the same study the antimicrobial activity of cefpirome was studied against B-lactamase
producing strains with comparison to cefoperazone, moxalactum, ceftazidime and
cefotaxime.
The following table shows the comparative study of the antimicrobial activity of cetpirome
against B-lactamase producing strains:
Test strains MIC ( mcg / ml )
cefpirome ceftazidime moxalactum cefoperazone
Escherichia coli GN5482 0.1 3.13 1.56 0.78
Enterobacter cloacae GN7471 0.78 25 6.25 25
Citrobacter freundiiGN346 0.39 25 3.13 12.5
Citrobacter freundiiGN7391 6.25 200 50 200
Serratia marcescensGN 10857 1.56 3.13 12.5 50
Cefpirome had the highest activity against Escherichia coli GN5482, Enterobacter cloacae
GN7471 and C.freundiiGN346andGN 7391 among the cephalosporin used.
In another study, which was conducted by Department of Microbiology, Chinese
university of Hong Kong. Cefpirome was highly active against most of the
Enterobacteriaceae, including indole-positive Proteus spp., Aeromonasspp., (MIC < or= 1
mcg/ml). Neisseria gonorrhoeae and haemophilus influenzae (including B-lactamase)
were all susceptible with MIC less than 0.5 and 0.2 5 mcg/ml respectively.
(J. Antimicrob chemother .1993 may.,31 (5) :699-709)
a. Septicemia
The dysfunction of the immune system, the possibility of the gastro-intestinal translocation,
prolonged hospitalization and invasive diagnostic and therapeutic procedure contribute to
septicemia. Severe infections of lung will often give rise to septicemia. septicemia is fatal in
about one in four cases because of the effects of large numbers of multiplying bacteria and
the toxins they released in the blood. The bacteria strains most commonly responsible
include Escherichia coli (E. coli), Pneumococcus, Klebsiella, Pseudomonas, Staphylococcus
and Streptococcus. In septicemia, the bacteria are present in the blood stream and cause
systemic symptoms such as fever and hypotension. It is the most common cause of systemic
inflammatory response syndrome.
Some facts
' Septicemia is the 10th most common death in the world.
(Martin, et al NEJM 2003 346:1546-64)
• Mortality rate ranges from 20% for septicemia to 40% for severe septicemia to more than
60 % for septic shock.
' Septicemia occupies 25% of intensive care unit (ICU) bed utilization.
' 63-75% death from burns injury is due to Sepsis.
(Annuals of burns and fire disasters -vol-15 )
• It is the leading cause of death in non-coronary ICU patient.
Septicemia in community
• UTI-over half of urinary-tract infections are caused by Escherichia coli.
' Skin ulcers and areas of cellulites have a Gram-positive flora of streptococci or
staphylococci. If there is frank cellulites of the perineum or a decubitus ulcer, anaerobes
such as Bacteroides fragilis are the only organism present in the bloodstream in half the
cases and are one component of the mixture in others.
' RTI - H. influenzae causes pneumonia and septicemia in an adult, and another organism
seen from time to time is Acinetobacter.
• PID causing septicemia - Young women may acquire septicemia because of pelvic
inflammatory disease. Most pelvic infections cause septicemia with E. coli, group B
streptococci, or anaerobic cocci.
Septicemia in Hospital
The most important reasons from the diagnostic point of view are the portals of entry for
organisms that are provided by surgical wounds, urinary and vascular catheters, and the
other impedimenta of modern medicine.
Common cause of septicemia in the hospital :
• Septicemia associated with UTI
• Septicemia associated with Surgical wound
• Septicemia associated with Burns
1) Septcemia associated with UTI
The most common focus of infection is the urinary tract. It is estimated that 10% of all
patients in hospital have an indwelling urinary catheter and even with the best care, 25% of
those will be infected by the 14th day.
Responsible microbes : E.coli, Klebsiella, Proteus, Serratia, and Pseudomonas.
CEFOVIN"" efficacy
Excellent efficacy of the drug in septicemia caused by the gram +veand gram-ve microbes.
A study includes the 378 patient of septicemia treated with the Cefpirome. Gm-neg
organism were the causative organism in half of the patient includes E.coli and the
gram-positive organism Streptococcus pneumoniae
The causative organisms were eradicated in over 90 % of patient. Drug of choice in the
empiric treatment of bacteremia/sepsis
0 Med Assoc Thai. 1999 Jul- 82(7)- 648-53)
2) Septicemia associated with Surgical wound
The second most common source of sepsis is surgical wound which includes the deep-seated
processes such as mediastinitis, leaking intestinal anastomoses and infections of the renal
transplant bed. Surgical wounds result from the trauma induced by surgery.
Surgical wounds include
' Post-surgical incisions
• Suture site wounds
• Donor site wounds such as in blood donation
• IV site wounds
• Skin graft wound
Responsible microbes : S. aureus. S. epidermidis and f. coli or mixed anaerobes.
CEFOVIN™ efficacy
Cefpirome having an excellent efficacy against Staphylococci and Enterococci, which are the
main causative pathogen of septicemia.
Cefpirome having a lower MIC against the gram- positive pathogen like E.faecalis and
Staphylococci.
Cefpirome inhibited 70% of the clinically isolated Staphylococcus aureus and
Staphylococcus epidermidis strains when used at 0.59-0.84 mcg/ml.
(J chemother .1992 Dee .,4(6):338)
Cefpirome shows good activity against most common pathogens as compare to other
cephalosporins in surgical wounds, which leads to septicemia.
Cefpirome is active against both gram-positive and gram-negative organism including
Staphylococcus aureus and Pseudomonas aeruginosa.
(Chemother 1999 Dec., 11(6): 486-93)
3) Septicemia associated with Burns
Burns injury causes devitalisation of tissue. The dead and denatured burn, char and the moist
wound environment favour the colonization and proliferation of variety of micro-organisms.
Burned patient are very susceptible to septicemia because the dead skin rapidly become
colonized with the bacteria.
CEFOVIN™ efficacy
The efficacy of the cefpirome was estimated in the treatment of the patient suffering from
burns involving 8-40 percent of the body surface. The clinical and the bacteriological
efficacies of the treatment in the patient of burns are 90 and 80 percent respectively.
(Antibiot Khimioter. 1996;41(12):24-9).
CEFOVIN™ efficacy in septicemia
• Comparative chemotherapeutic activity of cefpirome and imipenem in the experimental
infection.
(J Antibiot (Tokyo). 1990 Jan;43(1): 100-6)
in systemic and local infections, the therapeutic efficacy of cefpirome was compared to
that of imipenern and cefotaxime. Murine septicemia induced with methicillin-sensitive
and methicillin-resistant Staphylococcus aureus strains responded well to cefpirome and
imipenern therapy, the ED, values ranged from 0.8 to 28.40 mg/kg and 0.5 to 15.58
mg/kg, respectively.
Cefpirome is more active than imipenem in protecting infection challenged with
Enterobacteriaceae, Klebsiella pneumonia and the Escherichia coli.
' Cefpirome has an excellent activity against the B-lactamase producing strains.
Cefpirome is active against the number of Enterobacteria, Escherichia coli, Klebsiella
pneumoniae, Enterobacter cloacae, Enterobacter aerogenes and Serratia marcescens
responsible for the several nosocomial septicemia
(Infection 1995 Nov-Dec-23f6)-384-7)
Objective : Bactericidal activity of cefpirome (HR 810) against 513 gram-negative bacteria
isolated from blood of septicemic patients.
Method : The profile of antibacterial activity of cefpirome was compared with that of nine
other antimicrobial agents against 513 gram-negative bacteria isolated from septicemic
patients. All strains were evaluated for their sensitivity by disc diffusion and broth dilutior
tests (MIC and MBC). Cefpirome was compared to cefazolin, cefuroxime, ceftazidime,
ceftriaxone, aztreonam, imipenem, ticarcillin, tobramycin.
Result
Among all the tested drug, cefpirome was most active against all isolates. The MIC.,o anc
MICgo of eight isolates of Acinetobacter calcoaceticus were 2 and 4 mg/l and those of 8<
Pseudomonas aeruginosa were 2 and 8 mg/l, respectively. The MICgo values of cefpirome fo;
all other groups of bacteria were < 1 mg/l. The activity of cefpirome against gram-negativ*
bacteria is as good as that of aztreonam and imipenem.
Conclusion : The above data shows that cefpirome is having a good anti-microbial activity in
curing the septicemic patient.
(Infection. 1994 Jul-Aua;22(4):299-305.
b Neutropenia
Neutropenia is defined as a circulating neutrophil count is less than 1,000/mm' of the blood.
The risk of infection begins to increase as the circulating neutrophil count falls below
1.000/mm3 There is an increase in the risk of infection when the neutrophil count is below
500/mm3 and is greatest when the neutrophil count is < 100/mm3 or lower. A rapid decrease
in neutrophil count is a greater risk factor for infection than a slow, gradual decrease and
neutropenia of greater than 10 days duration is associated with a greater risk of infection
than durations of neutropenia less than 10 days.
Patients with cancer and neutropenic fever often have an established or an occult infection
and septicemia is observed in approximately 20% of cases. Because of the high likelihood of
infection in a patient with febrile neutropenia with )ut localizing symptoms or signs, and the
potential for rapid progression to severe sepsis, prompt initiation of empiric antibiotics is
essential. The established criteria for neutropenic fever is as follows:
• A single oral temperature of greater than 38.3°C (101 °F) or temperature greater than or
equal to 38.0°C (100.4°F) for at least 1 hour.
• Absolute Neutrophills Count (ANC) less than 500/mm3 or less than 1000/mm' with
predicted rapid decline to less than 500/mm'
Neutropenic patients may develop an infection when they become febrile. An infection can
be observed in approximately 47% of patients with fever and neutropenia, whereas 53% are
considered to havefever of undetermined origin.
The frequency of microbiologically documented infections differs from institution to
institution and is influenced by factors such as the usage of prophylactic antibiotics in high-
risk patients : Institutions that routinely use prophylactic antibiotics will probably have a
lower incidence of microbiologically documented infections.
Neutropenia occur when the patient have impaired cellular immunity or impaired humoral
immunity and the use of external medical devices.
Fact
» Neutropenia remains the major reason for hospitalization during or after chemotherapy.
• About half of the cancer chemotherapy patient develop neutropenia.
• 48% to 60% of neutropenic patients who become febrile have an infection.
' Only 50% of infected patients will have microbiological determination of an organism
• Approximately 16% to 20% of patients with neutrophil counts of 100/mm' have
bacteremias.
' Gram-positive infections account for approximately 60% to 70% of microbiologically
determined infections.
Neutropenia causing organism
Gram +ve gram -ve
Coagulase negative Staphylococci Escherichia coli
S. aureus P. aeruginosa
Corynebacterium spp. Klebsiella spp.
Streptococcus Spp. Enterobacter spp.
Enterococcus spp. acinetobacter
Other gram +ve organism
Potential sites of infection
The most common site of infection in neutropenic patients are as follows:
Bloodstream : Approximately 15% to 20% of patients with documented infection may
develop bloodstream infection.
Tissue-based sites : Gastrointestinal tract, Neutropenic enterocolitis and perirectal
infections, skin sites, particularly vascular access or catheter insertion sites and pulmonary
sites (sinusitis and pneumonia).
Gram-positive
1 ) Coagulase-negative staphylococci
These are the most frequently isolated orqanisms in the bloodstream.
CEFOVIN™ efficacy
CEFOVIN™ shows good activity against coagulase-negative Staphylococci and the activity is
Superior to imipenern.
Two-thirds or more of coagulase-negative Staphylococci resistant to any single agent,
including imipenern, maintained their susceptibility to cefpirome
Cefpirome was more active than ceftazidime against bacteria resistant to both piperacillin
and gentamicin, especially coagulase-negative Staphylococci (76% vs. 6%)
(Ref: Scand J Infect DisSuppI. 1993; 91:25-32.)
2) Staphylococcus aureus
It is frequently isolated microbe in the case of the neutropenia with a significant rate of the
mortality. In the community 40%-50% are methicillin resistant. The potential site of this
infection are skin and soft tissues.
CEFOVIN™ efficacy
CEFOVIN™ shows excellent activity against Staphylococcus aureus in the neutropenia.
In an in-vitro study of the bactericidal activity of cefpirome in combination with
vancomycin against 1 I clinical isolates of staphylococci, cefpirome at a concentration of
0.25timestheMICactedsynergisticallywith vancomycin (ataconcentrationofO.S, I or 2
times the MIC) against Staphylococcus aureus and coagulase-negative staphylococci
susceptible or resistant to methicillin.
Antimicrob Chemother. 1996 Dec;38(6):1067-71.)
3) Streptococcus spp. and Enterococcus spp.
A very important group of organisms, viridens-group streptococci cause infection,
particularly in patient who have received high intensity chemotherapy, who have lot of
mucositis or those who have received prophylaxis with some quinolones. These microbes
infect through peridontium gingival, Buccal mucosa and posterior pharynxand perirectum.
CEFOVIN™ efficacy
Cefpirome was active against Streptococcus pneumoniae. Streptococcus bovis and
coagulase-negative staphylococci (MIC < or = 0.5 mg/L)
(Journal ofAntimicrobial Chemotherapy, Vol 31, 699-709)
Gram-negative
Escherichia coli, Pseudomanas aeruginosa and Klebsiella spp.
It has been quite clear that the primary Gram-negative pathogens, the so-called "big 3," are
Escherichia coli, Pseudomonas aeruginosa, and Klebsiella. However, in 1970s and early 1980s
these organisms probably caused 85% to 95% of Gram-negative infections; now a days, they
are responsible for about 55% to 60% of infections. The rest of the Gram-negative infections
are being caused by other Gram-negatives including Enterobacter species, Acinetobacter,
Stenotrophomonas maltophilia, non-aeruginosa Pseudomonas species, Alcaligenes species,
and a variety of other emerging Gram-negatives. All of these have one characteristic in
common either they have intrinsic resistance to many of the agents that we use for empiric
antibiotic therapy in febrile neutropenic patients or they have the capability of developing
resistance while patients are on therapy. So they have a significant problem with several
different kinds of resistance being described. The potential site of infection of these microbes
is Lungs.
CEFOVIN™ efficacy
CEFOVIN™ has a broad spectrum having a good activity against both gram +ve and gram -
ve microbes.
• Excellent activity against gram positive and gram negative bacteria with significant
antipseudomonal activity & extremely high antistaphylococcal activity.
In vitro susceptibility study of cefpirome versus piperacillin and imipenern was conducted
combination with tobramycin. cefpirome alone was more active (MIC,g 64mcg/ml) than
piperacillin (MIC,, 128mcg/ml). The combination of tobramycin and cefpirome proved to
be additive or synergistic for 82% of the isolates (highest rate) compared to 31% with
imipenern (lowest rate)
Diagn Microbial infect Dis.1989jul-aug 12(4):337-41
The potent in vitro antipseudomonal activity of cefpirome alone and in combination with an
aminoglycoside (tobramycin) suggests that this agent play useful role in the therapy of
infection duetoPaeruginosa.
In a comparative chemotherapeutic activity of cefpirome and imipenern, the cefpirome
was more active than imipenern against Enterobacteriaceae. It was more effective than
imipenern in infections caused by Klebsiella pneumonia and E. coli.
Antimicrobial activity of Cefpirome
Micro-organism MIC ( mcg / ml )
Range 90%
P. aeruginosi 1-16 8
Enterococci 0.5-16 8
S.epidermidi 0.125-05 0.5
MSSA 0.25-0.5 0.5
The Ultimate Winm
CEFOVIN
Cefpirome
c. Nosocomial infection
i) Nosocomial pneumonia
Nosocomial pneumonia is an infection contracted during a hospital stay which develops with
in 48 hour or more of hospital admission and was absent at the time of admission.
Nosocomial pneumonia significantly contributed to morbidity, mortility and escalating
health care cost because of length of ICU stay and hospital stay. Pneumonia that is acquired
in the hospital or another type of institution tends to be far more severe than pneumonia
acquired in the community. The organisms from hospitals tend to be more aggressive and
harder to treat. Additionally, people in hospitals and nursing homes are sicker even without
pneumonia than those living in the community.
Some facts
• 15% of death occurred in the hospital are caused by nosocomial pneumonia.
• It results into 6.3% of death per year worldwide.
• 25 to 50% of people with gram-negative pneumonia die.
• The death rate caused by Staphylococcus pneumonia 15-40%
Gram-negative Bacterial Pneumonia
Gram-negative bacteria such as Klebsiella, Pseudomonas, Enterobacter, Proteus, Serratia,
and Acinetobacter cause pneumonia that tends to be serious.
Gram-negative bacterial pneumonias occur only in people who are hospitalized or who live in
nursing homes; they rarely infect the lungs of healthy adults. Gram-negative bacteria are
particularly common causes of pneumonia in people who are on ventilators (breathing
machines used in intensive care units). Other people at risk are infants, older people,
alcoholics and people with chronic diseases, especially immune system disorders.
The symptoms of gram-negative bacterial pneumonia are same as for gram-positive
pneumonia, except that people tend to be sicker and worsen quickly. Gram-negative bacteria
may rapidly destroy lung tissue so gram-negative pneumonia tends to become serious
quickly. Fever, coughing, and shortness of breath are common. The coughed-up sputum may
be thick and red in color.
Because of the seriousness of the infection, the person is treated intensively in the hospital
with antibiotics, supplemental oxygen, and intravenous fluids. Sometimes the person may
put on a ventilator. Despite receiving excellent treatment, about 25 to 50% of people
with qram-neqative pneumonia die.
Gram-positive bacterial pneumonia
Staphylococcal Pneumonia
Staphylococcus aureus causes only 2% of community-acquired pneumonias, but it causes
10 to 15% of hospital-acquired pneumonias. This type of pneumonia is most likely occur
while people are hospitalized for another disorder, and it tends to develop in the very young,
very old, and people who are already debilitated by other illnesses. It also tends to occur in
alcoholics. Although uncommon, it is serious-the death rate is about 15 to 40% because
those who develop staphylococcal pneumonia are already seriously ill.
Staphylococcus causes typical pneumonia symptoms, but chills and fever are more persistent
in staphylococcal pneumonia than in pneumococcal pneumonia. Sometimes the symptoms
worsen rapidly, with severe and potentially fatal deterioration in lung function.
Staphylococcus may occasionally cause collections of pus (abscesses) in the lungs of the
children may produce lung cysts that contains air (pneumatoceles). Bacteria may be carried
from the lung by the bloodstream and produces pus elsewhere.
(Nihon Kyobu Shikkan Gakkai Zasshi. 1994 Sep; 32(9): 851-5.)
CEFOVIN™ in Nosocomial Pneumonia
Cefpirome is the drug of choice in case of Nosocomial pneumonia. As the infection occur due
to the number of gram-positive and gram-negative micro-organism and it results into the
inflammation of the lungs.
Cefpirome is having an excellent lung tissue penetration which covers the caused pathogen
of the pneumonia.
The concentration of cefpirome in lung interstitial fluid reached 66% of the plasma
concentration within the four-hour observation period. This finding supports favorable
tissue-penetration profile, especially because about 10% of the drug is bound to plasma
proteins after administration.
The cefpirome level in the interstitial lung fluid exceeded the minimum inhibitory
concentration needed to suppress at least 90% of isolates (MICgg) for most relevant
bacteria-Klebsiella species. Streptococcus pneumonlae, Staphylococcus aureus, and
Pseudomonas aeruginosa. It may surpassed the MIG,, for S aureus and P aeruginosa for
more than 9 hours and the MIG,, for Klebsiella and S pneumoniae for more than 12 hours,
the investigators estimated.
(Mayor BX, Holliston U, Brunner M, et al. Micellar electrokinetic chromatography for the
analysis of cefpirome in microdialysis and plasma samples obtained in vivo from human)
volunteers. Electrophoresis)
Cefpirome exceeded MIC Values of potential respiratory pathogens
Micro0organism MIC (mcg/ml )
Streptococcus pneumoniae 0.03
Klebsiella species 0.25
Pseudomonas aeruginosa 8
Staphylococcus aureus 2
According to this study it is proved that the Cefpirome is having a good lung tissue
penetration and cover the causative gram-positive and gram -negative organism of the
pneumonia.
Clinical study
a) Objective : Cefpirome-a fourth generation antibiotic for the treatment of severe hospital
infections.
b) Method : The efficacy of cefpirome was estimated in the treatment of 12 patients with
severe hospital infections. The positive clinical effect at the background of the cefpirome
use was recorded in 111 patients. The eradication of the primary pathogens was stated in
10 patients. 116 isolates were tested for their susceptibility to cefpirome. 92% of the
isolates from outpatients and 79% of the isolates from in patients proved to be
susceptible to the antibiotic.
c) Result : The results of the cefpirome use in the treatment of patients with various
infections in 6 hospitals of Moscow were analyzed. The positive clinical effect was
observed in 103 out of 111 patients (93%). The eradication of the primary pathogens was
recorded in 90 out of 102 patients (88 percent). In the treatment of the lower respiratory
tract infection the positive clinical results were stated in 91% of the cases respectively.
Insignificant or moderate side effects of the drug were observed in 17 patients.
Discontinuation of the drug because of the side effects was observed in 2 of them.
d) Conclusion : The results showed that the use of cefpirome in the monotherapy of various
severe hospital infections was efficient and safe.
(Antibiot Khimioter. 1996:41 (1 2):34-9.)
ii) Hospital acquired UTI
A hospital acquired UTI is one of the biggest concern in the hospital about 5-10% of patients
admitted in the hospitals develops the Nosocomial infection.
Some facts
• UTI's rank second to respiratory infections.
• Urinary tract infections (UTIs) account for about 9.6 million patients.
• The female-male ratio in case acquired urinary tract infection is 30:1 .
• 40% of all women have at least one episode of UTI at some time in their lives.
• UTI are estimated to cause more than 100,000 hospital admissions per year in this
country (mostly for acute pyelonephritis.
Nosocomial urinary tract infection is a type of the complicated UTI. It is really a serious cause
of concern, which includes:
' Catheter induced UTI
• UTI due to prostatitis
• Complicated pyelonephritis
• Patient on dialysis
Hospital acquired urinary tract infection present a challenge to the practitioners, as they are
most often caused by bacteria that are resistant to the routinely prescribed antibiotic, they
may be polymicrobial or accompanied by anatomical/structural abnormality in the urinary
tract
1) Catheter induced UTI
Catheter-induced UTI is one of the most common nosocomial infection encountered and in
some studies it accounted for nearly 40% of hospital acquired infections. Up to 4% of
patients with catheter-associated UTI develop bacteremia, and up to 30% of those episodes
are fatal. Female sex, a longer duration of catheterization .improper catheter care and a lack
of antibiotic therapy have been identified as being independently associated with the
presence of infection in the catheterized patient.
The healthy urinary bladder is sterile a catheter can pick up the bacteria from the urethra and
allow them into bladder causing the infection to start. Bacteria from the intestinal tract are
the most common tvoe to cause UTI.
A study was carried out to determine the prevalence of the UTI. The overall prevalence of
the UTI was 1.7%. Over 60% (65.3%) of urinary tract infections were associated with
urinary catheters. Escherichia coli (32.4%) was the most common reported pathogen,
follwed by Klebsiella spp.(17%), Candida spp (12.8%), Pseudomonas aeruginosa(11.7)
and Enterococci(8.5%).
(Decartment of infectious disease and clinical microbioloav. Ondokuz Turkey)
2) UTI due to prostatitis
Urinary tract infection is unusual in men. They usually stem from an obstruction - for
example, an enlarged prostate or a urinary stone or a medical procedure involving a catheter.
The first step in the treatment is to identify the infecting organism and the drug to which it is
sensitive.
3) Complicated acute Pyelonephritis
It is often caused by antibiotic-resistant bacteria and is associated with an increased risk of
Bacteremia, Septic shock and local supportive complications.
For complicated pyelonephritis in hospitalized patients, broad spectrum parenteral
antibiotic therapy should be prescribed that is very likely to be effective against both
potential antibiotic-susceptible and antibiotic-resistant pathogens.
4) Patients on dialysis
Patient on dialysis are also more prone to the infections cause in urinary tract. It is also one of
the most severe type of the hospital acquired UTI.
Choice of drug
The antibiotic cures the UTI should have the following characteristics:
• Bactericidal rather than bacteriostatic
• Effective tissue penetration.
' Effective against resistant strains.
• A broad antibacterial spectrum that covers all pathogens.
CEFOVIN™ the drug of choice in hospital acquired UTI.
• Cefpirome is highly bactericidal to a wide spectrum of organism especially gram-negative
bacteria causing UTI.
' Cefpirome is active against the Pseudomonas aeruginosa, which commonly causes UTI in
catheterized patients.
• Cefpirome is stable to common chromosomally and plasmid mediated B-lactamases.
• Cefpirome is synergistic with other antibiotic like aminoglycosides.
The majority of UTIs are caused by Escherichia coil. More than 80% of UTIs may be caused by
this organism, with the balance resulting from infection Staphylococcus saprophyticus,
Klebsiella, Proteus mirabilis, and other Enterobacteriaceae.
Cefpirome is having a good activity against the Nosocomial UTI causing micro-organism like
E.coli, Klebsiella spp. and Pseudomonas.
Escherichia coli was generally good and especially cefpirome (CPR) showed the highest
activity (MiC90- 90% stable at the highest concentration tested
Drug (s) Time ( h, min ) at 0c
37 0c 25 0c
Cefpirome 7, 15 23, 40
Cefepime 13 20, 30
Imipenem + cilastatin 2, 45 3, 30
Meropenem 1, 50 5, 15
b) Effective in the combination with the aminoglycosides
In vitro susceptibility study of cefpirome versus piperacillin and imipenern was conducted
combination with tobramycin. Cefpirome alone was more active (MICg„ 64mcg/ml) th.
piperacillin (MIC,, 128mcg/ml). The combination of tobramycin and cefpirome proved to I
additive or synergistic for 82% of the isolates(highest rate) compared to 31% with imipenem
( lowest rate ).
c) Effectiveness of the cefpirome is more than the carbapenern against many
pathogens.
• Cefpirome is most active than imipenern in infection challenged with Enterobacteriaceae.
• Cefpirome is more effective than imipenem and cefotaxime against experimental
Klebsiella pneumonia and the Escherichia coli.
* Two-third or more of coagulase-negative staphylococci resistant to any single agent,
including imipenern, maintained their susceptibility to cefpirome.
d) Dosage and patient compliance
The dosage is also the main concern in the practice as if the drug is having the comparable
result than it is better to provide the patient compliance.
Dose of Cefpirome : 1 gm IV 12 hourly.
Dose of Meropenem : 1 gm IV 8 hourly
As the cefpirome is having a good antibacterial spectrum and a higher activity against the
B-lactamase with the added advantage of the convenient dose which adds value in the
patient economy.
5. Prescribing Information
Dosage and Administration
The following dosages are recommended for moderate to severe infections in patients with
normal renal function:
Indications dose interval total daily dose
Complicated upper & lower urinary 1.0 12 2.0
tract infections
Skin & soft tissue infections 1.0 12 2.0
Lower respiratory tract infections 1.0 or 2.0 12 2.0
Bacteremia/septicemia; severe 2.0 12 4.0
infections in intensive care patients
Infections in neutropenic patients 2.0 12 4.0
For urinary tract and skin and soft tissue infections, the unit dose may be increased to 2 g in
very severe cases.
Dosage in Patients with Impaired Renal Function
Cefpirome is excreted principally by the kidney. The dose must therefore be reduced in
patients with impaired renal function to compensate for the slower excretion.
The following doses are recommended creatinine, clearena
Normal renal Function Severe infection Life threatening infection
>50ml/min < 50ml/min 1 q b.i.d. 2g b.i.d.2g
1 g loading dose loading dose
Then :50-20ml/min Dose Adjustment Dose Adjustmenti g
20-5mlVmin <5ml/min 0.5 g b.i.d. 0.5 g once daily b.i.d.l g once daily
(haemodialysis patients) 0.5 g daily + 0.25 g 1 g daily +0.5 g
immediately after dialysis immediately after dialysis
Dosage in Elderly Patients
No adjustment is required unless renal impairment is present
Reconstitution
The contents of vial of 1 g cefpirome are dissolved in 10 ml sterile water for injection, and
then injected over 3-5 minutes either directly into a vein or into the distal section of a
clamped-off infusion tube. For patients with renal impairment, 0.25 g or 0.5 g cefpirome are
dissolved in 2 or 5 ml of water for injection respectively.
The contents of 1 g vial of cefpirome are dissolved in 100 ml sterile water for injections and
then infused over 20-30 minutes. The following infusion solutions may also be used: 0.9%
sodium chloride solution. Ringer's solution 5 to 10% glucose solution, 5% fructose solution,
6% glucose + 0.9% sodium chloride solution.
Effervescence occurs on dissolution of cefpirome, and the vial has to be tipped gently from
side to side for approximately 1 minute before cefpirome is completely dissolved. A pale
yellow, clear solution is formed when the sterile powder is dissolved in water for injection.
The vials containing the solvent and powder for reconstitution should be held horizontal
when preparing the infusion solution, and the cannula should be inserted rapidly. The
amount of 100 ml solvent must be adhered to as precisely as possible.
Instructions for Use/Handling
The vials are manufactured under slight negative pressure. The negative pressure facilitates
the addition of the solvent. Carbon dioxide is released when the solvent and the powder for
reconstitution are mixed, and an increase in pressure occurs. The solution may still contain
bubbles of carbon dioxide, but these have no adverse effects on efficacy.
Precautions
Children
Cefpirome should not be used in children until adequate clinical experience has been gained.
Pseudomembraneous Colitis
Severe and persistent diarrhoea may occur during treatment or after some weeks thereafter
with cephalosporins. Once pseudomembranous colitis is diagnosed or suspected, treatment
must be stopped immediately and specific antibiotic therapy must be started without delay.
Pregnancy and Lactation
The safety of cefpirome in pregnancy has not been established. Evaluation of animal studies
has not indicated harmful effects in reproduction and development of the embryo or foetus.
Nursing mothers should not be treated with cefpirome.
Contraindications
Hvpersensitivitv to cephalosporins
Adverse Effects
Cefpirome is generally well tolerated. The following adverse events have been reported with
cefpirome.
Angio-oedema, bronchospasm, malaise, rash, pruritis, urticaria, toxic epidermal necrolysis,
nausea and vomiting, abdominal pain, diarrhoea, pseudomembraneous colitis may rarely
occur.
Very few cases of convulsions have been reported. Reversible encephalopathy (eg.
impairment of consciousness, abnormal movements, convulsions) may occur with high
doses of B-lactams including cefpirome, especially in patients with renal insufficiency.
Interactions
Probenecid interferes with the renal tubular transfer of cephalosporins, delaying their
excretion and thereby increasing their plasma concentrations.
Overdosage
There is no clinical experience with overdoses of cefpirome. There is a risk of reversible
encephalopathy with high dose of B-lactam antibiotics including cefpirome.
Storage
Store finished product (sterile powder) below 25°C. Protect from light. Cefpirome solutions
should be used as soon as possible after reconstitution. They may be kept for up to 6 hrs at
room temperature in indoor light (do not expose to direct sunlight), or for 24 hrs protected
from light in a refrigerator at between 2° and 8°C, when prepared in Water for Injection or isotonic sodium chloride solution.