my $str      = 'Fsih my test variable is fsihd or is it gfsih or gfsih
+d fsih';
#                                        1111            2222     3333
+  4444
my $substr   = 'fsih';
my $regexp   = qr/\Q$substr\E/;
my $replace  = 'fish';
my $instance = 3;  # 3rd

print("$str\n");

scalar $str =~ /\G.*?$regexp/gc
   while --$instance;

$str =~ s/\G(.*?)$regexp/$1$replace/;

print("$str\n");
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The /c is needed in case there are less than $instance instances of the search string.